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Sample records for early replication events

  1. Early Events in Alphavirus Replication Determine the Outcome of Infection

    PubMed Central

    Frolov, Ilya; Akhrymuk, Maryna; Akhrymuk, Ivan; Atasheva, Svetlana

    2012-01-01

    Alphaviruses are a group of important human and animal pathogens. They efficiently replicate to high titers in vivo and in many commonly used cell lines of vertebrate origin. They have also evolved effective means of interfering with development of the innate immune response. Nevertheless, most of the alphaviruses are known to induce a type I interferon (IFN) response in vivo. The results of this study demonstrate that the first hours postinfection play a critical role in infection spread and development of the antiviral response. During this window, a balance is struck between virus replication and spread in vertebrate cells and IFN response development. The most important findings are as follows: (i) within the first 2 to 4 h postinfection, alphavirus-infected cells become unable to respond to IFN-?, and this occurs before the virus-induced decrease in STAT1 phosphorylation in response to IFN treatment. (ii) Most importantly, very low, subprotective doses of IFN-?, which do not induce the antiviral response in uninfected cells, have a very strong stimulatory effect on the cells' ability to express type I IFN and activate interferon-stimulated genes during subsequent infection with Sindbis virus (SINV). (iii) Small changes in SINV nsP2 protein affect its ability to inhibit cellular transcription and IFN release. Thus, the balance between type I IFN induction and the ability of the virus to develop further rounds of infection is determined in the first few hours of virus replication, when only low numbers of cells and infectious virus are involved. PMID:22345447

  2. [Replication inhibitors targeting early events in the HIV-1 life cycle].

    PubMed

    Ichiyama, Kozi; Yamamoto, Naoki

    2002-04-01

    Most of the compounds currently used for treatment of HIV-1 infection are reverse transcriptase inhibitors and protease inhibitors. Several early steps in the HIV-1 life cycle such as virus attachment to host cell and cell-virus fusion are potential targets for drugs. Since most of the target molecules involved in this infection step are cellular, it is expected that the drug resistant mutations occur less frequently than those against viral enzymes. In this review, new inhibitors of entry and fusion are summarized that are promising. PMID:11968789

  3. Inhibiting Early-Stage Events in HIV-1 Replication by Small-Molecule Targeting of the HIV-1 Capsid

    PubMed Central

    Kortagere, Sandhya; Madani, Navid; Mankowski, Marie K.; Schön, Arne; Zentner, Isaac; Swaminathan, Gokul; Princiotto, Amy; Anthony, Kevin; Oza, Apara; Sierra, Luz-Jeannette; Passic, Shendra R.; Wang, Xiaozhao; Jones, David M.; Stavale, Eric; Krebs, Fred C.; Martín-García, Julio; Freire, Ernesto; Ptak, Roger G.; Sodroski, Joseph

    2012-01-01

    The HIV-1 capsid (CA) protein plays essential roles in both early and late stages of virl replication and has emerged as a novel drug target. We report hybrid structure-based virtual screening to identify small molecules with the potential to interact with the N-terminal domain (NTD) of HIV-1 CA and disrupt early, preintegration steps of the HIV-1 replication cycle. The small molecule 4,4?-[dibenzo[b,d]furan-2,8-diylbis(5-phenyl-1H-imidazole-4,2-diyl)]dibenzoic acid (CK026), which had anti-HIV-1 activity in single- and multiple-round infections but failed to inhibit viral replication in peripheral blood mononuclear cells (PBMCs), was identified. Three analogues of CK026 with reduced size and better drug-like properties were synthesized and assessed. Compound I-XW-053 (4-(4,5-diphenyl-1H-imidazol-2-yl)benzoic acid) retained all of the antiviral activity of the parental compound and inhibited the replication of a diverse panel of primary HIV-1 isolates in PBMCs, while displaying no appreciable cytotoxicity. This antiviral activity was specific to HIV-1, as I-XW-053 displayed no effect on the replication of SIV or against a panel of nonretroviruses. Direct interaction of I-XW-053 was quantified with wild-type and mutant CA protein using surface plasmon resonance and isothermal titration calorimetry. Mutation of Ile37 and Arg173, which are required for interaction with compound I-XW-053, crippled the virus at an early, preintegration step. Using quantitative PCR, we demonstrated that treatment with I-XW-053 inhibited HIV-1 reverse transcription in multiple cell types, indirectly pointing to dysfunction in the uncoating process. In summary, we have identified a CA-specific compound that targets and inhibits a novel region in the NTD-NTD interface, affects uncoating, and possesses broad-spectrum anti-HIV-1 activity. PMID:22647699

  4. Early events in the pathogenesis of foot-and-mouth disease in pigs; identification of oropharyngeal tonsils as sites of primary and sustained viral replication

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A time-course study was performed to elucidate the early events of foot-and-mouth disease virus (FMDV) infection in pigs subsequent to simulated natural inoculation. The earliest detectable event was primary infection in the lingual and paraepiglotic tonsils at 6 hours post inoculation (hpi) charact...

  5. DNA breaks early in replication in B cell cancers

    Cancer.gov

    Research by scientists at the NCI has identified a new class of DNA sites in cells that break early in the replication process. They found that these break sites correlate with damage often seen in B cell cancers, such as diffuse large B cell lymphoma.

  6. Early Replication of Short Telomeres in Budding Yeast

    E-print Network

    Halazonetis, Thanos

    Early Replication of Short Telomeres in Budding Yeast Alessandro Bianchi1, * and David Shore1 1.bianchi@molbio.unige.ch DOI 10.1016/j.cell.2007.01.041 SUMMARY The maintenance of an appropriate number of telomere repeats by telomerase is essential for proper chromosome protection. The action of telomerase at the telomere terminus

  7. Early initiation of a replication origin tethered at the nuclear periphery

    PubMed Central

    Ebrahimi, Hani; Robertson, E. Douglas; Taddei, Angela; Gasser, Susan M.; Donaldson, Anne D.; Hiraga, Shin-ichiro

    2010-01-01

    Peripheral nuclear localization of chromosomal loci correlates with late replication in yeast and metazoan cells. To test whether peripheral positioning can impose late replication, we examined whether artificial tethering of an early-initiating replication origin to the nuclear periphery delays its replication in budding yeast. We tested the effects of three different peripheral tethering constructs on the time of replication of the early replication origin ARS607. Using the dense-isotope transfer method to assess replication time, we found that ARS607 still replicates early when tethered to the nuclear periphery using the Yif1 protein or a fragment of Sir4, whereas tethering using a Yku80 construct produces only a very slight replication delay. Single-cell microscopic analysis revealed no correlation between peripheral positioning of ARS607 in individual cells and delayed replication. Overall, our results demonstrate that a replication origin can initiate replication early in S phase, even if artificially relocated to the nuclear periphery. PMID:20197407

  8. Early Word Comprehension in Infants: Replication and Extension

    ERIC Educational Resources Information Center

    Bergelson, Elika; Swingley, Daniel

    2015-01-01

    A handful of recent experimental reports have shown that infants of 6-9 months know the meanings of some common words. Here, we replicate and extend these findings. With a new set of items, we show that when young infants (age 6-16 months, n = 49) are presented with side-by-side video clips depicting various common early words, and one clip is…

  9. Early viral replication in the brain of SIV-infected rhesus monkeys.

    PubMed Central

    Chakrabarti, L.; Hurtrel, M.; Maire, M. A.; Vazeux, R.; Dormont, D.; Montagnier, L.; Hurtrel, B.

    1991-01-01

    To investigate the mechanism of simian immunodeficiency virus (SIV) entry into the central nervous system (CNS) and the initial events leading to neuropathogenesis, SIV replication was studied by in situ hybridization in the CNS of 5 Rhesus macaques at 7 days, 1, 2, and 3 months after SIV intravenous inoculation. CNS infection was found to be a frequent and early event, as SIV was detected in the CNS of all the animals studied and as early as 7 days postinoculation. At the earliest stage, the infection localized mainly to perivascular cells. Using combined immunohistochemistry and in situ hybridization, infected cells were shown to express the CD68 marker, suggesting that infected mononuclear phagocytes crossing the blood-brain barrier represent the main source of virus in the CNS. Early viral replication coincided with neuropathologic changes, consisting in gliosis, perivascular infiltrates and rare glial nodules. Immunophenotyping of brain tissue showed that increased macrophage infiltration, microglial reactivity and MHC class II induction occurred within the first week of infection, indicating a possible immunopathologic mechanism in early CNS pathogenesis. Images Figure 1 PMID:1750503

  10. A post-entry role for CD63 in early HIV-1 replication

    SciTech Connect

    Li Guangyu; Dziuba, Natallia; Friedrich, Brian; Murray, James L.; Ferguson, Monique R.

    2011-04-10

    Macrophages and CD4{sup +} lymphocytes are the major reservoirs for HIV-1 infection. CD63 is a tetraspanin transmembrane protein, which has been shown to play an essential role during HIV-1 replication in macrophages. In this study, we further confirm the requirement of CD63 in early HIV-1 replication events in both macrophages and a CD4{sup +} cell line. Further analysis revealed that viral attachment and cell-cell fusion were unaffected by CD63 silencing. However, CD63-depleted macrophages showed a significant decrease in the initiation and completion of HIV-1 reverse transcription, affecting subsequent events of the HIV-1 life cycle. Integration of HIV-1 cDNA as well as the formation of 2-LTR circles was notably reduced. Reporter assays showed that CD63 down regulation reduced production of the early HIV protein Tat. In agreement, CD63 silencing also inhibited production of the late protein p24. These findings suggest that CD63 plays an early post-entry role prior to or at the reverse transcription step.

  11. At Short Telomeres Tel1 Directs Early Replication and Phosphorylates Rif1

    PubMed Central

    Sridhar, Akila; Kedziora, Sylwia; Donaldson, Anne D.

    2014-01-01

    The replication time of Saccharomyces cerevisiae telomeres responds to TG1–3 repeat length, with telomeres of normal length replicating late during S phase and short telomeres replicating early. Here we show that Tel1 kinase, which is recruited to short telomeres, specifies their early replication, because we find a tel1? mutant has short telomeres that nonetheless replicate late. Consistent with a role for Tel1 in driving early telomere replication, initiation at a replication origin close to an induced short telomere was reduced in tel1? cells, in an S phase blocked by hydroxyurea. The telomeric chromatin component Rif1 mediates late replication of normal telomeres and is a potential substrate of Tel1 phosphorylation, so we tested whether Tel1 directs early replication of short telomeres by inactivating Rif1. A strain lacking both Rif1 and Tel1 behaves like a rif1? mutant by replicating its telomeres early, implying that Tel1 can counteract the delaying effect of Rif1 to control telomere replication time. Proteomic analyses reveals that in yku70? cells that have short telomeres, Rif1 is phosphorylated at Tel1 consensus sequences (S/TQ sites), with phosphorylation of Serine-1308 being completely dependent on Tel1. Replication timing analysis of a strain mutated at these phosphorylation sites, however, suggested that Tel1-mediated phosphorylation of Rif1 is not the sole mechanism of replication timing control at telomeres. Overall, our results reveal two new functions of Tel1 at shortened telomeres: phosphorylation of Rif1, and specification of early replication by counteracting the Rif1-mediated delay in initiation at nearby replication origins. PMID:25329891

  12. At short telomeres Tel1 directs early replication and phosphorylates Rif1.

    PubMed

    Sridhar, Akila; Kedziora, Sylwia; Donaldson, Anne D

    2014-10-01

    The replication time of Saccharomyces cerevisiae telomeres responds to TG1-3 repeat length, with telomeres of normal length replicating late during S phase and short telomeres replicating early. Here we show that Tel1 kinase, which is recruited to short telomeres, specifies their early replication, because we find a tel1? mutant has short telomeres that nonetheless replicate late. Consistent with a role for Tel1 in driving early telomere replication, initiation at a replication origin close to an induced short telomere was reduced in tel1? cells, in an S phase blocked by hydroxyurea. The telomeric chromatin component Rif1 mediates late replication of normal telomeres and is a potential substrate of Tel1 phosphorylation, so we tested whether Tel1 directs early replication of short telomeres by inactivating Rif1. A strain lacking both Rif1 and Tel1 behaves like a rif1? mutant by replicating its telomeres early, implying that Tel1 can counteract the delaying effect of Rif1 to control telomere replication time. Proteomic analyses reveals that in yku70? cells that have short telomeres, Rif1 is phosphorylated at Tel1 consensus sequences (S/TQ sites), with phosphorylation of Serine-1308 being completely dependent on Tel1. Replication timing analysis of a strain mutated at these phosphorylation sites, however, suggested that Tel1-mediated phosphorylation of Rif1 is not the sole mechanism of replication timing control at telomeres. Overall, our results reveal two new functions of Tel1 at shortened telomeres: phosphorylation of Rif1, and specification of early replication by counteracting the Rif1-mediated delay in initiation at nearby replication origins. PMID:25329891

  13. Resolving Paradoxical Criteria for the Expansion and Replication of Early Childhood Care and Education Programs.

    ERIC Educational Resources Information Center

    Yoshikawa, Hirokazu; Rosman, Elisa Altman; Hsueh, JoAnn

    2002-01-01

    Identifies underlying paradoxical bases for expansion and replication of early childhood care and education (ECCE) programs. Presents history of ECCE in the United States. Proposes typology of expansion and replication processes, and considers paradoxes associated with replication process. Offers recommendations for funders, policymakers, and…

  14. Early Events in RNA Folding

    NASA Astrophysics Data System (ADS)

    Thirumalai, D.; Lee, Namkyung; Woodson, Sarah A.; Klimov, Dk

    2001-10-01

    We describe a conceptual framework for understanding the way large RNA molecules fold based on the notion that their free-energy landscape is rugged. A key prediction of our theory is that RNA folding can be described by the kinetic partitioning mechanism (KPM). According to KPM a small fraction of molecules folds rapidly to the native state whereas the remaining fraction is kinetically trapped in a low free-energy non-native state. This model provides a unified description of the way RNA and proteins fold. Single-molecule experiments on Tetrahymena ribozyme, which directly validate our theory, are analyzed using KPM. We also describe the earliest events that occur on microsecond time scales in RNA folding. These must involve collapse of RNA molecules that are mediated by counterion-condensation. Estimates of time scales for the initial events in RNA folding are provided for the Tetrahymena ribozyme.

  15. Early Events of DNA Photodamage

    NASA Astrophysics Data System (ADS)

    Schreier, Wolfgang J.; Gilch, Peter; Zinth, Wolfgang

    2015-04-01

    Ultraviolet (UV) radiation is a leading external hazard to the integrity of DNA. Exposure to UV radiation triggers a cascade of chemical reactions, and many molecular products (photolesions) have been isolated that are potentially dangerous for the cellular system. The early steps that take place after UV absorption by DNA have been studied by ultrafast spectroscopy. The review focuses on the evolution of excited electronic states, the formation of photolesions, and processes suppressing their formation. Emphasis is placed on lesions involving two thymine bases, such as the cyclobutane pyrimidine dimer, the (6-4) lesion, and its Dewar valence isomer.

  16. Early intranuclear replication of African swine fever virus genome modifies the landscape of the host cell nucleus.

    PubMed

    Simões, Margarida; Martins, Carlos; Ferreira, Fernando

    2015-12-01

    Although African swine fever virus (ASFV) replicates in viral cytoplasmic factories, the presence of viral DNA within the host cell nucleus has been previously reported to be essential for productive infection. Herein, we described, for the first time, the intranuclear distribution patterns of viral DNA replication events, preceding those that occur in the cytoplasmic compartment. Using BrdU pulse-labelling experiments, newly synthesized ASFV genomes were exclusively detected inside the host cell nucleus at the early phase of infection, both in swine monocyte-derived macrophages (MDMs) and Vero cells. From 8hpi onwards, BrdU labelling was only observed in ASFV cytoplasmic factories. Our results also show that ASFV specifically activates the Ataxia Telangiectasia Mutated Rad-3 related (ATR) pathway in ASFV-infected swine MDMs from the early phase of infection, most probably because ASFV genome is recognized as foreign DNA. Morphological changes of promyelocytic leukaemia nuclear bodies (PML-NBs), nuclear speckles and Cajal bodies were also found in ASFV-infected swine MDMs, strongly suggesting the viral modulation of cellular antiviral responses and cellular transcription, respectively. As described for other viral infections, the nuclear reorganization that takes place during ASFV infection may also provide an environment that favours its intranuclear replication events. Altogether, our results contribute for a better understanding of ASFV replication strategies, starting with an essential intranuclear DNA replication phase which induces host nucleus changes towards a successful viral infection. PMID:26183880

  17. Unraveling the early steps of prokaryotic replication Erin L Cunningham and James M Berger

    E-print Network

    Berger, James M.

    Unraveling the early steps of prokaryotic replication Erin L Cunningham and James M Berger In prokaryotes, many of the physical mechanisms governing the process of initiating DNA replication are now studies have shown that prokaryotic initiator structures are both modular and conserved, and have begun

  18. Early events in axon/dendrite polarization.

    PubMed

    Cheng, Pei-lin; Poo, Mu-ming

    2012-01-01

    Differentiation of axons and dendrites is a critical step in neuronal development. Here we review the evidence that axon/dendrite formation during neuronal polarization depends on the intrinsic cytoplasmic asymmetry inherited by the postmitotic neuron, the exposure of the neuron to extracellular chemical factors, and the action of anisotropic mechanical forces imposed by the environment. To better delineate the functions of early signals among a myriad of cellular components that were shown to influence axon/dendrite formation, we discuss their functions by distinguishing their roles as determinants, mediators, or modulators and consider selective degradation of these components as a potential mechanism for axon/dendrite polarization. Finally, we examine whether these early events of axon/dendrite formation involve local autocatalytic activation and long-range inhibition, as postulated by Alan Turing for the morphogenesis of patterned biological structure. PMID:22715881

  19. The Chemistry of Early Self-Replicating Systems

    NASA Technical Reports Server (NTRS)

    Bada, Jeffrey L.

    2004-01-01

    On June 10, 2003, a symposium 'Celebrating 50 Years of Prebiotic Chemistry' honoring the 50th Anniversary of the 1953 publication of the Miller Experiment in SCIENCE was held at the University of California, San Diego. This event was organized and hosted by the NASA Specialized Center of Research and Training in Exobiology. It was sponsored by NASA, the Dean of Physical Sciences and the Department of Chemistry and Biochemistry at the University of California, San Diego (UCSD). The following events were held: 1) For the symposium, public lectures and a reception were held at UCSD on June 10, 2003 in honor of the 50th Anniversary of the Miller Experiment. The speakers were the NSCORT/Exobiology Principal Investigators Dr. Jeffrey L. Bada and Dr. Gerald F. Joyce and the moderator, Dr. Leslie Orgel; 2) A evening discussion seminar and dinner was held at UCSD with invited scientists, NSCORT investigators, NASA Headquarters Officials and the Chancellor and Officials of the University of California, San Diego. Stanley Miller has had a long history of support from the NASA Exobiology Section. This event commemorated the anniversary of his classic experiment and was a small recognition of his contributions to the field.

  20. Amphotericin B delays both scrapie agent replication and PrP-res accumulation early in infection.

    PubMed Central

    McKenzie, D; Kaczkowski, J; Marsh, R; Aiken, J

    1994-01-01

    Amphotericin B delays the onset of clinical symptoms in hamsters infected with scrapie agent strain 263K. Here we show that accumulation of a scrapie-specific isoform of the prion protein (PrP-res) and agent replication were delayed early in amphotericin B-treated animals. By 8 weeks postinfection, only untreated animals exhibited clinical symptoms of scrapie infection whereas PrP-res levels and titers were similar in treated and untreated animals. This suggests that although PrP-res accumulation and agent replication are linked, they are not the sole factors required for the onset of clinical disease. Images PMID:7933137

  1. ATP Utilization by Yeast Replication Factor C II. MULTIPLE STEPWISE ATP BINDING EVENTS ARE REQUIRED TO LOAD PROLIFERATING CELL

    E-print Network

    Burgers, Peter M.

    ATP Utilization by Yeast Replication Factor C II. MULTIPLE STEPWISE ATP BINDING EVENTS ARE REQUIRED of adenosine (3-thiotriphosphate) (ATP S), a nonhydrolyzable analog of ATP, to replication factor C with a N-terminal truncation ( 2­273) of the Rfc1 sub- unit (RFC) was studied by filter binding. RFC alone bound 1.8 ATP

  2. Immediate and delayed incorporations of events into dreams: further replication and implications for dream function.

    PubMed

    Nielsen, Tore A; Kuiken, Don; Alain, Geneviève; Stenstrom, Philippe; Powell, Russell A

    2004-12-01

    The incorporation of memories into dreams is characterized by two types of temporal effects: the day-residue effect, involving immediate incorporations of events from the preceding day, and the dream-lag effect, involving incorporations delayed by about a week. This study was designed to replicate these two effects while controlling several prior methodological problems and to provide preliminary information about potential functions of delayed event incorporations. Introductory Psychology students were asked to recall dreams at home for 1 week. Subsequently, they were instructed to select a single dream and to retrieve past events related to it that arose from one of seven randomly determined days prior to the dream (days 1-7). They then rated both their confidence in recall of events and the extent of correspondence between events and dreams. Judges evaluated qualities of the reported events using scales derived from theories about the function of delayed incorporations. Average ratings of correspondences between dreams and events were high for predream days 1 and 2, low for days 3 and 4 and high again for days 5-7, but only for participants who rated their confidence in recall of events as high and only for females. Delayed incorporations were more likely than immediate incorporations to refer to events characterized by interpersonal interactions, spatial locations, resolved problems and positive emotions. The findings are consistent with the possibility that processes with circaseptan (about 7 days) morphology underlie dream incorporation and that these processes subserve the functions of socio-emotional adaptation and memory consolidation. PMID:15560767

  3. Noise-Induced Mechanism for Biological Homochirality of Early Life Self-Replicators

    NASA Astrophysics Data System (ADS)

    Jafarpour, Farshid; Biancalani, Tommaso; Goldenfeld, Nigel

    2015-10-01

    The observed single-handedness of biological amino acids and sugars has long been attributed to autocatalysis. However, the stability of homochiral states in deterministic autocatalytic systems relies on cross inhibition of the two chiral states, an unlikely scenario for early life self-replicators. Here, we present a theory for a stochastic individual-level model of autocatalysis due to early life self-replicators. Without chiral inhibition, the racemic state is the global attractor of the deterministic dynamics, but intrinsic multiplicative noise stabilizes the homochiral states, in both well-mixed and spatially extended systems. We conclude that autocatalysis is a viable mechanism for homochirality, without imposing additional nonlinearities such as chiral inhibition.

  4. High-resolution dating of Early Aptian Oceanic Anoxic Events

    NASA Astrophysics Data System (ADS)

    Moreno-Bedmar, J.; Bover-Arnal, T.; Barragan-Manzo, R.; Company, M.; Nuñez, F.

    2013-05-01

    Ammonoid biostratigraphy is the most accurate relative dating method that exists for the Aptian. It divides the Early Aptian into four zones, for comparison, planktonic foraminifera and calcareous nannofossil biozonations only divide this substage into two zones (Fig. 1). In the study of the Early Aptian Oceanic Anoxic Event 1a (OAE 1a), the most commonly used biostratigraphy to calibrate its age has been the planktonic foraminifera biozonation. This anoxic event, also known as Livello Selli, was initially believed to be the only oceanic anoxic event that occurred within the Early Aptian. From our own and other published data, we recognized that more than one oceanic anoxic event took place within the Early Aptian. Our purpose is to clearly characterize and date these events using the ammonite biozonation. Four years ago, a second oceanic anoxic event of uppermost Early Aptian age, the Aparein level, was identified in the Basque Cantabrian Basin, in Spain. The age of this event was calibrated using ammonites. More recently, the Aparein level was pinpointed by us in northern Mexico. A potential third oceanic anoxic event was recognized, around fifteen years ago in the section of La Bédoule, in France. The onset of this possible event would correspond to a negative carbon-isotope excursion in the uppermost Late Barremian-lowermost Early Aptian. The latter hypothesis remains un-worked and only some authors have recently started to use the term pre-Selli in reference to this event. The ammonite zonation is precise enough to clearly differentiate these three Early Aptian oceanic anoxic events (Fig. 1). The pre-Selli event, began in the uppermost Late Barremian and ended in the lower part of the Deshayesites oglanlensis Zone. The OAE 1a occurred within the Roloboceras hambrovi Subzone. The Aparein level was coeval with the Dufrenoyia dufrenoyi Subzone.; Figure 1: Chronological position of the known Early Aptian oceanic anoxic events against ammonite, planktonic foraminifera and calcareous nannofossil biozonations.

  5. DNA replication stress induces deregulation of the cell cycle events in root meristems of Allium cepa

    PubMed Central

    ?abka, Aneta; Polit, Justyna Teresa; Maszewski, Janusz

    2012-01-01

    Background and Aims Prolonged treatment of Allium cepa root meristems with changing concentrations of hydroxyurea (HU) results in either premature chromosome condensation or cell nuclei with an uncommon form of biphasic chromatin organization. The aim of the current study was to assess conditions that compromise cell cycle checkpoints and convert DNA replication stress into an abnormal course of mitosis. Methods Interphase-mitotic (IM) cells showing gradual changes of chromatin condensation were obtained following continuous 72 h treatment of seedlings with 0·75 mm HU (without renewal of the medium). HU-treated root meristems were analysed using histochemical stainings (DNA-DAPI/Feulgen; starch-iodide and DAB staining for H2O2 production), Western blotting [cyclin B-like (CBL) proteins] and immunochemistry (BrdU incorporation, detection of ?-H2AX and H3S10 phosphorylation). Key Results Continuous treatment of onion seedlings with a low concentration of HU results in shorter root meristems, enhanced production of H2O2, ?-phosphorylation of H2AX histones and accumulation of CBL proteins. HU-induced replication stress gives rise to axially elongated cells with half interphase/half mitotic structures (IM-cells) having both decondensed and condensed domains of chromatin. Long-term HU treatment results in cell nuclei resuming S phase with gradients of BrdU labelling. This suggests a polarized distribution of factors needed to re-initiate stalled replication forks. Furthermore, prolonged HU treatment extends both the relative time span and the spatial scale of H3S10 phosphorylation known in plants. Conclusions The minimum cell length and a threshold level of accumulated CBL proteins are both determining factors by which the nucleus attains commitment to induce an asynchronous course of chromosome condensation. Replication stress-induced alterations in an orderly route of the cell cycle events probably reflect a considerable reprogramming of metabolic functions of chromatin combined with gradients of morphological changes spread along the nucleus. PMID:23087128

  6. DNA replication origin interference increases the spacing between initiation events in human cells.

    PubMed

    Lebofsky, Ronald; Heilig, Roland; Sonnleitner, Max; Weissenbach, Jean; Bensimon, Aaron

    2006-12-01

    Mammalian DNA replication origins localize to sites that range from base pairs to tens of kilobases. A regular distribution of initiations in individual cell cycles suggests that only a limited number of these numerous potential start sites are converted into activated origins. Origin interference can silence redundant origins; however, it is currently unknown whether interference participates in spacing functional human initiation events. By using a novel hybridization strategy, genomic Morse code, on single combed DNA molecules from primary keratinocytes, we report the initiation sites present on 1.5 Mb of human chromosome 14q11.2. We confirm that initiation zones are widespread in human cells, map to intergenic regions, and contain sequence motifs found at other mammalian initiation zones. Origins used per cell cycle are less abundant than the potential sites of initiation, and their limited use increases the spacing between initiation events. Between-zone interference decreases in proportion to the distance from the active origin, whereas within-zone interference is 100% efficient. These results identify a hierarchical organization of origin activity in human cells. Functional origins govern the probability that nearby origins will fire in the context of multiple potential start sites of DNA replication, and this is mediated by origin interference. PMID:17005913

  7. Expert Panel Workshop on Early-Life Events and Cancer

    Cancer.gov

    NCI's Division of Cancer Control and Population Sciences (DCCPS) and Division of Cancer Epidemiology and Genetics (DCEG) sponsored an Expert Panel Workshop on Early-Life Events and Cancer on May 25, 2011. There is emerging epidemiological and animal evidence that early-life events and exposures are important determinants of cancer development later in life. However, understanding how to study the impact of early-life exposures on human cancers later in life is a new challenge for cancer research.

  8. Wound healing: calcium flashes illuminate early events.

    PubMed

    Wood, Will

    2012-01-10

    What are the earliest signals produced at a wound edge that mobilise epithelial cells to heal the wound? Live analysis of wound healing in the worm Caenorhabditis elegans shows that calcium may be the key early trigger. PMID:22240471

  9. Early events in geotropism of seedling shoots

    NASA Technical Reports Server (NTRS)

    Pickard, B. G.

    1985-01-01

    Developments during the first ten minutes of geotropic stimulation in plant seedling shoots are reviewed. Topics include induction and curvature; early processes; the relationship between auxin, electric field, calcium, and differential growth; gravity reception leading to Went-Cholodny transport; and comparison of root and shoot. Early processes reviewed are sedimentation of amyloplasts, release of ethylene, rise of electrical and auxin asymmetry, redistribution of calcium, asymmetric vascular transport, increase in tendency to deposit callose, and simulation of putative exocytotic voltage transients.

  10. Viral terminal protein directs early organization of phage DNA replication at the bacterial nucleoid

    PubMed Central

    Muñoz-Espín, Daniel; Holguera, Isabel; Ballesteros-Plaza, David; Carballido-López, Rut; Salas, Margarita

    2010-01-01

    The mechanism leading to protein-primed DNA replication has been studied extensively in vitro. However, little is known about the in vivo organization of the proteins involved in this fundamental process. Here we show that the terminal proteins (TPs) of phages ?29 and PRD1, infecting the distantly related bacteria Bacillus subtilis and Escherichia coli, respectively, associate with the host bacterial nucleoid independently of other viral-encoded proteins. Analyses of phage ?29 revealed that the TP N-terminal domain (residues 1–73) possesses sequence-independent DNA-binding capacity and is responsible for its nucleoid association. Importantly, we show that in the absence of the TP N-terminal domain the efficiency of ?29 DNA replication is severely affected. Moreover, the TP recruits the phage DNA polymerase to the bacterial nucleoid, and both proteins later are redistributed to enlarged helix-like structures in an MreB cytoskeleton-dependent way. These data disclose a key function for the TP in vivo: organizing the early viral DNA replication machinery at the cell nucleoid. PMID:20823229

  11. Early apoptosis of porcine alveolar macrophages limits avian influenza virus replication and pro-inflammatory dysregulation.

    PubMed

    Chang, Pengxiang; Kuchipudi, Suresh V; Mellits, Kenneth H; Sebastian, Sujith; James, Joe; Liu, Jinhua; Shelton, Holly; Chang, Kin-Chow

    2015-01-01

    Pigs are evidently more resistant to avian than swine influenza A viruses, mediated in part through frontline epithelial cells and alveolar macrophages (AM). Although porcine AM (PAM) are crucial in influenza virus control, their mode of control is unclear. To gain insight into the possible role of PAM in the mediation of avian influenza virus resistance, we compared the host effects and replication of two avian (H2N3 and H6N1) and three mammalian (swine H1N1, human H1N1 and pandemic H1N1) influenza viruses in PAM. We found that PAM were readily susceptible to initial infection with all five avian and mammalian influenza viruses but only avian viruses caused early and extensive apoptosis (by 6?h of infection) resulting in reduced virus progeny and moderated pro-inflammation. Full length viral PB1-F2 present only in avian influenza viruses is a virulence factor that targets AM for mitochondrial-associated apoptotic cell death. With the use of reverse genetics on an avian H5N1 virus, we found that full length PB1-F2 contributed to increased apoptosis and pro-inflammation but not to reduced virus replication. Taken together, we propose that early apoptosis of PAM limits the spread of avian influenza viruses and that PB1-F2 could play a contributory role in the process. PMID:26642934

  12. Early apoptosis of porcine alveolar macrophages limits avian influenza virus replication and pro-inflammatory dysregulation

    PubMed Central

    Chang, Pengxiang; Kuchipudi, Suresh V.; Mellits, Kenneth H.; Sebastian, Sujith; James, Joe; Liu, Jinhua; Shelton, Holly; Chang, Kin-Chow

    2015-01-01

    Pigs are evidently more resistant to avian than swine influenza A viruses, mediated in part through frontline epithelial cells and alveolar macrophages (AM). Although porcine AM (PAM) are crucial in influenza virus control, their mode of control is unclear. To gain insight into the possible role of PAM in the mediation of avian influenza virus resistance, we compared the host effects and replication of two avian (H2N3 and H6N1) and three mammalian (swine H1N1, human H1N1 and pandemic H1N1) influenza viruses in PAM. We found that PAM were readily susceptible to initial infection with all five avian and mammalian influenza viruses but only avian viruses caused early and extensive apoptosis (by 6?h of infection) resulting in reduced virus progeny and moderated pro-inflammation. Full length viral PB1-F2 present only in avian influenza viruses is a virulence factor that targets AM for mitochondrial-associated apoptotic cell death. With the use of reverse genetics on an avian H5N1 virus, we found that full length PB1-F2 contributed to increased apoptosis and pro-inflammation but not to reduced virus replication. Taken together, we propose that early apoptosis of PAM limits the spread of avian influenza viruses and that PB1-F2 could play a contributory role in the process. PMID:26642934

  13. Chasing the Origin of Viruses: Capsid-Forming Genes as a Life-Saving Preadaptation within a Community of Early Replicators

    PubMed Central

    Jalasvuori, Matti; Mattila, Sari; Hoikkala, Ville

    2015-01-01

    Virus capsids mediate the transfer of viral genetic information from one cell to another, thus the origin of the first viruses arguably coincides with the origin of the viral capsid. Capsid genes are evolutionarily ancient and their emergence potentially predated even the origin of first free-living cells. But does the origin of the capsid coincide with the origin of viruses, or is it possible that capsid-like functionalities emerged before the appearance of true viral entities? We set to investigate this question by using a computational simulator comprising primitive replicators and replication parasites within a compartment matrix. We observe that systems with no horizontal gene transfer between compartments collapse due to the rapidly emerging replication parasites. However, introduction of capsid-like genes that induce the movement of randomly selected genes from one compartment to another rescues life by providing the non-parasitic replicators a mean to escape their current compartments before the emergence of replication parasites. Capsid-forming genes can mediate the establishment of a stable meta-population where parasites cause only local tragedies but cannot overtake the whole community. The long-term survival of replicators is dependent on the frequency of horizontal transfer events, as systems with either too much or too little genetic exchange are doomed to succumb to replication-parasites. This study provides a possible scenario for explaining the origin of viral capsids before the emergence of genuine viruses: in the absence of other means of horizontal gene transfer between compartments, evolution of capsid-like functionalities may have been necessary for early life to prevail. PMID:25955384

  14. Abnormal Early Cleavage Events Predict Early Embryo Demise: Sperm Oxidative Stress and Early Abnormal Cleavage

    PubMed Central

    Burruel, Victoria; Klooster, Katie; Barker, Christopher M.; Pera, Renee Reijo; Meyers, Stuart

    2014-01-01

    Human embryos resulting from abnormal early cleavage can result in aneuploidy and failure to develop normally to the blastocyst stage. The nature of paternal influence on early embryo development has not been directly demonstrated although many studies have suggested effects from spermatozoal chromatin packaging, DNA damage, centriolar and mitotic spindle integrity, and plasma membrane integrity. The goal of this study was to determine whether early developmental events were affected by oxidative damage to the fertilizing sperm. Survival analysis was used to compare patterns of blastocyst formation based on P2 duration. Kaplan-Meier survival curves demonstrate that relatively few embryos with short (<1?hr) P2 times reached blastocysts, and the two curves diverged beginning on day 4, with nearly all of the embryos with longer P2 times reaching blastocysts by day 6 (p < .01). We determined that duration of the 2nd to 3rd mitoses were sensitive periods in the presence of spermatozoal oxidative stress. Embryos that displayed either too long or too short cytokineses demonstrated an increased failure to reach blastocyst stage and therefore survive for further development. Although paternal-derived gene expression occurs later in development, this study suggests a specific role in early mitosis that is highly influenced by paternal factors. PMID:25307782

  15. Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication.

    PubMed

    Kristoff, Jan; Haret-Richter, George; Ma, Dongzhu; Ribeiro, Ruy M; Xu, Cuiling; Cornell, Elaine; Stock, Jennifer L; He, Tianyu; Mobley, Adam D; Ross, Samantha; Trichel, Anita; Wilson, Cara; Tracy, Russell; Landay, Alan; Apetrei, Cristian; Pandrea, Ivona

    2014-06-01

    Damage to the intestinal mucosa results in the translocation of microbes from the intestinal lumen into the circulation. Microbial translocation has been proposed to trigger immune activation, inflammation, and coagulopathy, all of which are key factors that drive HIV disease progression and non-HIV comorbidities; however, direct proof of a causal link is still lacking. Here, we have demonstrated that treatment of acutely SIV-infected pigtailed macaques with the drug sevelamer, which binds microbial lipopolysaccharide in the gut, dramatically reduces immune activation and inflammation and slightly reduces viral replication. Furthermore, sevelamer administration reduced coagulation biomarkers, confirming the contribution of microbial translocation in the development of cardiovascular comorbidities in SIV-infected nonhuman primates. Together, our data suggest that early control of microbial translocation may improve the outcome of HIV infection and limit noninfectious comorbidities associated with AIDS. PMID:24837437

  16. Replisome stall events have shaped the distribution of replication origins in the genomes of yeasts

    PubMed Central

    Newman, Timothy J.; Mamun, Mohammed A.; Nieduszynski, Conrad A.; Blow, J. Julian

    2013-01-01

    During S phase, the entire genome must be precisely duplicated, with no sections of DNA left unreplicated. Here, we develop a simple mathematical model to describe the probability of replication failing due to the irreversible stalling of replication forks. We show that the probability of complete genome replication is maximized if replication origins are evenly spaced, the largest inter-origin distances are minimized, and the end-most origins are positioned close to chromosome ends. We show that origin positions in the yeast Saccharomyces cerevisiae genome conform to all three predictions thereby maximizing the probability of complete replication if replication forks stall. Origin positions in four other yeasts—Kluyveromyces lactis, Lachancea kluyveri, Lachancea waltii and Schizosaccharomyces pombe—also conform to these predictions. Equating failure rates at chromosome ends with those in chromosome interiors gives a mean per nucleotide fork stall rate of ?5 × 10?8, which is consistent with experimental estimates. Using this value in our theoretical predictions gives replication failure rates that are consistent with data from replication origin knockout experiments. Our theory also predicts that significantly larger genomes, such as those of mammals, will experience a much greater probability of replication failure genome-wide, and therefore will likely require additional compensatory mechanisms. PMID:23963700

  17. Method for early detection of cooling-loss events

    SciTech Connect

    Bermudez, Sergio A.; Hamann, Hendrik; Marianno, Fernando J.

    2015-06-30

    A method of detecting cooling-loss event early is provided. The method includes defining a relative humidity limit and change threshold for a given space, measuring relative humidity in the given space, determining, with a processing unit, whether the measured relative humidity is within the defined relative humidity limit, generating a warning in an event the measured relative humidity is outside the defined relative humidity limit and determining whether a change in the measured relative humidity is less than the defined change threshold for the given space and generating an alarm in an event the change is greater than the defined change threshold.

  18. Method for early detection of cooling-loss events

    DOEpatents

    Bermudez, Sergio A.; Hamann, Hendrik F.; Marianno, Fernando J.

    2015-12-22

    A method of detecting cooling-loss event early is provided. The method includes defining a relative humidity limit and change threshold for a given space, measuring relative humidity in the given space, determining, with a processing unit, whether the measured relative humidity is within the defined relative humidity limit, generating a warning in an event the measured relative humidity is outside the defined relative humidity limit and determining whether a change in the measured relative humidity is less than the defined change threshold for the given space and generating an alarm in an event the change is greater than the defined change threshold.

  19. Operational early warning platform for extreme meteorological events

    NASA Astrophysics Data System (ADS)

    Mühr, Bernhard; Kunz, Michael

    2015-04-01

    Operational early warning platform for extreme meteorological events Most natural disasters are related to extreme weather events (e.g. typhoons); weather conditions, however, are also highly relevant for humanitarian and disaster relief operations during and after other natural disaster like earthquakes. The internet service "Wettergefahren-Frühwarnung" (WF) provides various information on extreme weather events, especially when these events are associated with a high potential for large damage. The main focus of the platform is on Central Europe, but major events are also monitored worldwide on a daily routine. WF provides high-resolution forecast maps for many weather parameters which allow detailed and reliable predictions about weather conditions during the next days in the affected areas. The WF service became operational in February 2004 and is part of the Center for Disaster Management and Risk Reduction Technology (CEDIM) since 2007. At the end of 2011, CEDIM embarked a new type of interdisciplinary disaster research termed as forensic disaster analysis (FDA) in near real time. In case of an imminent extreme weather event WF plays an important role in CEDIM's FDA group. It provides early and precise information which are always available and updated several times during a day and gives advice and assists with articles and reports on extreme events.

  20. APOBEC-Induced Cancer Mutations Are Uniquely Enriched in Early-Replicating, Gene-Dense, and Active Chromatin Regions.

    PubMed

    Kazanov, Marat D; Roberts, Steven A; Polak, Paz; Stamatoyannopoulos, John; Klimczak, Leszek J; Gordenin, Dmitry A; Sunyaev, Shamil R

    2015-11-10

    An antiviral component of the human innate immune system-the APOBEC cytidine deaminases-was recently identified as a prominent source of mutations in cancers. Here, we investigated the distribution of APOBEC-induced mutations across the genomes of 119 breast and 24 lung cancer samples. While the rate of most mutations is known to be elevated in late-replicating regions that are characterized by reduced chromatin accessibility and low gene density, we observed a marked enrichment of APOBEC mutations in early-replicating regions. This unusual mutagenesis profile may be associated with a higher propensity to form single-strand DNA substrates for APOBEC enzymes in early-replicating regions and should be accounted for in statistical analyses of cancer genome mutation catalogs aimed at understanding the mechanisms of carcinogenesis as well as highlighting genes that are significantly mutated in cancer. PMID:26527001

  1. APOBEC3G restricts early HIV-1 replication in the cytoplasm of target cells

    SciTech Connect

    Anderson, Jenny L.; Hope, Thomas J.

    2008-05-25

    Cellular APOBEC3G (A3G) protein is packaged into human immunodeficiency virus type 1 (HIV-1) virions in producer cells yet restricts viral replication in target cells. To characterize this restriction in target cells, the effect of A3G on generating various HIV-1 cDNA products was measured by quantitative real-time PCR. A3G decreased cDNA products from Vif-deficient HIV-1, with minor effects on early reverse transcripts and larger declines in late reverse transcripts. However, the greatest decline was typically observed in nuclear 2-LTR circles. Moreover, the magnitude of these declines varied with A3G dose. Adding integration inhibitor did not stop the A3G-mediated loss in 2-LTR circles. Moreover, obstructing HIV-1 nuclear entry using vesicular stomatitis virus matrix protein did not stop the A3G-mediated decline in late reverse transcripts. Collectively, these data suggest that A3G has important restriction activity in the cytoplasm and progressively diminishes viral cytoplasmic and nuclear cDNA forms with increasing magnitude during restriction.

  2. Early Events in Mycobacterium tuberculosis Infection in Cynomolgus Macaques†

    PubMed Central

    Lin, Philana Ling; Pawar, Santosh; Myers, Amy; Pegu, Amarenda; Fuhrman, Carl; Reinhart, Todd A.; Capuano, Saverio V.; Klein, Edwin; Flynn, JoAnne L.

    2006-01-01

    Little is known regarding the early events of infection of humans with Mycobacterium tuberculosis. The cynomolgus macaque is a useful model of tuberculosis, with strong similarities to human tuberculosis. In this study, eight cynomolgus macaques were infected bronchoscopically with low-dose M. tuberculosis; clinical, immunologic, microbiologic, and pathologic events were assessed 3 to 6 weeks postinfection. Gross pathological abnormalities were observed as early as 3 weeks, including Ghon complex formation by 5 weeks postinfection. Caseous granulomas were observed in the lung as early as 4 weeks postinfection. Only caseous granulomas were observed in the lungs at these early time points, reflecting a rigorous initial response. T-cell activation (CD29 and CD69) and chemokine receptor (CXCR3 and CCR5) expression appeared localized to different anatomic sites. Activation markers were increased on cells from airways and only at modest levels on cells in peripheral blood. The priming of mycobacterium-specific T cells, characterized by the production of gamma interferon occurred slowly, with responses seen only after 4 weeks of infection. These responses were observed from T lymphocytes in blood, airways, and hilar lymph node, with responses predominantly localized to the site of infection. From these studies, we conclude that immune responses to M. tuberculosis are relatively slow in the local and peripheral compartments and that necrosis occurs surprisingly quickly during granuloma formation. PMID:16790751

  3. Absence of the BaeR protein leads to the early initiation of DNA replication in Escherichia coli.

    PubMed

    Yao, Y; Wunier, W; Morigen, M

    2015-01-01

    Escherichia coli cells have dozens of two-component systems to sense and respond to various stimuli, and thereby cope with changing environments. BaeS/BaeR is one such two-component system, and it deals with a variety of envelope stresses. Interestingly, the ArcA/ArcB and TorS/TorR two-component systems are known to be associated with initiation of DNA replication; however, the effects of BaeS/BaeR on initiation of DNA replication remain unknown. Flow cytometry analysis revealed that the average number of replication origins (oriCs) per cell in ?baeR mutants was approximately 30% higher than that in wild-type cells. So was the growth rate of ?baeR cells. Ectopic expression of BaeR from the pbaeR plasmid reversed the ?baeR mutant phenotypes. The results indicate that absence of BaeR leads to the early initiation of DNA replication. Further, deletion of BaeR caused an increase in the amount of DnaA per cell, but did not change concentration of DnaA, which is the initiator protein.The average number of oriCs per cell in ?spy mutants was the same as that found in the wild-type cells although spy gene expression is controlled by BaeR. These results suggest that BaeR may indirectly affect initiation of replication by controlling expression of the dnaA gene. PMID:26681035

  4. Population resilience to catastrophic mortality events during early life stages.

    PubMed

    Ohlberger, Jan; Langangen, Øystein

    2015-07-01

    Catastrophic mortality events that drastically reduce the abundance of a population or a particular life stage can have long-term ecological and economic effects, and are of great concern in species conservation and management. Severe die-offs may be caused by natural catastrophes such as disease outbreaks and extreme climates, or human-caused disturbances such as toxic spills. Forecasting potential impacts of such disturbances is difficult and highly uncertain due to unknown future conditions, including population status and environmental conditions at the time of impact. Here, we present a framework for quantifying the range of potential, population-level effects of catastrophic events based on a hindcasting approach. A dynamic population model with Bayesian parameter estimation is used to simulate the impact of severe (50-99%) mortality events during the early life stages of Northeast Arctic cod (Gadus morhua), an abundant marine fish population of high economic value. We quantify the impact of such die-offs in terms of subsequent changes in population biomass and harvest through direct comparison of simulated and historical trends, and estimate the duration of the impact as a measure of population resilience. Our results demonstrate strong resilience to catastrophic events that affect early life stages owing to density dependence in survival and a broad population age structure. Yet, while population recovery is. relatively fast, losses in harvest and economic value can be substantial. Future research efforts should focus on long-term and indirect effects via food web interactions in order to better understand the ecological and economic ramifications of catastrophic mortality events. PMID:26485960

  5. Importance of Bacterial Replication and Alveolar Macrophage-Independent Clearance Mechanisms during Early Lung Infection with Streptococcus pneumoniae

    PubMed Central

    Camberlein, Emilie; Cohen, Jonathan M.; José, Ricardo; Hyams, Catherine J.; Callard, Robin; Chimalapati, Suneeta; Yuste, Jose; Edwards, Lindsey A.; Marshall, Helina; van Rooijen, Nico; Noursadeghi, Mahdad

    2015-01-01

    Although the importance of alveolar macrophages for host immunity during early Streptococcus pneumoniae lung infection is well established, the contribution and relative importance of other innate immunity mechanisms and of bacterial factors are less clear. We have used a murine model of S. pneumoniae early lung infection with wild-type, unencapsulated, and para-amino benzoic acid auxotroph mutant TIGR4 strains to assess the effects of inoculum size, bacterial replication, capsule, and alveolar macrophage-dependent and -independent clearance mechanisms on bacterial persistence within the lungs. Alveolar macrophage-dependent and -independent (calculated indirectly) clearance half-lives and bacterial replication doubling times were estimated using a mathematical model. In this model, after infection with a high-dose inoculum of encapsulated S. pneumoniae, alveolar macrophage-independent clearance mechanisms were dominant, with a clearance half-life of 24 min compared to 135 min for alveolar macrophage-dependent clearance. In addition, after a high-dose inoculum, successful lung infection required rapid bacterial replication, with an estimated S. pneumoniae doubling time of 16 min. The capsule had wide effects on early lung clearance mechanisms, with reduced half-lives of 14 min for alveolar macrophage-independent and 31 min for alveolar macrophage-dependent clearance of unencapsulated bacteria. In contrast, with a lower-dose inoculum, the bacterial doubling time increased to 56 min and the S. pneumoniae alveolar macrophage-dependent clearance half-life improved to 42 min and was largely unaffected by the capsule. These data demonstrate the large effects of bacterial factors (inoculum size, the capsule, and rapid replication) and alveolar macrophage-independent clearance mechanisms during early lung infection with S. pneumoniae. PMID:25583525

  6. Impact Constraints on Major Events in Early Mars History

    NASA Technical Reports Server (NTRS)

    Frey, H. V.

    2004-01-01

    MOLA data have revealed a large population of "Quasi-Circular Depressions" (QCDs) with little or no visible expression in image data. These likely buried impact basins have important implications for the age of the lowland crust, how that compares with original highland crust, and when and how the crustal dichotomy may have formed. The buried lowlands are of Early Noachian age, likely slightly younger than the buried highlands but older than the exposed (visible) highland surface. A depopulation of large visible basins at diameters 800 to 1300 km suggests some global scale event early in martian history, maybe related to the formation of the lowlands and/or the development of Tharsis. A suggested early disappearance of the global magnetic field can be placed within a temporal sequence of formation of the very largest impact basins. The global field appears to have disappeared at about the time the lowlands formed. It seems likely the topographic crustal dichotomy was produced very early in martian history by processes which operated very quickly. Thus there appears to have been a northern lowland throughout nearly all of martian history, predating the last of the really large impacts (Hellas, Argyre and Isidis) and their likely very significant environmental consequences.

  7. Characterization of a Replication-Incompetent Pseudorabies Virus Mutant Lacking the Sole Immediate Early Gene IE180

    PubMed Central

    Wu, Brendan W.

    2014-01-01

    ABSTRACT The alphaherpesvirus pseudorabies virus (PRV) encodes a single immediate early gene called IE180. The IE180 protein is a potent transcriptional activator of viral genes involved in DNA replication and RNA transcription. A PRV mutant with both copies of IE180 deleted was constructed 20 years ago (S. Yamada and M. Shimizu, Virology 199:366–375, 1994, doi:10.1006/viro.1994.1134), but propagation of the mutant depended on complementing cell lines that expressed the toxic IE180 protein constitutively. Recently, Oyibo et al. constructed a novel set of PRV IE180 mutants and a stable cell line with inducible IE180 expression (H. Oyibo, P. Znamenskiy, H. V. Oviedo, L. W. Enquist, A. Zador, Front. Neuroanat. 8:86, 2014, doi:10.3389/fnana.2014.00086), which we characterized further here. These mutants failed to replicate new viral genomes, synthesize immediate early, early, or late viral proteins, and assemble infectious virions. The PRV IE180-null mutant did not form plaques in epithelial cell monolayers and could not spread from primary infected neurons to second-order neurons in culture. PRV IE180-null mutants lacked the property of superinfection exclusion. When PRV IE180-null mutants infected cells first, subsequent superinfecting viruses were not blocked in cell entry and formed replication compartments in epithelial cells, fibroblasts, and neurons. Cells infected with PRV IE180-null mutants survived as long as uninfected cells in culture while expressing a fluorescent reporter gene. Transcomplementation with IE180 in epithelial cells restored all mutant phenotypes to wild type. The conditional expression of PRV IE180 protein enables the propagation of replication-incompetent PRV IE180-null mutants and will facilitate construction of long-term single-cell-infecting PRV mutants for precise neural circuit tracing and high-capacity gene delivery vectors. PMID:25389174

  8. Astronomical forcing and chronology of the early Toarcian (Early Jurassic) oceanic anoxic event in Yorkshire, UK

    NASA Astrophysics Data System (ADS)

    Kemp, David B.; Coe, Angela L.; Cohen, Anthony S.; Weedon, Graham P.

    2011-11-01

    During the early Toarcian (˜183 Ma ago), a high rate of organic carbon burial globally over a brief interval of time has led to the recognition of a major oceanic anoxic event (OAE). A pronounced negative excursion in the carbon-isotope composition of marine organic matter, marine carbonate and terrestrial plant material is a key feature of this event but the precise timescale and cause(s) of this isotopic anomaly are debated. Associated with the negative carbon-isotope excursion is evidence for a coeval rise in seawater palaeotemperature, an increase in continental weathering rates, and the mass extinction of marine invertebrate species. The early Toarcian OAE provides evidence for the Earth's response during rapid climate change, and critical to our understanding of the event is a high-resolution timescale that allows us to quantify the rates, duration and lead/lag times of environmental processes. In this study, we present 2743 new high-resolution organic carbon, sulphur and carbonate concentration data from samples of well-preserved organic-rich mudrocks spanning the early Toarcian OAE in Yorkshire, UK. We have used these data to document the geochemical changes and significantly extend and refine the astronomical timescale across this event. Our detailed analysis of the relationship between astronomical forcing and carbon isotope changes in both Yorkshire and a section from Peniche, Portugal, indicates that astronomical forcing paced the timing of major shifts in ?13C and hence climate in both sections. Our analyses also demonstrate that there was a marked increase in the relative strength of astronomical forcing recorded at the onset of the OAE, and that the recorded nature of astronomical forcing changed during the event. Both the Yorkshire and Peniche cyclostratigraphies suggest that one astronomical forcing parameter paced environmental change through the ?13C event, and that this parameter was obliquity or precession.

  9. The Salmonella?Typhimurium effector protein SopE transiently localizes to the early SCV and contributes to intracellular replication.

    PubMed

    Vonaesch, Pascale; Sellin, Mikael E; Cardini, Steven; Singh, Vikash; Barthel, Manja; Hardt, Wolf-Dietrich

    2014-12-01

    Salmonella enterica serovar Typhimurium (S. Tm) is a facultative intracellular pathogen that induces entry into non-phagocytic cells by a Type III secretion system (TTSS) and cognate effector proteins. Upon host cell entry, S. Tm expresses a second TTSS and subverts intracellular trafficking to create a replicative niche - the Salmonella-containing vacuole (SCV). SopE, a guanidyl exchange factor (GEF) for Rac1 and Cdc42, is translocated by the TTSS-1 upon host cell contact and promotes entry through triggering of actin-dependent ruffles. After host cell entry, the bulk of SopE undergoes proteasomal degradation. Here we show that a subfraction is however detectable on the nascent SCV membrane up to ??6?h post infection. Membrane localization of SopE and the closely related SopE2 differentially depend on the Rho-GTPase-binding GEF domain, and to some extent involves also the unstructured N-terminus. SopE localizes transiently to the early SCV, dependent on continuous synthesis and secretion by the TTSS-1 during the intracellular state. Mutant strains lacking SopE or SopE2 are attenuated in early intracellular replication, while complementation restores this defect. Hence, the present study reveals an unanticipated role for SopE and SopE2 in establishing the Salmonella replicative niche, and further emphasizes the importance of entry effectors in later stages of host-cell manipulation. PMID:25052734

  10. Rhythmic Engagement with Music in Early Childhood: A Replication and Extension

    ERIC Educational Resources Information Center

    Ilari, Beatriz

    2015-01-01

    The purpose of this study was to replicate and extend previous findings on spontaneous movement and rhythmic engagement with music in infancy. Using the identical stimuli and procedures from the original study, I investigated spontaneous rhythmic movements in response to music, infant-directed speech, and contrasting rhythmic patterns in 30…

  11. Replication Study of the First Step to Success Early Intervention Program

    ERIC Educational Resources Information Center

    Lien-Thorne, Stephanie; Kamps, Debra

    2005-01-01

    This article describes a replication of the "First Step to Success" program (Walker, Stiller, Severson, & Golly, 1998) with at-risk students in the first and second grade to determine program effectiveness in decreasing inappropriate behaviors and increasing academic engagement time. This expands the "First Step to Success" program to (1) serve…

  12. Model of early self-replication based on covalent complementarity for a copolymer of glycerate-3-phosphate and glycerol-3-phosphate

    NASA Technical Reports Server (NTRS)

    Weber, Arthur L.

    1989-01-01

    Glyceraldehyde-3-phosphate acts as the substrate in a model of early self-replication of a phosphodiester copolymer of glycerate-3-phosphate and glycerol-3-phosphate. This model of self-replication is based on covalent complementarity in which information transfer is mediated by a single covalent bond, in contrast to multiple weak interactions that establish complementarity in nucleic acid replication. This replication model is connected to contemporary biochemistry through its use of glyceraldehyde-3-phosphate, a central metabolite of glycolysis and photosynthesis.

  13. Specific posttranslational modification regulates early events in mammary carcinoma formation

    PubMed Central

    Guo, Hua-Bei; Johnson, Heather; Randolph, Matthew; Nagy, Tamas; Blalock, Ryan; Pierce, Michael

    2010-01-01

    The expression of an enzyme, GnT-V, that catalyzes a specific posttranslational modification of a family of glycoproteins, namely a branched N-glycan, is transcriptionally up-regulated during breast carcinoma oncogenesis. To determine the molecular basis of how early events in breast carcinoma formation are regulated by GnT-V, we studied both the early stages of mammary tumor formation by using 3D cell culture and a her-2 transgenic mouse mammary tumor model. Overexpression of GnT-V in MCF-10A mammary epithelial cells in 3D culture disrupted acinar morphogenesis with impaired hollow lumen formation, an early characteristic of mammary neoplastic transformation. The disrupted acinar morphogenesis of mammary tumor cells in 3D culture caused by her-2 expression was reversed in tumors that lacked GnT-V expression. Moreover, her-2-induced mammary tumor onset was significantly delayed in the GnT-V null tumors, evidence that the lack of the posttranslational modification catalyzed by GnT-V attenuated tumor formation. Inhibited activation of both PKB and ERK signaling pathways was observed in GnT-V null tumor cells. The proportion of tumor-initiating cells (TICs) in the mammary tumors from GnT-V null mice was significantly reduced compared with controls, and GnT-V null TICs displayed a reduced ability to form secondary tumors in NOD/SCID mice. These results demonstrate that GnT-V expression and its branched glycan products effectively modulate her-2-mediated signaling pathways that, in turn, regulate the relative proportion of tumor initiating cells and the latency of her-2-driven tumor onset. PMID:21078982

  14. Early Function of the Abutilon Mosaic Virus AC2 Gene as a Replication Brake

    PubMed Central

    Krenz, Björn; Deuschle, Kathrin; Deigner, Tobias; Unseld, Sigrid; Kepp, Gabi; Wege, Christina; Kleinow, Tatjana

    2015-01-01

    ABSTRACT The C2/AC2 genes of monopartite/bipartite geminiviruses of the genera Begomovirus and Curtovirus encode important pathogenicity factors with multiple functions described so far. A novel function of Abutilon mosaic virus (AbMV) AC2 as a replication brake is described, utilizing transgenic plants with dimeric inserts of DNA B or with a reporter construct to express green fluorescent protein (GFP). Their replicational release upon AbMV superinfection or the individual and combined expression of epitope-tagged AbMV AC1, AC2, and AC3 was studied. In addition, the effects were compared in the presence and in the absence of an unrelated tombusvirus suppressor of silencing (P19). The results show that AC2 suppresses replication reproducibly in all assays and that AC3 counteracts this effect. Examination of the topoisomer distribution of supercoiled DNA, which indicates changes in the viral minichromosome structure, did not support any influence of AC2 on transcriptional gene silencing and DNA methylation. The geminiviral AC2 protein has been detected here for the first time in plants. The experiments revealed an extremely low level of AC2, which was slightly increased if constructs with an intron and a hemagglutinin (HA) tag in addition to P19 expression were used. AbMV AC2 properties are discussed with reference to those of other geminiviruses with respect to charge, modification, and size in order to delimit possible reasons for the different behaviors. IMPORTANCE The (A)C2 genes encode a key pathogenicity factor of begomoviruses and curtoviruses in the plant virus family Geminiviridae. This factor has been implicated in the resistance breaking observed in agricultural cotton production. AC2 is a multifunctional protein involved in transcriptional control, gene silencing, and regulation of basal biosynthesis. Here, a new function of Abutilon mosaic virus AC2 in replication control is added as a feature of this protein in viral multiplication, providing a novel finding on geminiviral molecular biology. PMID:25589661

  15. Sequence of Events in Measles Virus Replication: Role of Phosphoprotein-Nucleocapsid Interactions

    PubMed Central

    Brunel, Joanna; Chopy, Damien; Dosnon, Marion; Bloyet, Louis-Marie; Devaux, Patricia; Urzua, Erica; Cattaneo, Roberto; Longhi, Sonia

    2014-01-01

    ABSTRACT The genome of nonsegmented negative-strand RNA viruses is tightly embedded within a nucleocapsid made of a nucleoprotein (N) homopolymer. To ensure processive RNA synthesis, the viral polymerase L in complex with its cofactor phosphoprotein (P) binds the nucleocapsid that constitutes the functional template. Measles virus P and N interact through two binding sites. While binding of the P amino terminus with the core of N (NCORE) prevents illegitimate encapsidation of cellular RNA, the interaction between their C-terminal domains, PXD and NTAIL is required for viral RNA synthesis. To investigate the binding dynamics between the two latter domains, the PXD F497 residue that makes multiple hydrophobic intramolecular interactions was mutated. Using a quantitative mammalian protein complementation assay and recombinant viruses, we found that an increase in PXD-to-NTAIL binding strength is associated with a slower transcript accumulation rate and that abolishing the interaction renders the polymerase nonfunctional. The use of a newly developed system allowing conditional expression of wild-type or mutated P genes, revealed that the loss of the PXD-NTAIL interaction results in reduced transcription by preformed transcriptases, suggesting reduced engagement on the genomic template. These intracellular data indicate that the viral polymerase entry into and progression along its genomic template relies on a protein-protein interaction that serves as a tightly controlled dynamic anchor. IMPORTANCE Mononegavirales have a unique machinery to replicate RNA. Processivity of their polymerase is only achieved when the genome template is entirely embedded into a helical homopolymer of nucleoproteins that constitutes the nucleocapsid. The polymerase binds to the nucleocapsid template through the phosphoprotein. How the polymerase complex enters and travels along the nucleocapsid template to ensure uninterrupted synthesis of up to ?6,700-nucleotide messenger RNAs from six to ten consecutive genes is unknown. Using a quantitative protein complementation assay and a biGene-biSilencing system allowing conditional expression of two P genes copies, the role of the P-to-N interaction in polymerase function was further characterized. We report here a dynamic protein anchoring mechanism that differs from all other known polymerases that rely only onto a sustained and direct binding to their nucleic acid template. PMID:25008930

  16. Early Steps: Replicating the Effects of a First-Grade Reading Intervention Program.

    ERIC Educational Resources Information Center

    Morris, Darrell; Tyner, Beverly; Perney, Jan

    2000-01-01

    Examines the effectiveness of Early Steps, a first-grade reading intervention program in which at-risk students receive one-to-one tutoring lessons. Results reveal that at the end of the school year, the Early Steps group outperformed a comparison group on a variety of reading measures, including oral reading accuracy, comprehension, and…

  17. Early Initiation of Deoxyribonucleic Acid Replication and Shortening of Generation Time Associated with Inhibition of Lateral Wall Formation by Mecillinam

    PubMed Central

    Satta, G.; Botta, G.; Canepari, P.; Fontana, R.

    1981-01-01

    The effects of mecillinam on the growth of rods of the pH-conditional morphology mutant MirM7 was studied. It has been found that mecillinam causes, coincident with transition to coccal shape, a balanced rise in the rate of viable count increase and the rate of macromolecular synthesis which lasts either until the cells enter a stationary growth phase or indefinitely, in the case of continuously diluted cultures. When the antibiotic is removed from cells which have already become coccoid, cells continue to grow at a faster rate until they resume the rod shape. No change in the per-cell rate of protein synthesis has been seen in untreated or mecillinam-treated cells before or after the change in growth rate. Studies with synchronously growing cells have shown that the antibiotic causes a shortening in the I period (initiation of deoxyribonucleic acid replication). Evaluation of the residual divisions in nalidixic acid-treated, exponential-phase cells has shown that mecillinam also shortens the D period (cell division). It is proposed that, in strain MirM7, inhibition of lateral wall elongation by the antibiotic allows the initiation of a new septum, though inhibition is still in progress. The initiation of a new septum is, in turn, responsible for both the early inibition of deoxyribonucleic acid replication and accelerated division. In the parental strain, MirA12, as well as in other sensitive gram-negative rods which divide, become cocci, and stop dividing after addition of the antibiotic, inhibition of lateral wall formation activates a feedback mechanism which prevents insertion of new septa (Satta et al., J. Bacteriol. 142:43-51, 1980). Consequently, no early initiation of deoxyribonucleic acid replication is observed, and the last division allowed by the antibiotic occurs in due time. This negative control is missing in MirM7. PMID:6270055

  18. Replicating vaccines

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Early work on fish immunology and disease resistance demonstrated fish (like animals and humans) that survived infection were typically resistant to re-infection with the same pathogen. The concepts of resistance upon reinfection lead to the research and development of replicating (live) vaccines in...

  19. Topologically associating domains and their long-range contacts are established during early G1 coincident with the establishment of the replication-timing program.

    PubMed

    Dileep, Vishnu; Ay, Ferhat; Sima, Jiao; Vera, Daniel L; Noble, William S; Gilbert, David M

    2015-08-01

    Mammalian genomes are partitioned into domains that replicate in a defined temporal order. These domains can replicate at similar times in all cell types (constitutive) or at cell type-specific times (developmental). Genome-wide chromatin conformation capture (Hi-C) has revealed sub-megabase topologically associating domains (TADs), which are the structural counterparts of replication domains. Hi-C also segregates inter-TAD contacts into defined 3D spatial compartments that align precisely to genome-wide replication timing profiles. Determinants of the replication-timing program are re-established during early G1 phase of each cell cycle and lost in G2 phase, but it is not known when TAD structure and inter-TAD contacts are re-established after their elimination during mitosis. Here, we use multiplexed 4C-seq to study dynamic changes in chromatin organization during early G1. We find that both establishment of TADs and their compartmentalization occur during early G1, within the same time frame as establishment of the replication-timing program. Once established, this 3D organization is preserved either after withdrawal into quiescence or for the remainder of interphase including G2 phase, implying 3D structure is not sufficient to maintain replication timing. Finally, we find that developmental domains are less well compartmentalized than constitutive domains and display chromatin properties that distinguish them from early and late constitutive domains. Overall, this study uncovers a strong connection between chromatin re-organization during G1, establishment of replication timing, and its developmental control. PMID:25995270

  20. Rif1 regulates the replication timing domains on the human genome.

    PubMed

    Yamazaki, Satoshi; Ishii, Aii; Kanoh, Yutaka; Oda, Masako; Nishito, Yasumasa; Masai, Hisao

    2012-09-12

    DNA replication is spatially and temporally regulated during S-phase. DNA replication timing is established in early-G1-phase at a point referred to as timing decision point. However, how the genome-wide replication timing domains are established is unknown. Here, we show that Rif1 (Rap1-interacting-factor-1), originally identified as a telomere-binding factor in yeast, is a critical determinant of the replication timing programme in human cells. Depletion of Rif1 results in specific loss of mid-S replication foci profiles, stimulation of initiation events in early-S-phase and changes in long-range replication timing domain structures. Analyses of replication timing show replication of sequences normally replicating early is delayed, whereas that normally replicating late is advanced, suggesting that replication timing regulation is abrogated in the absence of Rif1. Rif1 tightly binds to nuclear-insoluble structures at late-M-to-early-G1 and regulates chromatin-loop sizes. Furthermore, Rif1 colocalizes specifically with the mid-S replication foci. Thus, Rif1 establishes the mid-S replication domains that are restrained from being activated at early-S-phase. Our results indicate that Rif1 plays crucial roles in determining the replication timing domain structures in human cells through regulating higher-order chromatin architecture. PMID:22850674

  1. Early Paleozoic and Early Mesozoic intraplate tectonic and magmatic events in the Cathaysia Block, South China

    NASA Astrophysics Data System (ADS)

    Shu, Liangshu; Wang, Bo; Cawood, Peter A.; Santosh, M.; Xu, Zhiqin

    2015-08-01

    The geodynamic framework of the South China Craton in the Early Paleozoic and Early Mesozoic has been modeled as developing through either oceanic convergence or intracontinental settings. On the basis of an integrated structural, geochemical, zircon U-Pb and Hf isotopic, and mica 40Ar/39Ar geochronologic study we establish that an intracontinental setting is currently the best fit for the available data. Our results suggest that widespread tectonomagmatic activity involving granite emplacement and mylonitic deformation occurred during two distinct stages: ~435-415 Ma and ~230-210 Ma. The coeval nature of emplacement of the plutons and their ductile deformation is corroborated by the subparallel orientation of the mylonitic foliation along the pluton margins, gneissose foliation in the middle part of pluton, the magmatic foliation within the plutons, and the schistosity in the surrounding metamorphosed country rocks. The 435-415 Ma granitoids exhibit peraluminous, high-K characteristics, and zircons show negative ?Hf(t) values (average -6.2, n = 66), and Paleoproterozoic two-stage model ages of circa 2.21-1.64 Ga (average 1.84 Ga). The data suggest that the Early Paleozoic plutons were derived from the partial melting of the Paleoproterozoic basement of the Cathaysia Block. The 230-210 Ma granites are potassic and have zircons with ?Hf(t) values of -2.8--8.7 (average -5.4, n = 62), corresponding to TDM2 ages ranging from 2.0 to 1.44 Ga (average 1.64 Ga), suggesting that the Early Mesozoic partial melts in Cathaysia were also derived from basement. The geochemical distinction between the two phases of granites traces continental crustal evolution with time, with the Early Mesozoic crust enriched in potassium, silicon, and aluminum, but deficient in calcium, relative to the Paleozoic crust. Kinematical investigations provide evidence for an early-stage ductile deformation with a doubly vergent thrusting pattern dated at 433 ± 1 to 428 ± 1 Ma (40Ar/39Ar furnace step-heating pseudoplateau ages obtained on muscovite and biotite from mylonite and deformed granite) and a late-stage strike-slip movement with sinistral sense of ductile shearing at 232 ± 1 to 234 ± 1 Ma (40Ar/39Ar furnace step-heating pseudoplateau ages) along an E-W direction. The geological, geochemical, and isotopic signatures likely reflect far-field effects in response to continental assembly events at these times.

  2. COLORECTAL CANCER Increased microvascular blood content is an early event in

    E-print Network

    Kim, Young L.

    COLORECTAL CANCER Increased microvascular blood content is an early event in colon carcinogenesis R independent prognostic indi- cator in patients with colorectal cancer (CRC).1 Their therapeutic implications carcinogenesis. These findings may provide novel insights into early biological events in colorectal

  3. Early Adverse Events, HPA Activity and Rostral Anterior Cingulate Volume in MDD

    PubMed Central

    Treadway, Michael T.; Grant, Merida M.; Ding, Zhaohua; Hollon, Steven D.; Gore, John C.; Shelton, Richard C.

    2009-01-01

    Background Prior studies have independently reported associations between major depressive disorder (MDD), elevated cortisol concentrations, early adverse events and region-specific decreases in grey matter volume, but the relationships among these variables are unclear. In the present study, we sought to evaluate the relationships between grey matter volume, early adverse events and cortisol levels in MDD. Methods/Results Grey matter volume was compared between 19 controls and 19 individuals with MDD using voxel-based morphometry. A history of early adverse events was assessed using the Childhood Trauma Questionnaire. Subjects also provided salivary cortisol samples. Depressed patients showed decreased grey matter volume in the rostral ACC as compared to controls. Rostral ACC volume was inversely correlated with both cortisol and early adverse events. Conclusions These findings suggest a key relationship between ACC morphology, a history of early adverse events and circulating cortisol in the pathophysiology of MDD. PMID:19325704

  4. Eclipse period during replication of plasmid R1: contributions from structural events and from the copy-number control system.

    PubMed

    Olsson, Jan A; Berg, Otto G; Dasgupta, Santanu; Nordström, Kurt

    2003-10-01

    The eclipse period (the time period during which a newly replicated plasmid copy is not available for a new replication) of plasmid R1 in Escherichia coli was determined with the classic Meselson-Stahl density-shift experiment. A mini-plasmid with the wild-type R1 replicon and a mutant with a thermo-inducible runaway-replication phenotype were used in this work. The eclipses of the chromosome and of the wild-type plasmid were 0.6 and 0.2 generation times, respectively, at temperatures ranging from 30 degrees C to 42 degrees C. The mutant plasmid had a similar eclipse at temperatures up to 38 degrees C. At 42 degrees C, the plasmid copy number increased rapidly because of the absence of replication control and replication reached a rate of 350-400 plasmid replications per cell and cell generation. During uncontrolled replication, the eclipse was about 3 min compared with 10 min at controlled replication (the wild-type plasmid at 42 degrees C). Hence, the copy-number control system contributed significantly to the eclipse. The eclipse in the absence of copy-number control (3 min) presumably is caused by structural requirements: the covalently closed circular plasmid DNA has to regain the right degree of superhelicity needed for initiation of replication and it takes time to assemble the initiation factors. PMID:14507381

  5. Early Jurassic mass extinction: A global long-term event Crispin T. S. Little

    E-print Network

    Benton, Michael

    Early Jurassic mass extinction: A global long-term event Crispin T. S. Little Department of Geology-Pliensbachian extinction event (187 Ma) has been in- terpreted either as one of 10 global periodically recurring mass extinctions of the past 250 m.y. or as a minor localized European event. Elevated levels of family extinction

  6. Event Conceptualization by Early Dutch-German Bilinguals: Insights from Linguistic and Eye-Tracking Data

    ERIC Educational Resources Information Center

    Flecken, Monique

    2011-01-01

    This experimental study investigates event construal by early Dutch-German bilinguals, as reflected in their oral depiction of everyday events shown in video clips. The starting point is the finding that the expression of an aspectual perspective (progressive aspect), and its consequences for event construal, is dependent on the extent to which…

  7. Replicating the Ice-Volume Signal of the Early Pleistocene with a Complex Earth System Model

    NASA Astrophysics Data System (ADS)

    Tabor, C. R.; Poulsen, C. J.; Pollard, D.

    2013-12-01

    Milankovitch theory proposes high-latitude summer insolation intensity paces the ice ages by controlling perennial snow cover amounts (Milankovitch, 1941). According to theory, the ~21 kyr cycle of precession should dominate the ice-volume records since it has the greatest influence on high-latitude summer insolation. Modeling experiments frequently support Milankovitch theory by attributing the majority of Northern Hemisphere high-latitude summer snowmelt to changes in the cycle of precession (e.g. Jackson and Broccoli, 2003). However, ice-volume proxy records, especially those of the Early Pleistocene (2.6-0.8 Ma), display variability with a period of ~41 kyr (Raymo and Lisiecki, 2005), indicative of insolation forcing from obliquity, which has a much smaller influence on summer insolation intensity than precession. Several hypotheses attempt to explain the discrepancies between Milkankovitch theory and the proxy records by invoking phenomena such as insolation gradients (Raymo and Nisancioglu, 2003), hemispheric offset (Raymo et al., 2006; Lee and Poulsen, 2009), and integrated summer energy (Huybers, 2006); however, all of these hypotheses contain caveats (Ruddiman, 2006) and have yet to be supported by modeling studies that use a complex GCM. To explore potential solutions to this '41 kyr problem,' we use an Earth system model composed of the GENESIS GCM and Land Surface model, the BIOME4 vegetation model, and the Pennsylvania State ice-sheet model. Using an asynchronous coupling technique, we run four idealized transient combinations of obliquity and precession, representing the orbital extremes of the Pleistocene (Berger and Loutre, 1991). Each experiment is run through several complete orbital cycles with a dynamic ice domain spanning North America and Greenland, and fixed preindustrial greenhouse-gas concentrations. For all orbital configurations, model results produce greater ice-volume spectral power at the frequency of obliquity despite significantly greater summer insolation variability from the cycle of precession. We find obliquity enhances the climate sensitivity to direct insolation forcing through positive high-latitude surface feedbacks between vegetation, sea-ice, and mean-annual insolation while the seasonal dichotomy of precessional forcing leads to climate counterbalancing that dampens the annual ice-volume response. Longer cycle duration further amplifies the ice-volume response to obliquity. Our results help remedy the discrepancies between Milankovitch theory and the ice-volume proxy records. However, summer insolation intensity remains the most important factor for determining ice-volume rate-of-change in our experiments. Consequently, we still find a significant ice-volume response to precession, which is inconsistent with the Early Pleistocene records. The disconnect is likely attributable to climate phenomena not accounted for in the model or our choice of initial conditions, which are poorly constrained for the Early Pleistocene and ice-sheet modeling in general. Future work will examine the importance of initial climate conditions on ice-volume response.

  8. HIV-protease inhibitors block the replication of both vesicular stomatitis and influenza viruses at an early post-entry replication step

    SciTech Connect

    Federico, Maurizio

    2011-08-15

    The inhibitors of HIV-1 protease (PIs) have been designed to block the activity of the viral aspartyl-protease. However, it is now accepted that this family of inhibitors can also affect the activity of cell proteases. Since the replication of many virus species requires the activity of host cell proteases, investigating the effects of PIs on the life cycle of viruses other than HIV would be of interest. Here, the potent inhibition induced by saquinavir and nelfinavir on the replication of both vesicular stomatitis and influenza viruses is described. These are unrelated enveloped RNA viruses infecting target cells upon endocytosis and intracellular fusion. The PI-induced inhibition was apparently a consequence of a block at the level of the fusion between viral envelope and endosomal membranes. These findings would open the way towards the therapeutic use of PIs against enveloped RNA viruses other than HIV.

  9. 1 Modeling and Analysis of Early Events in T-Lymphocyte Antigen ...

    E-print Network

    Greg

    identify potential regulatory mechanisms in the early T-cell signaling events. This integrated ... Although many of the proteins that participate in these biochemical reactions are known,. details of their ...... In E. coli, more than 50%. cell-cell ...

  10. Early Infection HIV-1 Envelope V1-V2 Genotypes Do Not Enhance Binding or Replication in Cells Expressing High Levels of ?4?7 Integrin

    PubMed Central

    Etemad, Behzad; Gonzalez, Oscar A.; McDonough, Sean; Pena-Cruz, Victor; Sagar, Manish

    2013-01-01

    It has been postulated that HIV-1 envelope properties, such as shorter and less glycosylated V1-V2 loops commonly observed among non-subtype B early – transmitted viruses, promote utilization of the gut homing integrin ?4?7. This property potentially confers an advantage to some HIV-1 variants early after acquisition. We found that replication competent recombinant viruses incorporating HIV-1 subtype A compact and less glycosylated early versus chronic phase V1-V2 loops demonstrated no significant difference in binding to ?4?7 high CD8+ T cells or replication in ?4?7 high CD4+ T cells. Integrin ?4?7 usage does not select for shorter less glycosylated envelopes during transmission. PMID:23797693

  11. EARLY CAREER: THE HAZARDS OF EXTREME CLIMATIC EVENTS: PREDICTING IMPACTS

    EPA Science Inventory

    One of the greatest threats to water quality is water-borne pathogens, which are more common now than they have been historically. A factor implicated in the emergence of water-borne diseases is climate change-driven increases in extreme climatic events. Although climatic e...

  12. Early Mechanistic Events in Biotin Dissociation from Streptavidin

    SciTech Connect

    Hyre, D. E.

    2002-01-01

    The streptavidin-biotin system has provided a unique opportunity to investigate the molecular details of ligand dissociation pathways. An underlying mechanistic question is whether ligand dissociation proceeds with a relatively ordered process of bond breaking and ligand escape. Here we report a joint computational and crystallographic study of the earliest events in biotin dissociation. In molecular dynamics potential of mean force simulations, a water molecule from a defined access channel intercalated into the hydrogen bond between Asp 128 and biotin, bridging them and stabilizing an intermediate state. In forced biotin dissociation simulations, this event led to subsequent bond breaking steps and ligand escape. In equilibrium simulations, the water molecule was sometimes observed to move back to the access channel with re-formation of the biotin hydrogen bond. Analysis of streptavidin crystal structures revealed a close overlap of crystallographically defined and simulated waters in the water access channel. These results suggest that biotin dissociation is initiated by stochastic coupling of water entry with lengthening of a specific biotin hydrogen-bonding interaction.

  13. Early LHC Underlying Event Data - Findings and Surprises

    E-print Network

    Rick Field

    2010-10-18

    The CDF PYTHIA 6.2 Tune DW predictions of the LHC underlying event (UE) data at 900 GeV and 7 TeV are examined in detail. The behavior of the UE at the LHC is roughly what we expected. The new LHC PYTHIA 6.4 Tune Z1 does an even better job describing the UE data at 900 GeV and 7 TeV. However, the modeling of "min-bias" at the LHC (i.e. the overall inelastic cross section) is a very different story. No model describes all the features of "min-bias" collisions at 900 GeV and 7 TeV.

  14. Molecular replication

    NASA Technical Reports Server (NTRS)

    Orgel, Leslie E.

    1992-01-01

    Recent experiments demonstrating nonenzymatic replication in molecular systems are reviewed. The difficulties facing nonenzymatic replication are discussed along with specificity, fidelity, and mutation in nonenzymatic replication. The prospects for research in this area are considered.

  15. Live Cell Imaging of Early Autophagy Events: Omegasomes and Beyond

    PubMed Central

    Karanasios, Eleftherios; Stapleton, Eloise; Walker, Simon A.; Manifava, Maria; Ktistakis, Nicholas T.

    2013-01-01

    Autophagy is a cellular response triggered by the lack of nutrients, especially the absence of amino acids. Autophagy is defined by the formation of double membrane structures, called autophagosomes, that sequester cytoplasm, long-lived proteins and protein aggregates, defective organelles, and even viruses or bacteria. Autophagosomes eventually fuse with lysosomes leading to bulk degradation of their content, with the produced nutrients being recycled back to the cytoplasm. Therefore, autophagy is crucial for cell homeostasis, and dysregulation of autophagy can lead to disease, most notably neurodegeneration, ageing and cancer. Autophagosome formation is a very elaborate process, for which cells have allocated a specific group of proteins, called the core autophagy machinery. The core autophagy machinery is functionally complemented by additional proteins involved in diverse cellular processes, e.g. in membrane trafficking, in mitochondrial and lysosomal biology. Coordination of these proteins for the formation and degradation of autophagosomes constitutes the highly dynamic and sophisticated response of autophagy. Live cell imaging allows one to follow the molecular contribution of each autophagy-related protein down to the level of a single autophagosome formation event and in real time, therefore this technique offers a high temporal and spatial resolution. Here we use a cell line stably expressing GFP-DFCP1, to establish a spatial and temporal context for our analysis. DFCP1 marks omegasomes, which are precursor structures leading to autophagosomes formation. A protein of interest (POI) can be marked with either a red or cyan fluorescent tag. Different organelles, like the ER, mitochondria and lysosomes, are all involved in different steps of autophagosome formation, and can be marked using a specific tracker dye. Time-lapse microscopy of autophagy in this experimental set up, allows information to be extracted about the fourth dimension, i.e. time. Hence we can follow the contribution of the POI to autophagy in space and time. PMID:23929131

  16. Identification of frequent La Niña events during the early 1800s in the east equatorial Pacific

    NASA Astrophysics Data System (ADS)

    Druffel, Ellen R. M.; Griffin, Sheila; Vetter, Desiree; Dunbar, Robert B.; Mucciarone, David M.

    2015-03-01

    We report measurements of near monthly ?14C and ?18O during selected decades from an east equatorial Pacific coral that grew during the past four centuries. We find that El Niño events occurred regularly during the late 1700s. During the early 1800s, El Niño events occurred less often, and La Niña conditions prevailed, which were accompanied by unprecedented, low cool season ?14C values and high cool season ?18O values. These results indicate that shallow overturning water (e.g., Central Mode Water) from the North Pacific was likely an important source of water to the Galapagos area during the early 1800s.

  17. Blunt splenic injury: are early adverse events related to trauma, nonoperative management, or surgery?

    PubMed Central

    Frandon, Julien; Rodiere, Mathieu; Arvieux, Catherine; Vendrell, Anne; Boussat, Bastien; Sengel, Christian; Broux, Christophe; Bricault, Ivan; Ferretti, Gilbert; Thony, Frédéric

    2015-01-01

    PURPOSE We aimed to compare clinical outcomes and early adverse events of operative management (OM), nonoperative management (NOM), and NOM with splenic artery embolization (SAE) in blunt splenic injury (BSI) and identify the prognostic factors. METHODS Medical records of 136 consecutive patients with BSI admitted to a trauma center from 2005 to 2010 were retrospectively reviewed. Patients were separated into three groups: OM, NOM, and SAE. We focused on associated injuries and early adverse events. Multivariate analysis was performed on 23 prognostic factors to find predictors. RESULTS The total survival rate was 97.1%, with four deaths all occurred in the OM group. The spleen salvage rate was 91% in NOM and SAE. At least one adverse event was observed in 32.8%, 62%, and 96% of patients in NOM, SAE, and OM groups, respectively (P < 0.001). We found significantly more deaths, infectious complications, pleural drainage, acute renal failures, and pancreatitis in OM and more pseudocysts in SAE. Six prognostic factors were statistically significant for one or more adverse events: simplified acute physiology score 2 ?25 for almost all adverse events, age ?50 years for acute respiratory syndrome, limb fracture for secondary bleeding, thoracic injury for pleural drainage, and at least one associated injury for pseudocyst. Adverse events were not related to the type of BSI management. CONCLUSION Patients with BSI present worse outcome and more adverse events in OM, but this is related to the severity of injury. The main predictor of adverse events remains the severity of injury. PMID:26081719

  18. Evidence for an early pliocene cold event in the southern oceans

    SciTech Connect

    Burckle, L.H.; Mortlock, R.A. ); Rudolph, S. )

    1993-01-01

    Although it is generally agreed that the early Pliocene witnessed the last great climate warming before the onset of Northern Hemisphere glaciation, it is generally not recognized that this time interval also witnessed what appear to be major glaciations in both northern and southern Hemispheres. This describes a study of brief, intense warm events in the early Pliocene as well as evidence for at least one major glaciation during this time interval. 13 refs.

  19. Temporal separation of replication and transcription during S-phase progression

    PubMed Central

    Meryet-Figuiere, Matthieu; Alaei-Mahabadi, Babak; Ali, Mohamad Moustafa; Mitra, Sanhita; Subhash, Santhilal; Pandey, Gaurav Kumar; Larsson, Erik; Kanduri, Chandrasekhar

    2014-01-01

    Transcriptional events during S-phase are critical for cell cycle progression. Here, by using a nascent RNA capture assay coupled with high-throughput sequencing, we determined the temporal patterns of transcriptional events that occur during S-phase. We show that genes involved in critical S-phase-specific biological processes such as nucleosome assembly and DNA repair have temporal transcription patterns across S-phase that are not evident from total RNA levels. By comparing transcription timing with replication timing in S-phase, we show that early replicating genes show increased transcription late in S-phase whereas late replicating genes are predominantly transcribed early in S-phase. Global anti-correlation between replication and transcription timing was observed only based on nascent RNA but not total RNA. Our data provides a detailed view of ongoing transcriptional events during the S-phase of cell cycle, and supports that transcription and replication are temporally separated. PMID:25485504

  20. Replication and Control of Circular Bacterial Plasmids

    PubMed Central

    del Solar, Gloria; Giraldo, Rafael; Ruiz-Echevarría, María Jesús; Espinosa, Manuel; Díaz-Orejas, Ramón

    1998-01-01

    An essential feature of bacterial plasmids is their ability to replicate as autonomous genetic elements in a controlled way within the host. Therefore, they can be used to explore the mechanisms involved in DNA replication and to analyze the different strategies that couple DNA replication to other critical events in the cell cycle. In this review, we focus on replication and its control in circular plasmids. Plasmid replication can be conveniently divided into three stages: initiation, elongation, and termination. The inability of DNA polymerases to initiate de novo replication makes necessary the independent generation of a primer. This is solved, in circular plasmids, by two main strategies: (i) opening of the strands followed by RNA priming (theta and strand displacement replication) or (ii) cleavage of one of the DNA strands to generate a 3?-OH end (rolling-circle replication). Initiation is catalyzed most frequently by one or a few plasmid-encoded initiation proteins that recognize plasmid-specific DNA sequences and determine the point from which replication starts (the origin of replication). In some cases, these proteins also participate directly in the generation of the primer. These initiators can also play the role of pilot proteins that guide the assembly of the host replisome at the plasmid origin. Elongation of plasmid replication is carried out basically by DNA polymerase III holoenzyme (and, in some cases, by DNA polymerase I at an early stage), with the participation of other host proteins that form the replisome. Termination of replication has specific requirements and implications for reinitiation, studies of which have started. The initiation stage plays an additional role: it is the stage at which mechanisms controlling replication operate. The objective of this control is to maintain a fixed concentration of plasmid molecules in a growing bacterial population (duplication of the plasmid pool paced with duplication of the bacterial population). The molecules involved directly in this control can be (i) RNA (antisense RNA), (ii) DNA sequences (iterons), or (iii) antisense RNA and proteins acting in concert. The control elements maintain an average frequency of one plasmid replication per plasmid copy per cell cycle and can “sense” and correct deviations from this average. Most of the current knowledge on plasmid replication and its control is based on the results of analyses performed with pure cultures under steady-state growth conditions. This knowledge sets important parameters needed to understand the maintenance of these genetic elements in mixed populations and under environmental conditions. PMID:9618448

  1. Early Events in Skin Appendage Formation: Induction of Epithelial Placodes and Condensation of Dermal Mesenchyme

    E-print Network

    Chuong, Cheng-Ming

    Early Events in Skin Appendage Formation: Induction of Epithelial Placodes and Condensation, University of Southern California, Los Angeles, California, U.S.A. The formation of skin appendages of skin appendage formation: induction. Key words: adhesion molecules/BMP/embryonic induction

  2. Early View (EV): 1-EV phylogenies and geological events). In light of this, vicari-

    E-print Network

    Penz, Carla

    ). Much work has focused on how geological processes shaped this region and influenced its biota (HoornEarly View (EV): 1-EV phylogenies and geological events). In light of this, vicari- ance (Vullo et al. 2009). Finally, organisms might encounter pre-existing barriers during the process of range

  3. Let's Party! How To Plan Special Events and Raise Money in Early Childhood Programs.

    ERIC Educational Resources Information Center

    Rice, Judith Anne

    This guide for early childhood program administrators provides guidelines and makes suggestions for planning special events to facilitate opportunities for parents, children, teachers, and organizations to connect in ways that strengthen individuals and communities and raise money for the organization. Part 1, "Planning," focuses on organization,…

  4. Neighborhood Disadvantage, Stressful Life Events, and Adjustment among Mexican American Early Adolescents

    ERIC Educational Resources Information Center

    Roosa, Mark W.; Burrell, Ginger L.; Nair, Rajni L.; Coxe, Stefany; Tein, Jenn-Yun; Knight, George P.

    2010-01-01

    This study examined a stress process model in which stressful life events and association with delinquent peers mediated the relationship of neighborhood disadvantage to Mexican American early adolescents' mental health. The authors also proposed that child gender, child generation, and neighborhood informal social control would moderate the…

  5. Early events in speciation: Polymorphism for hybrid male sterility in Drosophila

    E-print Network

    Markow, Therese

    Early events in speciation: Polymorphism for hybrid male sterility in Drosophila Laura K. Reed of hybrid male sterility in crosses between Drosophila mojavensis and its sister species, Drosophila variation in the Drosophila melanogaster species group. Mutations that rescue inviable hybrids have been

  6. Evidence for kill-butchery events of early Upper Paleolithic age at Kostenki, Russia

    E-print Network

    Holliday, Vance T.

    Evidence for kill-butchery events of early Upper Paleolithic age at Kostenki, Russia John F in revised form 3 December 2009 Accepted 4 December 2009 Keywords: Zooarchaeology Kill-butchery sites Eastern of kill-butchery assemblages. Excavations at Kostenki 12 in 2002­2003 uncovered a large quantity

  7. Genetic Moderation of Stability in Attachment Security from Early Childhood to Age 18 Years: A Replication Study

    ERIC Educational Resources Information Center

    Raby, K. Lee; Roisman, Glenn I.; Booth-LaForce, Cathryn

    2015-01-01

    A longstanding question for attachment theory and research is whether genetically based characteristics of the child influence the development of attachment security and its stability over time. This study attempted to replicate and extend recent findings indicating that the developmental stability of attachment security is moderated by oxytocin…

  8. Early Reading Success and Its Relationship to Reading Achievement and Reading Volume: Replication of "10 Years Later"

    ERIC Educational Resources Information Center

    Sparks, Richard L.; Patton, Jon; Murdoch, Amy

    2014-01-01

    Cunningham and Stanovich reported a longitudinal investigation over 10 years that examined the unique influence of exposure to print in explaining individual differences on various measures of reading achievement and declarative (general) knowledge. The present study replicated their investigation with a larger number of participants and…

  9. Replication-Fork Dynamics

    PubMed Central

    Duderstadt, Karl E.; Reyes-Lamothe, Rodrigo; van Oijen, Antoine M.; Sherratt, David J.

    2014-01-01

    The proliferation of all organisms depends on the coordination of enzymatic events within large multiprotein replisomes that duplicate chromosomes. Whereas the structure and function of many core replisome components have been clarified, the timing and order of molecular events during replication remains obscure. To better understand the replication mechanism, new methods must be developed that allow for the observation and characterization of short-lived states and dynamic events at single replication forks. Over the last decade, great progress has been made toward this goal with the development of novel DNA nanomanipulation and fluorescence imaging techniques allowing for the direct observation of replication-fork dynamics both reconstituted in vitro and in live cells. This article reviews these new single-molecule approaches and the revised understanding of replisome operation that has emerged. PMID:23881939

  10. G1 cyclin driven DNA replication.

    PubMed

    Palou, Roger; Malik, Asrar; Palou, Gloria; Zeng, Fanli; Ren, Ping; Quintana, David G

    2015-12-17

    The mitotic cell cycle is driven by Cyclin-Dependent Kinases (CDK). CDK activation requires the binding of activatory subunits termed cyclins. Different waves of cyclins are expressed during the cell cycle, enabling CDKs to trigger phase specific events. For instance, S phase cyclins promote the initiation of DNA replication but not chromosome segregation. There are at least 2 explanations for how such regulation is achieved. According to one of the visions, cyclins confer intrinsic substrate specificity to the CDK catalytic subunit. Alternatively a quantitative model has been proposed, according to which ever-increasing CDK activity is required to trigger cell cycle events from G1 to M. If a quantitative control prevails, then an early cyclin should trigger later cycle events if accumulated at high enough levels at the right time and place. We show here that a G1 phase cyclin bears the potential to trigger DNA replication and promote S and G2 phase specific transcription. PMID:26176277

  11. Modulation of in vitro transformation and the early and late modes of DNA replication of uv-irradiation Syrian hamster cells by caffeine

    SciTech Connect

    Doniger, J.; DiPaolo, J.A.

    1981-09-01

    The effect of caffeine on post-uv DNA replication was studied to determine its relevance to carcinogenesis. The level of uv-induced transformed colonies of Syrian hamster embryo cells (HEC) was increased up to fivefold when caffeine was added to cells between 0 and 6 h post-uv. The greatest increase was observed when the interval between uv irradiation and caffeine addition was 4 h. Two modes of DNA replication occurred after uv irradiation. During the early mode (0 to 3 h post-uv) the size of nascent strands, as measured by alkaline sucrose sedimentation, was smaller than those in nonirradiated cells, whereas during the late mode they recovered to normal size. Caffeine inhibited the rate of elongation of nascent strands during the early mode. When caffeine was added immediately after uv irradiation, the conversion of the early mode to the late mode was inhibited. Studies on the effects of caffeine have now been extended to the late mode. While caffeine has little effect with the fd elements beginning from the 10th day after irradiation is connected with their proliferation but not with the migration out from lymphoid organs.

  12. The role of parent, teacher, and peer events in maintaining depressive symptoms during early adolescence.

    PubMed

    Herres, Joanna; Kobak, Roger

    2015-02-01

    Negative interpersonal events have been consistently identified as both antecedents and sequalae of adolescent depressive symptoms. However, little is known about the relative contributions of specific domains of interpersonal events (parents, peers or teachers) to the maintenance of depressive symptoms during early adolescence or whether a lack of positive interpersonal interactions plays a direct role in maintaining depressive symptoms. Further, few studies have examined whether positive interpersonal events moderate associations between negative events and adolescents' depressive symptoms. This study combined stress generation and exposure models to evaluate the contribution of daily events to the maintenance of depressive symptoms in a sample of 132 adolescents (53 % female) followed from ages 13 to 15. Daily phone diaries collected at age 14 assessed adolescents' negative and positive interactions with parents, teachers, and peers in a sample of adolescents from economically disadvantaged families. Negative peer events uniquely accounted for the maintenance of depressive symptoms over the 2 years period. Results did not differ by gender; however, positive parent events buffered the effects of negative parent events for females but not for males. Findings highlight the significance of peer relationships during a period of vulnerability for depressive symptoms. PMID:24975941

  13. Rearranged JC Virus Noncoding Control Regions Found in Progressive Multifocal Leukoencephalopathy Patient Samples Increase Virus Early Gene Expression and Replication Rate ? †

    PubMed Central

    Gosert, Rainer; Kardas, Piotr; Major, Eugene O.; Hirsch, Hans H.

    2010-01-01

    Polyomavirus JC (JCV) infects ?60% of the general population, followed by asymptomatic urinary shedding in ?20%. In patients with pronounced immunodeficiency, including HIV/AIDS, JCV can cause progressive multifocal leukoencephalopathy (PML), a devastating brain disease of high mortality. While JCV in the urine of healthy people has a linear noncoding control region called the archetype NCCR (at-NCCR), JCV in brain and cerebrospinal fluid (CSF) of PML patients bear rearranged NCCRs (rr-NCCRs). Although JCV NCCR rearrangements are deemed pathognomonic for PML, their role as a viral determinant is unclear. We sequenced JCV NCCRs found in CSF of eight HIV/AIDS patients newly diagnosed with PML and analyzed their effect on early and late gene expression using a bidirectional reporter vector recapitulating the circular polyomavirus early and late gene organization. The rr-NCCR sequences were highly diverse, but all increased viral early reporter gene expression in progenitor-derived astrocytes, glia-derived cells, and human kidney compared to the expression levels with the at-NCCR. The expression of simian virus 40 (SV40) large T antigen or HIV Tat expression in trans was associated with a strong increase of at-NCCR-controlled early gene expression, while rr-NCCRs were less responsive. The insertion of rr-NCCRs into the JCV genome backbone revealed higher viral replication rates for rr-NCCR compared to those of the at-NCCR JCV in human progenitor-derived astrocytes or glia cells, which was abrogated in SV40 large T-expressing COS-7 cells. We conclude that naturally occurring JCV rr-NCCR variants from PML patients confer increased early gene expression and higher replication rates compared to those of at-NCCR JCV and thereby increase cytopathology. PMID:20686041

  14. Replicating nucleosomes

    PubMed Central

    Ramachandran, Srinivas; Henikoff, Steven

    2015-01-01

    Eukaryotic replication disrupts each nucleosome as the fork passes, followed by reassembly of disrupted nucleosomes and incorporation of newly synthesized histones into nucleosomes in the daughter genomes. In this review, we examine this process of replication-coupled nucleosome assembly to understand how characteristic steady-state nucleosome landscapes are attained. Recent studies have begun to elucidate mechanisms involved in histone transfer during replication and maturation of the nucleosome landscape after disruption by replication. A fuller understanding of replication-coupled nucleosome assembly will be needed to explain how epigenetic information is replicated at every cell division. PMID:26269799

  15. Replication Proteins and Human Disease

    PubMed Central

    Jackson, Andrew P.; Laskey, Ronald A.; Coleman, Nicholas

    2014-01-01

    In this article, we discuss the significance of DNA replication proteins in human disease. There is a broad range of mutations in genes encoding replication proteins, which result in several distinct clinical disorders that share common themes. One group of replication proteins, the MCMs, has emerged as effective biomarkers for early detection of a range of common cancers. They offer practical and theoretical advantages over other replication proteins and have been developed for widespread clinical use. PMID:23881941

  16. Marine signature of early Holocene glacial events of the eastern margin of the Laurentide Ice Sheet

    NASA Astrophysics Data System (ADS)

    Pearce, Christof; Seidenkrantz, Marit-Solveig

    2015-04-01

    The gradual demise of the Laurentide Ice Sheet during the last deglaciation was characterized by large-scale and abrupt glacial events along its eastern margin. During the early Holocene, several episodes of iceberg and meltwater release originated from glacial advances and retreats mostly from the Hudson Strait region. Evidence for these events can be found in marine sediment cores from large areas of the Labrador Sea as increased input of ice-rafted debris and detrital carbonate. These events are especially clear from sites proximal to Hudson Strait and downstream the Labrador Current on the Labrador Shelf. In this study we present signals for several of such early Holocene ice sheet instabilities from more distal study sites. Sedimentological analyses of marine sediment cores from different bays in eastern Newfoundland revealed long distance transport of detrital carbonate during short-lived intervals of the early Holocene. The layers were investigated using a multi-proxy approach consisting of high resolution X-ray fluorescence (XRF) core scans, grain size analysis, quantitative X-ray diffraction (XRD), and biomarker analysis. The presence of detrital carbonate was most clearly found from elevated calcium - strontium ratios based on XRF core scanning results and further confirmed by increased content of calcite and dolomite and an ancient biomarker composition. Based on radiocarbon dating, the detrital carbonate layers can be linked to glacial events Heinrich 0, the Gold Cove event and possibly the Noble Inlet advance. The wide spread signature of these glacial events can be used for correlation of climate archives over a large geographic area. We propose that by detailed fingerprinting of the composition of these layers, they can be used as time-synchronous correlation tools, which may be used to infer past leads and lags in climatic and oceanographic variability as well as help to unravel unknown past marine radiocarbon reservoir ages in the Labrador Sea.

  17. ENERGETIC PARTICLE CROSS-FIELD PROPAGATION EARLY IN A SOLAR EVENT

    SciTech Connect

    Laitinen, T.; Dalla, S.; Marsh, M. S.

    2013-08-20

    Solar energetic particles (SEPs) have been observed to easily spread across heliographic longitudes, and the mechanisms responsible for this behavior remain unclear. We use full-orbit simulations of a 10 MeV proton beam in a turbulent magnetic field to study to what extent the spread across the mean field can be described as diffusion early in a particle event. We compare the full-orbit code results to solutions of a Fokker-Planck equation including spatial and pitch angle diffusion, and of one including also propagation of the particles along random-walking magnetic field lines. We find that propagation of the particles along meandering field lines is the key process determining their cross-field spread at 1 AU at the beginning of the simulated event. The mean square displacement of the particles an hour after injection is an order of magnitude larger than that given by the diffusion model, indicating that models employing spatial cross-field diffusion cannot be used to describe early evolution of an SEP event. On the other hand, the diffusion of the particles from their initial field lines is negligible during the first 5 hr, which is consistent with the observations of SEP intensity dropouts. We conclude that modeling SEP events must take into account the particle propagation along meandering field lines for the first 20 hr of the event.

  18. Early spatial and temporal events of human T-lymphotropic virus type 1 spread following blood-borne transmission in a rabbit model of infection.

    PubMed

    Haynes, Rashade A H; Zimmerman, Bevin; Millward, Laurie; Ware, Evan; Premanandan, Christopher; Yu, Lianbo; Phipps, Andrew J; Lairmore, Michael D

    2010-05-01

    Human T-lymphotropic virus type 1 (HTLV-1) infection causes adult T-cell leukemia/lymphoma (ATL) and is associated with a variety of lymphocyte-mediated disorders. HTLV-1 transmission occurs by transmission of infected cells via breast-feeding by infected mothers, sexual intercourse, and contaminated blood products. The route of exposure and early virus replication events are believed to be key determinants of virus-associated spread, antiviral immune responses, and ultimately disease outcomes. The lack of knowledge of early events of HTLV-1 spread following blood-borne transmission of the virus in vivo hinders a more complete understanding of the immunopathogenesis of HTLV-1 infections. Herein, we have used an established animal model of HTLV-1 infection to study early spatial and temporal events of the viral infection. Twelve-week-old rabbits were injected intravenously with cell-associated HTLV-1 (ACH-transformed R49). Blood and tissues were collected at defined intervals throughout the study to test the early spread of the infection. Antibody and hematologic responses were monitored throughout the infection. HTLV-1 intracellular Tax and soluble p19 matrix were tested from ex vivo cultured lymphocytes. Proviral copy numbers were measured by real-time PCR from blood and tissue mononuclear leukocytes. Our data indicate that intravenous infection with cell-associated HTLV-1 targets lymphocytes located in both primary lymphoid and gut-associated lymphoid compartments. A transient lymphocytosis that correlated with peak virus detection parameters was observed by 1 week postinfection before returning to baseline levels. Our data support emerging evidence that HTLV-1 promotes lymphocyte proliferation preceding early viral spread in lymphoid compartments to establish and maintain persistent infection. PMID:20219918

  19. Early Events in the Pathogenesis of Foot-and-Mouth Disease in Cattle After Controlled Aerosol Exposure

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The goal of this study was to identify the primary sites of replication of foot-and-mouth disease virus (FMDV) in cattle subsequent to aerogenous inoculation. A novel aerosol inoculation method was developed to simulate natural, airborne transmission and thereby allow the identification of early rep...

  20. Early viral replication and induced or constitutive immunity in rainbow trout families with differential resistance to Infectious hematopoietic necrosis virus (IHNV)

    USGS Publications Warehouse

    Purcell, M.K.; LaPatra, S.E.; Woodson, J.C.; Kurath, G.; Winton, J.R.

    2010-01-01

    The main objective of this study was to assess correlates of innate resistance in rainbow trout full-sibling families that differ in susceptibility to Infectious hematopoietic necrosis virus (IHNV). As part of a commercial breeding program, full-sibling families were challenged with IHNV by waterborne exposure at the 1 g size to determine susceptibility to IHNV. Progeny from select families (N = 7 families) that varied in susceptibility (ranging from 32 to 90% cumulative percent mortality (CPM)) were challenged again at the 10 g size by intra-peritoneal injection and overall mortality, early viral replication and immune responses were evaluated. Mortality challenges included 20–40 fish per family while viral replication and immune response studies included 6 fish per family at each time point (24, 48 and 72 h post-infection (hpi)). CPM at the 1 g size was significantly correlated with CPM at the 10 g size, indicating that inherent resistance was a stable trait irrespective of size. In the larger fish, viral load was measured by quantitative reverse-transcriptase PCR in the anterior kidney and was a significant predictor of family disease outcome at 48 hpi. Type I interferon (IFN) transcript levels were significantly correlated with an individual's viral load at 48 and 72 hpi, while type II IFN gene expression was significantly correlated with an individual's viral load at 24 and 48 hpi. Mean family type I but not type II IFN gene expression was weakly associated with susceptibility at 72 hpi. There was no association between mean family susceptibility and the constitutive expression of a range of innate immune genes (e.g. type I and II IFN pathway genes, cytokine and viral recognition receptor genes). The majority of survivors from the challenge had detectable serum neutralizing antibody titers but no trend was observed among families. This result suggests that even the most resistant families experienced sufficient levels of viral replication to trigger specific immunity. In summary, disease outcome for each family was determined very early in the infection process and resistance was associated with lower early viral replication.

  1. Effects of 60 Hz electromagnetic fields on early growth in three plant species and a replication of previous results

    SciTech Connect

    Davis, M.S.

    1996-05-01

    In an attempt to replicate the findings of Smith et al., seeds of Raphanus sativus L. (radish), Sinapsis alba L. (mustard), and Hordeum vulgare L. (barley) were grown for between 9 and 21 days in continuous electromagnetic fields (EMFs) at ion-cyclotron resonance conditions for stimulation of Ca{sup 2+} (B{sub H} = 78.3 {micro}T, B{sub HAC} = 40 {micro}T peak-peak at 60 Hz, B{sub v} = 0). On harvesting, radish showed results similar to those of Smith et al. Dry stem weight and plant height were both significantly greater (Mann-Whitney tests, Ps < 0.05) in EMF-exposed plants than in control plants in each EMF experiment. Wet root weight was significantly greater in EMF-exposed plants in two out of three experiments, as were dry leaf weight, dry whole weight, and stem diameter. Dry root weight, wet leaf weight, and wet whole weight were significantly greater in EMF-exposed plants in one of three experiments. All significant differences indicated an increase in weight or size in the EMF-exposed plants. In each of the sham experiments, no differences between exposed and control plants were evident. Mustard plants failed to respond to the EMFs in any of the plant parameters measured. In one experiment, barley similarly failed to respond; but in another showed significantly greater wet root weight and significantly smaller stem diameter and dry seed weight at the end of the experiment in exposed plants compared to control plants. Although these results give no clue about the underlying bioelectromagnetic mechanism, they demonstrate that, at least for one EMF-sensitive biosystem, results can be independently replicated in another laboratory. Such replication is crucial in establishing the validity of bioelectromagnetic science.

  2. Dissemination of a highly virulent pathogen: tracking the early events that define infection.

    PubMed

    Gonzalez, Rodrigo J; Lane, M Chelsea; Wagner, Nikki J; Weening, Eric H; Miller, Virginia L

    2015-01-01

    The series of events that occurs immediately after pathogen entrance into the body is largely speculative. Key aspects of these events are pathogen dissemination and pathogen interactions with the immune response as the invader moves into deeper tissues. We sought to define major events that occur early during infection of a highly virulent pathogen. To this end, we tracked early dissemination of Yersinia pestis, a highly pathogenic bacterium that causes bubonic plague in mammals. Specifically, we addressed two fundamental questions: (1) do the bacteria encounter barriers in disseminating to draining lymph nodes (LN), and (2) what mechanism does this nonmotile bacterium use to reach the LN compartment, as the prevailing model predicts trafficking in association with host cells. Infection was followed through microscopy imaging in addition to assessing bacterial population dynamics during dissemination from the skin. We found and characterized an unexpected bottleneck that severely restricts bacterial dissemination to LNs. The bacteria that do not pass through this bottleneck are confined to the skin, where large numbers of neutrophils arrive and efficiently control bacterial proliferation. Notably, bottleneck formation is route dependent, as it is abrogated after subcutaneous inoculation. Using a combination of approaches, including microscopy imaging, we tested the prevailing model of bacterial dissemination from the skin into LNs and found no evidence of involvement of migrating phagocytes in dissemination. Thus, early stages of infection are defined by a bottleneck that restricts bacterial dissemination and by neutrophil-dependent control of bacterial proliferation in the skin. Furthermore, and as opposed to current models, our data indicate an intracellular stage is not required by Y. pestis to disseminate from the skin to draining LNs. Because our findings address events that occur during early encounters of pathogen with the immune response, this work can inform efforts to prevent or control infection. PMID:25611317

  3. Early prediction and characterization of high-impact world events using social media

    E-print Network

    Kalyanam, Janani; Poblete, Barbara; Lanckriet, Gert

    2015-01-01

    On-line social networks publish information about an enormous volume of real-world events almost instantly, becoming a primary source for breaking news. Many of the events reported in social media can be of high-impact to society, such as important political decisions, natural disasters and terrorist actions, but might go unnoticed in their early stages due to the overload of other information. We ask, is it possible to clearly and quickly identify which of these news events are going to have substantial impact before they actually become a trend in the network? We investigate real-world news discussed on Twitter for approximately 1 year, consisting of 5,234 news events that are composed of 43 million messages. We show that using just the first 5% of the events' lifetime evolution, we are able to predict with high precision the top 8% that have the most impact. We observe that events that have high impact present unique characteristics in terms of how they are adopted by the network and that these qualities a...

  4. An Early Warning System for Loan Risk Assessment Based on Rare Event Simulation

    NASA Astrophysics Data System (ADS)

    Zhou, Hong; Qiu, Yue; Wu, Yueqin

    System simulation is one of important tool for risk assessment. In this paper, a new method is presented to deal with credit risk assessment problems for commercial banks based on rare event simulation. The failure probability of repaying loans of listed company is taken as the criterion to measure the level of credit risk. The rare-event concept is adopted to construct the model of credit risk identification in commercial banks, and cross-entropy scheme is designed to implement the rare event simulation, based on which the loss probability can be assessed. Numerical experiments have shown that the method has a strong capability to identify the credit risk for commercial banks and offers a good tool for early warning.

  5. Rapid Determination of Event Source Parameters in Southern California for earthquake early warning

    NASA Astrophysics Data System (ADS)

    Allen, R. M.; Kanamori, H.

    2001-12-01

    The rapid increase in the number of seismic stations in earthquake prone regions, combined with the implementation of near real time data transmission technologies, provides the potential for earthquake early warning. In the absence of earthquake prediction methodologies in the foreseeable future, the rapid detection and analysis of a seismic event on its initiation, allowing the issuance of a ground motion warning of the order of seconds, is appealing. We present our efforts to design and implement such a system in southern California. The early warning systems currently operating in Mexico and Taiwan rely on significant distances (> 100 km) between the source and populated regions. In this scenario an early warning system can wait for several stations to detect an event, allowing the application of standard location and magnitude determination algorithms (a process that may take tens of seconds), and still issue a warning tens of seconds in advance of associated ground motion. The close proximity of fault zones to metropolitan areas in southern California precludes such an approach. Instead, we develop a system more similar to the UrEDAS warning system in Japan. The two event parameters needed are location and magnitude. The high density of seismic stations in southern California ( ~25 km spacing in populated areas) allows for an adequate location of events based solely on the first station to detect a P-arrival. The classical use of amplitude to determine magnitude is problematic due to its relatively high sensitivity to epicentral distance close to the source. Instead, we utilize the frequency dependence of the P-arrival to magnitude, which is less sensitive to epicentral distance. With this approach we estimate event magnitude with an accuracy of +/-1 magnitude unit using the P-arrival at one station only. As the P-arrival is recorded at additional stations, we average the magnitude estimates, which reduces the uncertainty. The event location and magnitude may then be used to estimate ground motion throughout the region using attenuation relations. Using the current TriNet infrastructure we expect to be able to reduce data transmission and analysis time sufficiently to be able to give zero to a few seconds warning prior to the onset of peak, damaging ground motion in the epicentral region. The warning time improves for locations further from the epicenter and, as the time-since-event initiation increases, the uncertainty in ground motion predictions decreases and warning messages can be updated.

  6. Elevated circulating branched chain amino acids are an early event in pancreatic adenocarcinoma development

    PubMed Central

    Kraft, Peter; Torrence, Margaret E.; Fiske, Brian P.; Yuan, Chen; Bao, Ying; Townsend, Mary K.; Tworoger, Shelley S.; Davidson, Shawn M.; Papagiannakopoulos, Thales; Yang, Annan; Dayton, Talya L.; Ogino, Shuji; Stampfer, Meir J.; Giovannucci, Edward L.; Qian, Zhi Rong; Rubinson, Douglas A.; Ma, Jing; Sesso, Howard D.; Gaziano, John Michael; Cochrane, Barbara B.; Liu, Simin; Wactawski–Wende, Jean; Manson, JoAnn E.; Pollak, Michael N.; Kimmelman, Alec C.; Souza, Amanda; Pierce, Kerry; Wang, Thomas J.; Gerszten, Robert E.; Fuchs, Charles S.; Heiden, Matthew G. Vander; Wolpin, Brian M.

    2014-01-01

    Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months1. PDAC has been linked with obesity and glucose intolerance2-4, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from pancreatic cancer cases and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched chain amino acids (BCAAs) are associated with a greater than 2–fold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years prior to diagnosis when occult disease is likely present. We show that plasma BCAAs are also elevated in mice with early stage pancreatic cancers driven by mutant Kras expression, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early stage disease. Together, these findings suggest that increased whole–body protein breakdown is an early event in development of PDAC. PMID:25261994

  7. Replication of an Inter-Disciplinary Approach to Early Education of Handicapped Children 0-3 Years.

    ERIC Educational Resources Information Center

    Smiley, Constance J.; And Others

    Presented is the guide to the Illinois project entitled "An Inter-Disciplinary Approach to Early Education of Handicapped Children Ages 0 - 3 Years" which includes information on funding and public awareness, diagnosis and evaluation, child development-home program, speech and language, structuring the day program, job descriptions and training,…

  8. The lncRNA NRON modulates HIV-1 replication in a NFAT-dependent manner and is differentially regulated by early and late viral proteins

    PubMed Central

    Imam, Hasan; Shahr Bano, Aalia; Patel, Paresh; Holla, Prasida; Jameel, Shahid

    2015-01-01

    A majority of the human genome is transcribed into noncoding RNAs, of which the functions of long noncoding RNAs (lncRNAs) are poorly understood. Many host proteins and RNAs have been characterized for their roles in HIV/AIDS pathogenesis, but there is only one lncRNA, NEAT1, which is shown to affect the HIV-1 life cycle. We profiled 90 disease-related lncRNAs and found NRON (noncoding repressor of Nuclear Factor of Activated T cells [NFAT]) to be one of several lncRNAs whose expression was significantly altered following HIV-1 infection. The regulation of NRON expression during the HIV-1 life cycle was complex; its levels were reduced by the early viral accessory protein Nef and increased by the late protein Vpu. Consequently, Nef and Vpu also modulated activity of the transcription factor NFAT. The knockdown of NRON enhanced HIV-1 replication through increased activity of NFAT and the viral LTR. Using siRNA-mediated NFAT knockdown, we show the effects of NRON on HIV-1 replication to be mediated by NFAT, and the viral Nef and Vpu proteins to modulate NFAT activity through their effects on NRON. These findings add the lncRNA, NRON to the vast repertoire of host factors utilized by HIV for infection and persistence. PMID:25728138

  9. Early Intervention with a Parent-Delivered Massage Protocol Directed at Tactile Abnormalities Decreases Severity of Autism and Improves Child-to-Parent Interactions: A Replication Study

    PubMed Central

    Silva, Louisa M. T.; Gabrielsen, Kristen R.; Budden, Sarojini S.; Buenrostro, Martha; Horton, Gretchen

    2015-01-01

    Tactile abnormalities are severe and universal in preschool children with autism. They respond well to treatment with a daily massage protocol directed at tactile abnormalities (QST massage for autism). Treatment is based on a model for autism proposing that tactile impairment poses a barrier to development. Two previous randomized controlled trials evaluating five months of massage treatment reported improvement of behavior, social/communication skills, and tactile and other sensory symptoms. This is the first report from a two-year replication study evaluating the protocol in 103 preschool children with autism. Parents gave daily treatment; trained staff gave weekly treatment and parent support. Five-month outcomes replicated earlier studies and showed normalization of receptive language (18%, P = .03), autistic behavior (32%, P = .006), total sensory abnormalities (38%, P = .0000005), tactile abnormalities (49%, P = .0002), and decreased autism severity (medium to large effect size, P = .008). In addition, parents reported improved child-to-parent interactions, bonding, and decreased parenting stress (44%, P = .00008). Early childhood special education programs are tasked with addressing sensory abnormalities and engaging parents in effective home programs. Until now, they have lacked research-based methods to do so. This program fulfills the need. It is recommended to parents and ECSE programs (ages 3–5) at autism diagnosis. PMID:25878901

  10. Early events in vascular injury in the rat induced by the phosphodiesterase IV inhibitor SCH 351591.

    PubMed

    Weaver, James L; Zhang, Jun; Knapton, Alan; Miller, Terry; Espandiari, Parvaneh; Smith, Roger; Gu, Yi-Zhong; Snyder, Ronald D

    2010-08-01

    Treatment with drugs from multiple classes induces vascular injury with medial necrosis, hemorrhage, endothelial damage, and inflammation. Previous research has suggested early events might be occurring well in advance of the full lesions that appear forty-eight to seventy-two hours after dosing with SCH 351591, a PDE IV inhibitor. This study was performed to study early events in detail. Rats were dosed with 20 mg/kg of drug by gavage and sacrificed at times between fifteen and 240 minutes after dosing. Tissues were collected for histopathological analysis and gene expression studies. Serum was collected for biomarker analysis. The data from biomarker analysis showed a three-part response with an early phase that was maximal at fifteen to thirty minutes, a second phase from forty-five to 180 minutes, and the third phase that was starting to rise at four hours. The first phase included increases in lymphocytes, serum histamine, and serum nitrite. The second phase shows continued elevation of serum nitrite. The third phase was marked by an increase in serum GRO/CINC-1. At fifteen minutes, histopathology showed activation of mast cells, but not degranulation. Increases in endothelial activation and perivascular inflammatory cells were first apparent at thirty minutes and increased through 240 minutes. PMID:20585143

  11. Early Events following Experimental Infection with Peste-Des-Petits Ruminants Virus Suggest Immune Cell Targeting

    PubMed Central

    Pope, Robert A.; Parida, Satya; Bailey, Dalan; Brownlie, Joe; Barrett, Thomas; Banyard, Ashley C.

    2013-01-01

    Peste-des-petits ruminants virus (PPRV) is a viral pathogen that causes a devastating plague of small ruminants. PPRV is an economically significant disease that continues to be a major obstacle to the development of sustainable agriculture across the developing world. The current understanding of PPRV pathogenesis has been heavily assumed from the closely related rinderpest virus (RPV) and other morbillivirus infections alongside data derived from field outbreaks. There have been few studies reported that have focused on the pathogenesis of PPRV and very little is known about the processes underlying the early stages of infection. In the present study, 15 goats were challenged by the intranasal route with a virulent PPRV isolate, Côte d’Ivoire ’89 (CI/89) and sacrificed at strategically defined time-points post infection to enable pre- and post-mortem sampling. This approach enabled precise monitoring of the progress and distribution of virus throughout the infection from the time of challenge, through peak viraemia and into a period of convalescence. Observations were then related to findings of previous field studies and experimental models of PPRV to develop a clinical scoring system for PPRV. Importantly, histopathological investigations demonstrated that the initial site for virus replication is not within the epithelial cells of the respiratory mucosa, as has been previously reported, but is within the tonsillar tissue and lymph nodes draining the site of inoculation. We propose that virus is taken up by immune cells within the respiratory mucosa which then transport virus to lymphoid tissues where primary virus replication occurs, and from where virus enters circulation. Based on these findings we propose a novel clinical scoring methodology for PPRV pathogenesis and suggest a fundamental shift away from the conventional model of PPRV pathogenesis. PMID:23418464

  12. Frequency, magnitude and character of hyperthermal events at the onset of the Early Eocene Climatic Optimum

    NASA Astrophysics Data System (ADS)

    Lauretano, V.; Littler, K.; Polling, M.; Zachos, J. C.; Lourens, L. J.

    2015-10-01

    Recent studies have shown that the Early Eocene Climatic Optimum (EECO) was preceded by a series of short-lived global warming events, known as hyperthermals. Here we present high-resolution benthic stable carbon and oxygen isotope records from ODP Sites 1262 and 1263 (Walvis Ridge, SE Atlantic) between ~ 54 and ~ 52 million years ago, tightly constraining the character, timing, and magnitude of six prominent hyperthermal events. These events, which include Eocene Thermal Maximum (ETM) 2 and 3, are studied in relation to orbital forcing and long-term trends. Our findings reveal an almost linear relationship between ?13C and ?18O for all these hyperthermals, indicating that the eccentricity-paced covariance between deep-sea temperature changes and extreme perturbations in the exogenic carbon pool persisted during these events towards the onset of the EECO, in accordance with previous observations for the Paleocene Eocene Thermal Maximum (PETM) and ETM2. The covariance of ?13C and ?18O during H2 and I2, which are the second pulses of the "paired" hyperthermal events ETM2-H2 and I1-I2, deviates with respect to the other events. We hypothesize that this could relate to a relatively higher contribution of an isotopically heavier source of carbon, such as peat or permafrost, and/or to climate feedbacks/local changes in circulation. Finally, the ?18O records of the two sites show a systematic offset with on average 0.2 ‰ heavier values for the shallower Site 1263, which we link to a slightly heavier isotopic composition of the intermediate water mass reaching the northeastern flank of the Walvis Ridge compared to that of the deeper northwestern water mass at Site 1262.

  13. Early maritime economy and El Nino events at Quebrada Tacahuay, Peru

    USGS Publications Warehouse

    Keefer, D.K.; DeFrance, Susan D.; Moseley, M.E.; Richardson, J. B., III; Satterlee, D.R.; Day-Lewis, A.

    1998-01-01

    The archaeological site of Quebrada Tacahuay, Peru, dates to 12,700 to 12,500 calibrated years before the present (10,770 to 10,530 carbon-14 years before the present). It contains some of the oldest evidence of maritime- based economic activity in the New World. Recovered materials include a hearth, lithic cutting tools and flakes, and abundant processed marine fauna, primarily seabirds and fish. Sediments below and above the occupation layer were probably generated by El Nino events, indicating that El Nino was active during the Pleistocene as well as during the early and middle Holocene.

  14. Rapid Eye Movement Sleep Behavioral Events: A New Marker for Neurodegeneration in Early Parkinson Disease?

    PubMed Central

    Sixel-Döring, Friederike; Trautmann, Ellen; Mollenhauer, Brit; Trenkwalder, Claudia

    2014-01-01

    Objective: To analyze potential markers in sleep for early recognition of neurodegenerative disease in newly diagnosed, unmedicated patients with Parkinson disease (PD) compared to controls. Methods: Videopolysomnography (vPSG) was available in 158 newly diagnosed, unmedicated patients with PD and 110 age-, sex-, and education-matched healthy controls (HC). Rapid eye movement (REM) sleep was analyzed for REM without atonia (RWA) and studied by review of time-synchronized video. Motor behaviors and/or vocalizations in REM sleep with a purposeful component other than comfort moves were identified as REM sleep behavioral events (RBE). Two or more events had to be present to be classified as “RBE positive.” RBE subjects included rapid eye movement sleep behavior disorder (RBD) and non-RBD subjects based on the presence or absence of RWA > 18.2%. Results: RBE were detected in 81 of 158 patients with de novo PD (51%) and 17 of 110 HC (15%) (P < 0.001). RBD was identified in 40/81 RBE-positive patients with PD (25% of all PD patients) and 2 of 17 RBE-positive HC (2% of all controls). RBE-positive patients showed no specific motor or neuropsychological features compared to RBE-negative patients. Patients with PD and HC with RBE had more REM sleep (P = 0.002) and a higher periodic leg movements in sleep index (P = 0.022) compared to subjects without RBE. Conclusion: This first description of REM sleep behavioral events (RBE) shows it occurs more frequently in patients with de novo Parkinson disease (PD) than in healthy controls and may be an early sign of neurodegeneration and precede rapid eye movement sleep behavior disorder (RBD). There is no specific phenotype of PD associated with newly defined RBE or RBD at this early stage. Citation: Sixel-Döring F; Trautmann E; Mollenhauer B; Trenkwalder C. Rapid eye movement sleep behavioral events: a new marker for neurodegeneration in early Parkinson disease? SLEEP 2014;37(3):431-438. PMID:24587564

  15. Evidence of systematic bias in sexual over- and underperception of naturally occurring events: a direct replication of Haselton (2003) in a more gender-equal culture.

    PubMed

    Bendixen, Mons

    2014-01-01

    Error Management Theory (Haselton and Buss, 2000; Haselton and Nettle, 2006) maintains that natural selection has engineered adaptations for judgment under uncertainty to minimize the overall cost of making errors, leading to universal biases in judgments of sexual interest in men and women. This study, using a sample of het erosexual Norwegian students (n = 308), was carried out as a direct replication of Haselton's (2003) original study of naturally occurring events of sexual misperception. The results strongly supported the main hypotheses in the original study, showing that women reported being subject to opposite-sex sexual overperception far more often relative to underperception, and that this difference was small for men. In support of Error Management Theory, and in contrast to Social Role / Structure Theory expectations, the pattern of misperception for women and men was largely invariant across studies and across demographic groups within a culture. The findings suggest that cross-national differences in the level of gender inequality do not influence reports of sexual over- and underperception in women and men. Beyond sex, factors associated with more sexual overperception relative to underperception were being single, young, and having attitudes condoning casual sex. PMID:25402231

  16. Early Cretaceous High Arctic Magmatism and the Oceanic Anoxic Event 1a

    NASA Astrophysics Data System (ADS)

    Planke, Sverre; Polteau, Stephane; Faleide, Jan Inge; Svensen, Henrik; Myklebust, Reidun; Midtkandal, Ivar; Corfu, Fernando

    2014-05-01

    The High Arctic Large Igneous Province (HALIP) comprises Early and Late Cretaceous igneous deposits extending from the Canadian Arctic Archipelago in the west to the east Siberian Island in the east. It also includes anomalously thick igneous crust in the Canada Basin. We have mapped out the distribution of HALIP volcanic extrusive and intrusive rocks in the Barents Sea based on field work and borehole data in Svalbard and extensive geophysical data in the offshore areas. The volcanic extrusive and intrusive rocks in the Barents Sea Large Igneous Province (BLIP) are present in a 700 000 km2 large region extending across the northern and eastern Barents Sea. The igneous complex is dominated by a large sill complex intruded into organic-rich Jurassic to Permian age sequences in the East Barents Basin, on Svalbard and on Franz Josef Land. Geochemical data suggest that the tholeiitic igneous rocks were likely formed during a short-lived melting event. New geochronology data (U/Pb on zircons) suggest that the igneous event occurred in the Early Aptian or Barremian. Marine and terrestrial Cretaceous shales and sandstones of the Carolinefjellet, Helvetiafjellet, and Rurikfjellet formations have recently been cored in four boreholes on Svalbard (the Longyearbyen CO2 Laboratory). We have completed a comprehensive analytical program of samples from the boreholes, including geochronology (Ar/Ar and zircon U/Pb), biostratigraphy (palynology), and geochemistry (ICP-MS, RockEval, TOC). In the boreholes, the Barremian-early Aptian Helvetiafjellet Formation is overlaid by early Aptian sapropel-rich shales of the Carolinefjellet Formation. Carbon isotope data reveal a negative excursion in this anoxic interval, most likely representing the Oceanic Anoxic Event 1a (OAE1a). The geochronology data suggest that the intrusive BLIP volcanism occurred at the tim e of the early Aptian OAE1a. We propose that the link between the BLIP and the OAE1a is a massive release of thermogenic methane from contact aureoles of thermally altered sediments surrounding the hot sill intrusions in the BLIP. We estimate that about 9000 Gt of carbon was potentially degassed from the contact aureoles in the East Barents Basin. A rapid release of isotopically light metamorphic greenhouse gases to the atmosphere is therefore a possible trigger for the OAE1a and the associated negative carbon isotope excursion. Subsequent lava degassing from the HALIP or the Ontong Java Plateau may have caused the subsequent increase in isotopically heavy carbon.

  17. Does Silent Reading Speed in Normal Adult Readers Depend on Early Visual Processes? Evidence from Event-Related Brain Potentials

    ERIC Educational Resources Information Center

    Korinth, Sebastian Peter; Sommer, Werner; Breznitz, Zvia

    2012-01-01

    Little is known about the relationship of reading speed and early visual processes in normal readers. Here we examined the association of the early P1, N170 and late N1 component in visual event-related potentials (ERPs) with silent reading speed and a number of additional cognitive skills in a sample of 52 adult German readers utilizing a Lexical…

  18. Increased Axonal Ribosome Numbers Is an Early Event in the Pathogenesis of Amyotrophic Lateral Sclerosis

    PubMed Central

    Verheijen, Mark H. G.; Peviani, Marco; Hendricusdottir, Rita; Bell, Erin M.; Lammens, Martin; Smit, August B.; Bendotti, Caterina; van Minnen, Jan

    2014-01-01

    Myelinating glia cells support axon survival and functions through mechanisms independent of myelination, and their dysfunction leads to axonal degeneration in several diseases. In amyotrophic lateral sclerosis (ALS), spinal motor neurons undergo retrograde degeneration, and slowing of axonal transport is an early event that in ALS mutant mice occurs well before motor neuron degeneration. Interestingly, in familial forms of ALS, Schwann cells have been proposed to slow disease progression. We demonstrated previously that Schwann cells transfer polyribosomes to diseased and regenerating axons, a possible rescue mechanism for disease-induced reductions in axonal proteins. Here, we investigated whether elevated levels of axonal ribosomes are also found in ALS, by analysis of a superoxide dismutase 1 (SOD1)G93A mouse model for human familial ALS and a patient suffering from sporadic ALS. In both cases, we found that the disorder was associated with an increase in the population of axonal ribosomes in myelinated axons. Importantly, in SOD1G93A mice, the appearance of axonal ribosomes preceded the manifestation of behavioral symptoms, indicating that upregulation of axonal ribosomes occurs early in the pathogenesis of ALS. In line with our previous studies, electron microscopy analysis showed that Schwann cells might serve as a source of axonal ribosomes in the disease-compromised axons. The early appearance of axonal ribosomes indicates an involvement of Schwann cells early in ALS neuropathology, and may serve as an early marker for disease-affected axons, not only in ALS, but also for other central and peripheral neurodegenerative disorders. PMID:24498056

  19. Environmental controls on marine ecosystems during the early Toarcian extinction event

    NASA Astrophysics Data System (ADS)

    Danise, Silvia; Twitchett, Richard J.

    2015-04-01

    The fossil record has the potential to provide valuable insights into species response to past climate change if paleontological data are combined with appropriate proxies of environmental change. In the early Toarcian (Early Jurassic, ˜183Ma ago) rapid warming coincided with a main perturbation in the carbon cycle, seal level rise, widespread deposition of organic-rich, black shales under anoxic conditions, increased weathering rates and a biotic crisis in the marine realm, with the extinction of approximately 5% of families and 26% of genera. Because of this complex suite of inter-linked environmental and oceanographic changes, a key challenge is to determine which of these were most influential in controlling specific aspects of extinction and ecological collapse. In this study we combine high resolution palaeontological and palaeoenvironmental data from the coastal sections of the Whitby Mudstone Formation in North Yorkshire, UK, to reconstruct how climate changes controlled the structure of benthic and nektonic communities through the event, over a time period of ˜1.7 Ma. We show that benthic and nektonic ecosystems became decoupled and were driven by different environmental variables. Although rapid warming has been invoked as the main trigger of this event, the palaeotemperature proxy was a poor predictor of marine community dynamics, and abiotic factors indirectly linked to temperature, such as change in seawater dissolved oxygen concentration and nutrient inputs, were more important.

  20. Stress Granule Components G3BP1 and G3BP2 Play a Proviral Role Early in Chikungunya Virus Replication

    PubMed Central

    Scholte, Florine E. M.; Tas, Ali; Albulescu, Irina C.; Žusinaite, Eva; Merits, Andres; Snijder, Eric J.

    2015-01-01

    ABSTRACT Stress granules (SGs) are protein-mRNA aggregates that are formed in response to environmental stresses, resulting in translational inhibition. SGs are generally believed to play an antiviral role and are manipulated by many viruses, including various alphaviruses. GTPase-activating protein (SH3 domain)-binding protein 1 (G3BP1) is a key component and commonly used marker of SGs. Its homolog G3BP2 is a less extensively studied SG component. Here, we demonstrate that Chikungunya virus (CHIKV) infection induces cytoplasmic G3BP1- and G3BP2-containing granules that differ from bona fide SGs in terms of morphology, composition, and behavior. For several Old World alphaviruses it has been shown that nonstructural protein 3 (nsP3) interacts with G3BPs, presumably to inhibit SG formation, and we have confirmed this interaction in CHIKV-infected cells. Surprisingly, CHIKV also relied on G3BPs for efficient replication, as simultaneous depletion of G3BP1 and G3BP2 reduced viral RNA levels, CHIKV protein expression, and viral progeny titers. The G3BPs colocalized with CHIKV nsP2 and nsP3 in cytoplasmic foci, but no colocalization with nsP1, nsP4, or dsRNA was observed. Furthermore, G3BPs could not be detected in a cellular fraction enriched for CHIKV replication/transcription complexes, suggesting that they are not directly involved in CHIKV RNA synthesis. Depletion of G3BPs did not affect viral entry, translation of incoming genomes, or nonstructural polyprotein processing but resulted in severely reduced levels of negative-stranded (and consequently also positive-stranded) RNA. This suggests a role for the G3BPs in the switch from translation to genome amplification, although the exact mechanism by which they act remains to be explored. IMPORTANCE Chikungunya virus (CHIKV) causes a severe polyarthritis that has affected millions of people since its reemergence in 2004. The lack of approved vaccines or therapeutic options and the ongoing explosive outbreak in the Caribbean underline the importance of better understanding CHIKV replication. Stress granules (SGs) are cytoplasmic protein-mRNA aggregates formed in response to various stresses, including viral infection. The RNA-binding proteins G3BP1 and G3BP2 are essential SG components. SG formation and the resulting translational inhibition are generally considered an antiviral response, and many viruses manipulate or block this process. Late in infection, we and others have observed CHIKV nonstructural protein 3 in cytoplasmic G3BP1- and G3BP2-containing granules. These virally induced foci differed from true SGs and did not appear to represent replication complexes. Surprisingly, we found that G3BP1 and G3BP2 were also needed for efficient CHIKV replication, likely by facilitating the switch from translation to genome amplification early in infection. PMID:25653451

  1. Novel three-dimensional organotypic liver bioreactor to directly visualize early events in metastatic progression.

    PubMed

    Yates, Clayton; Shepard, Chistopher R; Papworth, Glenn; Dash, Ajit; Beer Stolz, Donna; Tannenbaum, Steven; Griffith, Linda; Wells, Alan

    2007-01-01

    Metastatic seeding leads to most of the morbidity from carcinomas. However, little is known of this key event as current methods to study the cellular behaviors utilize nonrepresentative in vitro models or follow indirect subsequent developments in vivo. Therefore, we developed a system to visualize over a multiday to multiweek period the interactions between tumor cells and target organ parenchyma. We employ an ex vivo microscale perfusion culture system that provides a tissue-relevant environment to assess metastatic seeding behavior. The bioreactor recreates many features of the fluid flow, scale, and biological functionality of a hepatic parenchyma, a common site of metastatic spread for a wide range of carcinomas. As a test of this model, prostate and breast carcinoma cells were introduced. Tumor cell invasion and expansion could be observed by two-photon microscopy of red fluorescent protein (RFP)- and CellTracker-labeled carcinoma cells against a green fluorescent protein (GFP)-labeled hepatic tissue bed over a 14-day period. Tumors visible to the naked eye could be formed by day 25, without evident necrosis in the >0.3-mm tumor mass. These tumor cells failed to grow in the absence of the supporting three-dimensional (3D) hepatic microtissue, suggesting paracrine or stromal support function for the liver structure in tumor progression. Initial ultrastructural studies suggest that early during the tumor-parenchyma interactions, there are extensive interactions between and accommodations of the cancer and host cells, suggesting that the tumor-related epithelial-mesenchymal transition (EMT) reverts, at least transiently, to promote metastatic seeding. In sum, our 3D ex vivo organotypic liver tissue system presents a critical vehicle to examine tumor-host interactions during cancer metastasis and/or invasion. It also circumvents current limitations in assays to assess early events in metastasis, and provides new approaches to study molecular events during tumor progression. PMID:17419948

  2. Lithium-isotope evidence for enhanced silicate weathering during OAE 1a (Early Aptian Selli event)

    NASA Astrophysics Data System (ADS)

    Lechler, Maria; Pogge von Strandmann, Philip A. E.; Jenkyns, Hugh C.; Prosser, Giacomo; Parente, Mariano

    2015-12-01

    An abrupt rise in temperature, forced by a massive input of CO2 into the atmosphere, is commonly invoked as the main trigger for Oceanic Anoxic Events (OAEs). Global warming initiated a cascade of palaeoenvironmental perturbations starting with increased continental weathering and an accelerated hydrological cycle that delivered higher loads of nutrients to coastal areas, stimulating biological productivity. The end-result was widespread anoxia and deposition of black shales: the hallmarks of OAEs. In order to assess the role of weathering as both an OAE initiator and terminator (via CO2 sequestration) during the Early Aptian OAE 1a (Selli Event, ?120 Ma) the isotopic ratio of lithium isotopes was analysed in three sections of shallow-marine carbonates from the Pacific and Tethyan realms and one basinal pelagic section from the Tethyan domain. Because the isotopic composition of lithium in seawater is largely controlled by continental silicate weathering and high- and low-temperature alteration of basaltic material, a shift to lighter ?7Li values is expected to characterize OAEs. The studied sections illustrate this phenomenon: ?7Li values decrease to a minimum coincident with the negative carbon-isotope excursion that effectively records the onset of OAE 1a. A second negative ?7Li excursion occurs coeval with the minimum in strontium isotopes after the event. The striking similarity to the strontium-isotope record argues for a common driver. The formation and destruction (weathering) of an oceanic LIP could account for the parallel trend in both isotope systems. The double-spike in lithium isotopes is probably related to a change in weathering congruencies. Such a chemostratigraphy is consistent with the hypothesis that an increase in silicate weathering, in conjunction with organic-carbon burial, led to drawdown of atmospheric CO2 during the early Aptian OAE 1a.

  3. Characteristics of long recovery early VLF events observed by the North African AWESOME Network

    NASA Astrophysics Data System (ADS)

    Naitamor, S.; Cohen, M. B.; Cotts, B. R. T.; Ghalila, H.; Alabdoadaim, M. A.; Graf, K.

    2013-08-01

    Lightning strokes are capable of initiating disturbances in the lower ionosphere, whose recoveries persist for many minutes. These events are remotely sensed via monitoring subionospherically propagating very low frequency (VLF) transmitter signals, which are perturbed as they pass through the region above the lightning stroke. In this paper we describe the properties and characteristics of the early VLF signal perturbations, which exhibit long recovery times using subionospheric VLF transmitter data from three identical receivers located at Algiers (Algeria), Tunis (Tunisia), and Sebha (Libya). The results indicate that the observation of long recovery events depends strongly on the modal structure of the signal electromagnetic field and the distance from the disturbed region and the receiver or transmitter locations. Comparison of simultaneously collected data at the three sites indicates that the role of the causative lightning stroke properties (e.g., peak current and polarity), or that of transient luminous events may be much less important. The dominant parameter which determines the duration of the recovery time and amplitude appears to be the modal structure of the subionospheric VLF probe signal at the ionospheric disturbance, where scattering occurs, and the subsequent modal structure that propagates to the receiver location.

  4. Early detection of cell activation events by means of attenuated total reflection Fourier transform infrared spectroscopy

    NASA Astrophysics Data System (ADS)

    Titus, Jitto; Filfili, Chadi; Hilliard, Julia K.; Ward, John A.; Unil Perera, A. G.

    2014-06-01

    Activation of Jurkat T-cells in culture following treatment with anti-CD3 (Cluster of Differentiation 3) antibody is detectable by interrogating the treated T-cells using the Attenuated Total Reflection-Fourier Transform Infrared (ATR-FTIR) Spectroscopy technique. Cell activation was detected within 75 min after the cells encountered specific immunoglobulin molecules. Spectral markers noted following ligation of the CD3 receptor with anti CD3 antibody provides proof-of-concept that ATR-FTIR spectroscopy is a sensitive measure of molecular events subsequent to cells interacting with anti-CD3 Immunoglobulin G. The resultant ligation of the CD3 receptor results in the initiation of well defined, specific signaling pathways that parallel the measurable molecular events detected using ATR-FTIR. Paired t-test with post-hoc Bonferroni corrections for multiple comparisons has resulted in the identification of statistically significant spectral markers (p < 0.02) at 1367 and 1358 cm-1. Together, these data demonstrate that early treatment-specific cellular events can be measured by ATR-FTIR and that this technique can be used to identify specific agents via the responses of the cell biosensor at different time points postexposure.

  5. Alteration of tight junction proteins is an early event in psoriasis: putative involvement of proinflammatory cytokines.

    PubMed

    Kirschner, Nina; Poetzl, Claudia; von den Driesch, Peter; Wladykowski, Ewa; Moll, Ingrid; Behne, Martin J; Brandner, Johanna M

    2009-09-01

    Psoriasis is an inflammatory skin disease characterized by hyperproliferation of keratinocytes, impaired barrier function, and pronounced infiltration of inflammatory cells. Tight junctions (TJs) are cell-cell junctions that form paracellular barriers for solutes and inflammatory cells. Altered localization of TJ proteins in the epidermis was described in plaque-type psoriasis. Here we show that localization of TJ proteins is already altered in early-stage psoriasis. Occludin, ZO-1, and claudin-4 are found in more layers than in normal epidermis, and claudin-1 and -7 are down-regulated in the basal and in the uppermost layers. In plaque-type psoriasis, the staining patterns of occludin and ZO-1 do not change, whereas the claudins are further down-regulated. Near transmigrating granulocytes, all TJ proteins except for junctional adhesion molecule-A are down-regulated. Treatment of cultured keratinocytes with interleukin-1beta and tumor necrosis factor-alpha, which are present at elevated levels in psoriatic skin, results in an increase of transepithelial resistance at early time points and a decrease at later time points. Injection of interleukin-1beta into an ex vivo skin model leads to an up-regulation of occludin and ZO-1, resembling TJ protein alteration in early psoriasis. Our results show for the first time that alteration of TJ proteins is an early event in psoriasis and is not the consequence of the more profound changes found in plaque-type psoriasis. Our data indicate that cytokines are involved in alterations of TJ proteins observed in psoriasis. PMID:19661441

  6. Break-Induced DNA Replication

    PubMed Central

    Anand, Ranjith P.; Lovett, Susan T.; Haber, James E.

    2013-01-01

    Recombination-dependent DNA replication, often called break-induced replication (BIR), was initially invoked to explain recombination events in bacteriophage but it has recently been recognized as a fundamentally important mechanism to repair double-strand chromosome breaks in eukaryotes. This mechanism appears to be critically important in the restarting of stalled and broken replication forks and in maintaining the integrity of eroded telomeres. Although BIR helps preserve genome integrity during replication, it also promotes genome instability by the production of loss of heterozygosity and the formation of nonreciprocal translocations, as well as in the generation of complex chromosomal rearrangements. PMID:23881940

  7. Parvovirus replication.

    PubMed Central

    Berns, K I

    1990-01-01

    The members of the family Parvoviridae are among the smallest of the DNA viruses, with a linear single-stranded genome of about 5 kilobases. Currently the family is divided into three genera, two of which contain viruses of vertebrates and a third containing insect viruses. This review concentrates on the vertebrate viruses, with emphasis on recent advances in our insights into the molecular biology of viral replication. Traditionally the vertebrate viruses have been distinguished by the presence or absence of a requirement for a coinfection with a helper virus before productive infection can occur, hence the notion that the dependoviruses (adeno-associated viruses [AAV]) are defective. Recent data would suggest that not only is there a great deal of structural and genetic organizational similarity between the two types of vertebrate viruses, but also there is significant similarity in the molecular biology of productive replication. What differs is the physiological condition of the host cell that renders it permissive. Healthy dividing cells are permissive for productive replication by autonomous parvoviruses; such cells result in latent infection by dependoviruses. For a cell to become permissive for productive AAV replication, it must have been exposed to toxic conditions which activate a latent AAV genome. Such conditions can be caused by helper-virus infection or exposure to physical (UV light) or chemical (some carcinogens) agents. In this paper the molecular biology of replication is reviewed, with special emphasis on the role of the host and the consequences of viral infection for the host. PMID:2215424

  8. The influence of early phase remodeling events on the biomechanical properties of engineered vascular tissues

    PubMed Central

    Tosun, Zehra; Montoya, Carolina Villegas; McFetridge, Peter S.

    2011-01-01

    Objectives Over the last decade the use of ex vivo-derived materials designed for use as implant scaffolds has increased significantly. This is particularly so in the area of regenerative medicine, or tissue engineering, where the natural chemical and biomechanical properties has been shown to be advantageous. By focusing on detailed events that occur during early phase remodeling processes our objective was to detail progressive changes in graft biomechanics to further our understanding of these processes. Methods Using perfusion bioreactor system and acellular human umbilical veins (HUV) as a model 3D vascular scaffold, human myofibroblasts were seeded and cultured under either static or defined pulsatile conditions. Cell function in relation to graft mechanical properties were assessed. Results Cells were shown to have doubled in density from approximately 1 × 106 to 2 × 106 ± 0.4 × 106 cells/cm ringlet while static cultures remained unchanged. In both static and dynamic systems the materials compressive stiffness and ultimate tensile strength remained unchanged. However the Young’s modulus values increased significantly in the physiological range while in the failure range a significant reduction (66%) was shown under dynamic conditions. Conclusions We have shown that as pulse and flow conditions are modulated, complex mechanical changes are occurring that modifies the elastic modulus differentially in both physiological and failure ranges. It is clear that mechanical properties play an important role in graft patency, and that a dynamic relationship between structure and function occurs during graft remodeling. These investigations have shown as cells migrate into this model ex vivo scaffold significant variation in material elasticity occurs that may have important implications in our understanding of early stage vascular remodeling events. PMID:21872418

  9. Inflammation-induced microvascular insulin resistance is an early event in diet-induced obesity

    PubMed Central

    Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W.; Barrett, Eugene J.; Cao, Wenhong

    2015-01-01

    Endothelial dysfunction and vascular insulin resistance usually coexist and chronic inflammation engenders both. In the present study, we investigate the temporal relationship between vascular insulin resistance and metabolic insulin resistance. We assessed insulin responses in all arterial segments, including aorta, distal saphenous artery and the microvasculature, as well as the metabolic insulin responses in muscle in rats fed on a high-fat diet (HFD) for various durations ranging from 3 days to 4 weeks with or without sodium salicylate treatment. Compared with controls, HFD feeding significantly blunted insulin-mediated Akt (protein kinase B) and eNOS [endothelial nitric oxide (NO) synthase] phosphorylation in aorta in 1 week, blunted vasodilatory response in small resistance vessel in 4 weeks and microvascular recruitment in as early as 3 days. Insulin-stimulated whole body glucose disposal did not begin to progressively decrease until after 1 week. Salicylate treatment fully inhibited vascular inflammation, prevented microvascular insulin resistance and significantly improved muscle metabolic responses to insulin. We conclude that microvascular insulin resistance is an early event in diet-induced obesity and insulin resistance and inflammation plays an essential role in this process. Our data suggest microvascular insulin resistance contributes to the development of metabolic insulin resistance in muscle and muscle microvasculature is a potential therapeutic target in the prevention and treatment of diabetes and its related complications. PMID:26265791

  10. Early spring, severe frost events, and drought induce rapid carbon loss in high elevation meadows.

    PubMed

    Arnold, Chelsea; Ghezzehei, Teamrat A; Berhe, Asmeret Asefaw

    2014-01-01

    By the end of the 20th century, the onset of spring in the Sierra Nevada mountain range of California has been occurring on average three weeks earlier than historic records. Superimposed on this trend is an increase in the presence of highly anomalous "extreme" years, where spring arrives either significantly late or early. The timing of the onset of continuous snowpack coupled to the date at which the snowmelt season is initiated play an important role in the development and sustainability of mountain ecosystems. In this study, we assess the impact of extreme winter precipitation variation on aboveground net primary productivity and soil respiration over three years (2011 to 2013). We found that the duration of snow cover, particularly the timing of the onset of a continuous snowpack and presence of early spring frost events contributed to a dramatic change in ecosystem processes. We found an average 100% increase in soil respiration in 2012 and 2103, compared to 2011, and an average 39% decline in aboveground net primary productivity observed over the same time period. The overall growing season length increased by 57 days in 2012 and 61 days in 2013. These results demonstrate the dependency of these keystone ecosystems on a stable climate and indicate that even small changes in climate can potentially alter their resiliency. PMID:25207640

  11. Early Spring, Severe Frost Events, and Drought Induce Rapid Carbon Loss in High Elevation Meadows

    PubMed Central

    Arnold, Chelsea; Ghezzehei, Teamrat A.; Berhe, Asmeret Asefaw

    2014-01-01

    By the end of the 20th century, the onset of spring in the Sierra Nevada mountain range of California has been occurring on average three weeks earlier than historic records. Superimposed on this trend is an increase in the presence of highly anomalous “extreme” years, where spring arrives either significantly late or early. The timing of the onset of continuous snowpack coupled to the date at which the snowmelt season is initiated play an important role in the development and sustainability of mountain ecosystems. In this study, we assess the impact of extreme winter precipitation variation on aboveground net primary productivity and soil respiration over three years (2011 to 2013). We found that the duration of snow cover, particularly the timing of the onset of a continuous snowpack and presence of early spring frost events contributed to a dramatic change in ecosystem processes. We found an average 100% increase in soil respiration in 2012 and 2103, compared to 2011, and an average 39% decline in aboveground net primary productivity observed over the same time period. The overall growing season length increased by 57 days in 2012 and 61 days in 2013. These results demonstrate the dependency of these keystone ecosystems on a stable climate and indicate that even small changes in climate can potentially alter their resiliency. PMID:25207640

  12. Early Events in the Nonadiabatic Relaxation Dynamics of 4-(N,N-Dimethylamino)benzonitrile.

    PubMed

    Kochman, Micha? A; Tajti, Attila; Morrison, Carole A; Miller, R J Dwayne

    2015-03-10

    4-(N,N-Dimethylamino)benzonitrile (DMABN) is the archetypal system for dual fluorescence. Several past studies, both experimental and theoretical, have examined the mechanism of its relaxation in the gas phase following photoexcitation to the S2 state, without converging to a single description. In this contribution, we report first-principles simulations of the early events involved in this process performed using the nonadiabatic trajectory surface hopping (TSH) approach in combination with the ADC(2) electronic structure method. ADC(2) is verified to reproduce the ground- and excited-state structures of DMABN in reasonably close agreement with previous theoretical benchmarks. The TSH simulations predict that internal conversion from the S2 state to the S1 takes place as early as 8.5 fs, on average, after the initial photoexcitation, and with no significant torsion of the dimethylamino group relative to the aromatic ring. As evidenced by supporting EOM-CCSD calculations, the population transfer from S2 to S1 can be attributed to the skeletal deformation modes of the aromatic ring and the stretching of the ring-dimethylamino nitrogen bond. The non- or slightly twisted locally excited structure is the predominant product of the internal conversion, and the twisted intramolecular charge transfer structure is formed through equilibration with the locally excited structure with no change of adiabatic state. These findings point toward a new interpretation of data from previous time-resolved experiments. PMID:26579762

  13. Inflammation-induced microvascular insulin resistance is an early event in diet-induced obesity.

    PubMed

    Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W; Barrett, Eugene J; Cao, Wenhong; Liu, Zhenqi

    2015-12-01

    Endothelial dysfunction and vascular insulin resistance usually coexist and chronic inflammation engenders both. In the present study, we investigate the temporal relationship between vascular insulin resistance and metabolic insulin resistance. We assessed insulin responses in all arterial segments, including aorta, distal saphenous artery and the microvasculature, as well as the metabolic insulin responses in muscle in rats fed on a high-fat diet (HFD) for various durations ranging from 3 days to 4 weeks with or without sodium salicylate treatment. Compared with controls, HFD feeding significantly blunted insulin-mediated Akt (protein kinase B) and eNOS [endothelial nitric oxide (NO) synthase] phosphorylation in aorta in 1 week, blunted vasodilatory response in small resistance vessel in 4 weeks and microvascular recruitment in as early as 3 days. Insulin-stimulated whole body glucose disposal did not begin to progressively decrease until after 1 week. Salicylate treatment fully inhibited vascular inflammation, prevented microvascular insulin resistance and significantly improved muscle metabolic responses to insulin. We conclude that microvascular insulin resistance is an early event in diet-induced obesity and insulin resistance and inflammation plays an essential role in this process. Our data suggest microvascular insulin resistance contributes to the development of metabolic insulin resistance in muscle and muscle microvasculature is a potential therapeutic target in the prevention and treatment of diabetes and its related complications. PMID:26265791

  14. Enhanced tocopherol levels during early germination events in Chamaerops humilis var. humilis seeds.

    PubMed

    Siles, Laura; Alegre, Leonor; Tijero, Verónica; Munné-Bosch, Sergi

    2015-10-01

    Most angiosperms accumulate vitamin E in the form of tocopherols in seeds, exerting a protective antioxidant role. However, several palm trees principally accumulate tocotrienols, rather than tocopherols, in seeds, as it occurs in other monocots. To unravel the protective role of either tocopherols or tocotrienols against lipid peroxidation during seed germination in Chamaerops humilis var. humilis; seed viability, natural and induced germination capacity, seed water content, malondialdehyde levels (as an indicator of the extent of lipid peroxidation) and vitamin E levels (including both tocopherols and tocotrienols) were examined at various germination phases in a simulated, natural seed bank. At the very early stages of germination (operculum removal), malondialdehyde levels increased 2.8-fold, to decrease later up to 74%, thus indicating a transient lipid peroxidation at early stages of germination. Tocopherol levels were absent in quiescent seeds and did not increase during operculum removal, but increased later presumably dampening malondialdehyde accumulation. Thereafter, tocopherols continued increasing, while lipid peroxidation levels decreased. By contrast, tocotrienols levels remained constant or even decreased as germination progressed, showing no correlation with lipid peroxidation levels. We hypothesize that despite their high tocotrienol content, seeds synthesize tocopherols during germination to protect lipids from peroxidation events. PMID:26241488

  15. Membrane remodeling, an early event in benzo[alpha]pyrene-induced apoptosis

    SciTech Connect

    Tekpli, Xavier; Rissel, Mary; Huc, Laurence; Catheline, Daniel; Sergent, Odile; Rioux, Vincent; Legrand, Philippe; Holme, Jorn A.; Dimanche-Boitrel, Marie-Therese; Lagadic-Gossmann, Dominique

    2010-02-15

    Benzo[alpha]pyrene (B[alpha]P) often serves as a model for mutagenic and carcinogenic polycyclic aromatic hydrocarbons (PAHs). Our previous work suggested a role of membrane fluidity in B[alpha]P-induced apoptotic process. In this study, we report that B[alpha]P modifies the composition of cholesterol-rich microdomains (lipid rafts) in rat liver F258 epithelial cells. The cellular distribution of the ganglioside-GM1 was markedly changed following B[alpha]P exposure. B[alpha]P also modified fatty acid composition and decreased the cholesterol content of cholesterol-rich microdomains. B[alpha]P-induced depletion of cholesterol in lipid rafts was linked to a reduced expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase). Aryl hydrocarbon receptor (AhR) and B[alpha]P-related H{sub 2}O{sub 2} formation were involved in the reduced expression of HMG-CoA reductase and in the remodeling of membrane microdomains. The B[alpha]P-induced membrane remodeling resulted in an intracellular alkalinization observed during the early phase of apoptosis. In conclusion, B[alpha]P altered the composition of plasma membrane microstructures through AhR and H{sub 2}O{sub 2} dependent-regulation of lipid biosynthesis. In F258 cells, the B[alpha]P-induced membrane remodeling was identified as an early apoptotic event leading to an intracellular alkalinization.

  16. Expression of tight-junction protein claudin-7 is an early event in gastric tumorigenesis.

    PubMed

    Johnson, Adam H; Frierson, Henry F; Zaika, Alexander; Powell, Steven M; Roche, James; Crowe, Sheila; Moskaluk, Christopher A; El-Rifai, Wa'el

    2005-08-01

    Trefoil factor-1 (Tff1) expression is remarkably down-regulated in nearly all human gastric cancers. Therefore, we used the Tff1 knockout mouse model to detect molecular changes in preneoplastic gastric dysplasia. Oligonucleotide microarray gene expression analysis of gastric dysplasia of Tff1-/- mice was compared to that of normal gastric mucosa of wild-type mice. The genes most overexpressed in Tff1-/- mice included claudin-7 (CLDN7), early growth response-1 (EGR1), and epithelial membrane protein-1 (EMP1). Quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry showed that Cldn7 was overexpressed in all 10 Tff1-/- gastric dysplasia samples. Comparison with our serial analysis of gene expression database of human gastric cancer revealed similar deregulation in human gastric cancers. Quantitative real-time reverse transcriptase-polymerase chain reaction of human gastric adenocarcinoma samples indicated that, of these three genes, CLDN7 was the most frequently up-regulated gene. Using immunohistochemistry, both mouse and human gastric glands overexpressed Cldn7 in dysplastic but not surrounding normal glands. Cldn7 expression was observed in 30% of metaplasia, 80% of dysplasia, and 70% of gastric adenocarcinomas. Interestingly, 82% of human intestinal-type gastric adenocarcinomas expressed Cldn7 whereas diffuse-type gastric adenocarcinomas did not (P < 0.001). These results suggest that Cldn7 expression is an early event in gastric tumorigenesis that is maintained throughout tumor progression. PMID:16049341

  17. Combination therapy including CpG oligodeoxynucleotides and entecavir induces early viral response and enhanced inhibition of viral replication in a woodchuck model of chronic hepadnaviral infection.

    PubMed

    Meng, Zhongji; Zhang, Xiaoyong; Pei, Rongjuan; Zhang, Ejuan; Kemper, Thekla; Vollmer, Jörg; Davis, Heather L; Glebe, Dieter; Gerlich, Wolfram; Roggendorf, Michael; Lu, Mengji

    2016-01-01

    CpG oligodeoxynucleotides (ODNs) stimulate immune cells via TLR9 and are potentially useful immunomodulators for the treatment of chronic viral infections. In the present study, different classes of CpGs were tested for their capacities for innate immune activation and antiviral activities in the woodchuck model. A class P CpG ODN was found to stimulate interferon (IFN) production in woodchuck peripheral blood mononuclear cells (PBMCs) in vitro, and following subcutaneous administration in vivo, it was observed to induce IFN and MxA expression in woodchuck PBMCs. Combination treatment with CpG ODN and entecavir (ETV) led to effective suppression of the woodchuck hepatitis virus (WHV) load in the woodchucks, with early viral responses and inhibition of replication. The woodchuck hepatitis surface antigen (WHsAg) serum concentrations were strongly decreased by CpG and ETV together but not by either agent alone, indicating synergistic effects. However, viral control post-treatment was still transient, similar to that observed with ETV alone. Significantly elevated levels of serum aspartate aminotransferase (AST) but not of alanine aminotransferase (ALT) in some of the woodchucks receiving CpG ODN were noted, but these increases were resolved before the completion of treatment and were not associated with an elevated serum bilirubin level or coagulation disorders, suggesting the absence of a significant safety concern. PMID:26585244

  18. Constraints on early events in Martian history as derived from the cratering record

    SciTech Connect

    Barlow, N.G. )

    1990-08-30

    The shapes and densities of crater size-frequency distribution curves are used to constrain two major events early in Martian history: termination of high obliteration rates and viability of the multiple impact origin of the crustal dichotomy. Distribution curves of fresh craters superposed on uplands, intercrater plains, and ridged plains display shapes and densities indicative of formation prior to the end of heavy bombardment. This observation correlates with other geologic evidence, suggesting a major change in the erosional regime following the last major basin size impact (i.e., Argrye). In addition, the multisloped nature of the curves supports the idea that the downturn in the crater size-frequency distribution curves reflects the size-frequency distribution of the impactors rather than being the result of erosion. The crustal dichotomy formed prior to the heavy bombardment intermediate epoch based on distribution curves of knobby terrain; if the dichotomy resulted from a single gigantic impact, this observation places constraints on when this event happened. An alternate theory for dichotomy formation, the multiple-impact basin idea, is questioned: since distribution curves of large basins as well as heavy bombardment era units are not represented by a {minus}3 differential power law function, this study finds fewer basins missing on Mars compare to the Moon and Mercury than previously reported. The area covered by these missing basins is less than that covered the northern plains.

  19. Dephosphorylation of Ezrin as an Early Event in Renal Microvillar Breakdown and Anoxic Injury

    NASA Astrophysics Data System (ADS)

    Chen, Jing; Cohn, Jonathan A.; Mandel, Lazaro J.

    1995-08-01

    Disruption of the renal proximal tubule (PT) brush border is a prominent early event during ischemic injury to the kidney. The molecular basis for this event is unknown. Within the brush border, ezrin may normally link the cytoskeleton to the cell plasma membrane. Anoxia causes ezrin to dissociate from the cytoskeleton and also causes many cell proteins to become dephosphorylated in renal PTs. This study examines the hypothesis that ezrin dephosphorylation accompanies and may mediate the anoxic disruption of the rabbit renal PT. During normoxia, 73 ±. 3% of the cytoskeleton-associated (Triton-insoluble) ezrin was phosphorylated, but 88 ± 6% of dissociated (Triton-soluble) ezrin was dephosphorylated. Phosphorylation was on serine/threonine residues, since ezrin was not detectable by an antibody against phosphotyrosine. After 60 min of anoxia, phosphorylation of total intracellular ezrin significantly decreased from 72 ± 2% to 21 ± 9%, and ezrin association with the cytoskeleton decreased from 91 ± 2% to 58 ± 2%. Calyculin A (1 ?M), the serine/threonine phosphatase inhibitor, inhibited the dephosphorylation of ezrin during anoxia by 57% and also blocked the dissociation of ezrin from the cytoskeleton by 53%. Our results demonstrate that (i) the association of ezrin with the renal microvillar cytoskeleton is correlated with phosphorylation of ezrin serine/threonine residues and (ii) anoxia may cause disruption of the renal brush border by dephosphorylating ezrin and thereby dissociating the brush border membrane from the cytoskeleton.

  20. Diagnosis of second breast cancer events after initial diagnosis of early stage breast cancer.

    PubMed

    Buist, Diana S M; Abraham, Linn A; Barlow, William E; Krishnaraj, Arun; Holdridge, Regan C; Sickles, Edward A; Carney, Patricia A; Kerlikowske, Karla; Geller, Berta M

    2010-12-01

    To examine whether there are any characteristics of women or their initial tumors that might be useful for tailoring surveillance recommendations to optimize outcomes. We followed 17,286 women for up to 5 years after an initial diagnosis of ductal carcinoma in situ (DCIS) or early stage (I/II) invasive breast cancer diagnosed between 1996 and 2006. We calculated rates per 1,000 women years of recurrences and second breast primaries relative to demographics, risk factors, and characteristics of initial diagnosis: stage, treatment, mode of initial diagnosis. Nearly 4% had a second breast cancer event (314 recurrences and 344 second breast primaries). Women who used adjuvant hormonal therapy or were ? 80 years had the lowest rates of second events. Factors associated with higher recurrence and second primary rates included: initial DCIS or stage IIB, estrogen/progesterone receptor-negative, younger women (<50 years). Women with a family history or greater breast density had higher second primary rates, and women who received breast conserving surgery without radiation had higher recurrence rates. Roughly one-third of recurrences (37.6%) and second primaries (36.3%) were not screen-detected. Initial mode of diagnosis was a predictor of second events after adjusting for age, stage, primary treatment, and breast density. A recent negative mammogram should not falsely reassure physicians or women with new breast symptoms or changes because one-third of second cancers were interval cancers. This study does not provide any evidence in support of changing surveillance intervals for different subgroups. PMID:20700648

  1. Early pulmonary events of nose-only water pipe (shisha) smoking exposure in mice

    PubMed Central

    Nemmar, Abderrahim; Hemeiri, Ahmed Al; Hammadi, Naser Al; Yuvaraju, Priya; Beegam, Sumaya; Yasin, Javed; Elwasila, Mohamed; Ali, Badreldin H; Adeghate, Ernest

    2015-01-01

    Water pipe smoking (WPS) is increasing in popularity and prevalence worldwide. Convincing data suggest that the toxicants in WPS are similar to that of cigarette smoke. However, the underlying pathophysiologic mechanisms related to the early pulmonary events of WPS exposure are not understood. Here, we evaluated the early pulmonary events of nose-only exposure to mainstream WPS generated by commercially available honey flavored “moasel” tobacco. BALB/c mice were exposed to WPS 30 min/day for 5 days. Control mice were exposed using the same protocol to atmospheric air only. We measured airway resistance using forced oscillation technique, and pulmonary inflammation was evaluated histopathologically and by biochemical analysis of bronchoalveolar lavage (BAL) fluid and lung tissue. Lung oxidative stress was evaluated biochemically by measuring the level of reactive oxygen species (ROS), lipid peroxidation (LPO), reduced glutathione (GSH), catalase, and superoxide dismutase (SOD). Mice exposed to WPS showed a significant increase in the number of neutrophils (P < 0.05) and lymphocytes (P < 0.001). Moreover, total protein (P < 0.05), lactate dehydrogenase (P < 0.005), and endothelin (P < 0.05) levels were augmented in bronchoalveolar lavage fluid. Tumor necrosis factor ? (P < 0.005) and interleukin 6 (P < 0.05) concentrations were significantly increased in lung following the exposure to WPS. Both ROS (P < 0.05) and LPO (P < 0.005) in lung tissue were significantly increased, whereas the level and activity of antioxidants including GSH (P < 0.0001), catalase (P < 0.005), and SOD (P < 0.0001) were significantly decreased after WPS exposure, indicating the occurrence of oxidative stress. In contrast, airway resistance was not increased in WPS exposure. We conclude that subacute, nose-only exposure to WPS causes lung inflammation and oxidative stress without affecting pulmonary function suggesting that inflammation and oxidative stress are early markers of WPS exposure that precede airway dysfunction. Our data provide information on the initial steps involved in the respiratory effects of WPS, which constitute the underlying causal chain of reactions leading to the long-term effects of WPS. PMID:25780090

  2. A catastrophic event in Lake Geneva region during the Early Bronze Age?

    NASA Astrophysics Data System (ADS)

    Kremer, Katrina; Yrro, Blé; Marillier, François; Hilbe, Michael; Corboud, Pierre; Rachoud-Schneider, Anne-Marie; Girardclos, Stéphanie

    2013-04-01

    Similarly to steep oceanic continental margins, lake slopes can collapse, producing large sublacustrine landslides and tsunamis. Lake sediments are excellent natural archives of such mass movements and their study allows the reconstructions of these prehistoric events, such as the 563 AD large tsunami over Lake Geneva (Kremer et al, 2012). In Lake Geneva, more than 100 km of high-resolution seismic reflection profiles reveal the late Holocene sedimentation history. The seismic record shows a succession of five large lens-shaped seismic units (A to I), characterized by transparent/chaotic seismic facies with irregular lower boundaries, and interpreted as mass-movement deposits. These units are interbedded with parallel, continuous and strong amplitude reflections, interpreted as the 'background' lake sediments. The oldest dated mass movement (Unit D) covers a surface of 22 km2 in the deep basin, near the city of Lausanne. This deposit has an estimated minimum volume of 0.18 km3 and thus was very likely tsunamigenic (Kremer et al, 2012). A 12-m-long sediment core confirms the seismic interpretation of the mass movement unit and shows that the uppermost 3 m of Unit D are characterized by deformed hemipelagic sediments topped by a 5 cm thick turbidite. This deposit can be classified as a slump whose scar can be interpreted in the seismic data and visualized by multibeam bathymetry. This slump of Lausanne was likely triggered by an earthquake but a spontaneous slope collapse cannot be excluded (Girardclos et al, 2007). Radiocarbon dating of plant macro-remains reveals that the unit D happened during Early Bronze Age. Three other mass wasting deposits occurred during the same time period and may have been triggered during the same event, either by a single earthquake or by a tsunami generated by the slump of Lausanne. Although the exact trigger mechanism of the all these mass-wasting deposits remains unknown, a tsunami likely generated by this event may have affected the installation of palafittic villages on the shore of Lake Geneva during the Early Bronze Age. References: Girardclos S., Schmidt O.T., Sturm M., Ariztegui D., Pugin A., Anselmetti F.S., 2007, The 1996 AD delta collapse and large turbidite in Lake Brienz, Marine Geology (241), 137-154. Kremer K., Simpson G., Girardclos S., 2012, Giant Lake Geneva tsunami in 563 AD, Nature Geoscience (5), 756-757. This project is financed by the Swiss National Foundation project nr. 200021-121666/1 and the Fondation Ernest Boninchi.

  3. Subclinical alexithymia modulates early audio-visual perceptive and attentional event-related potentials

    PubMed Central

    Delle-Vigne, Dyna; Kornreich, Charles; Verbanck, Paul; Campanella, Salvatore

    2014-01-01

    Introduction: Previous studies have highlighted the advantage of using audio–visual oddball tasks (instead of unimodal ones) in order to electrophysiologically index subclinical behavioral differences. Since alexithymia is highly prevalent in the general population, we investigated whether the use of various bimodal tasks could elicit emotional effects in low- vs. high-alexithymic scorers. Methods: Fifty students (33 females and 17 males) were split into groups based on low and high scores on the Toronto Alexithymia Scale (TAS-20). During event-related potential (ERP) recordings, they were exposed to three kinds of audio–visual oddball tasks: neutral-AVN—(geometrical forms and bips), animal-AVA—(dog and cock with their respective shouts), or emotional-AVE—(faces and voices) stimuli. In each condition, participants were asked to quickly detect deviant events occurring amongst a train of repeated and frequent matching stimuli (e.g., push a button when a sad face–voice pair appeared amongst a train of neutral face–voice pairs). P100, N100, and P300 components were analyzed: P100 refers to visual perceptive and attentional processing, N100 to auditory ones, and the P300 relates to response-related stages, involving memory processes. Results: High-alexithymic scorers presented a particular pattern of results when processing the emotional stimulations, reflected in early ERP components by increased P100 and N100 amplitudes in the emotional oddball tasks [P100: F(2, 48) = 20,319, p < 0.001; N100: F(2, 96) = 8,807, p = 0.001] as compared to the animal or neutral ones. Indeed, regarding the P100, subjects exhibited a higher amplitude in the AVE condition (8.717 ?V), which was significantly different from that observed during the AVN condition (4.382 ?V, p < 0.001). For the N100, the highest amplitude was found in the AVE condition (?4.035 ?V) and the lowest was observed in the AVN condition (?2.687 ?V, p = 0.003). However, no effect was found on the later P300 component. Conclusions: Our findings suggest that high-alexithymic scorers require heightened early attentional resources in comparison to low scorers, particularly when confronted with emotional bimodal stimuli. PMID:24624070

  4. Over-expression of 14-3-3zeta is an early event in oral cancer

    PubMed Central

    Matta, Ajay; Bahadur, Sudhir; Duggal, Ritu; Gupta, Siddhartha D; Ralhan, Ranju

    2007-01-01

    Background The functional and clinical significance of 14-3-3 proteins in human cancers remain largely undetermined. Earlier, we have reported differential expression of 14-3-3? mRNA in oral squamous cell carcinoma (OSCC) by differential display. Methods The clinical relevance of 14-3-3? protein in oral tumorigenesis was determined by immunohistochemistry in paraffin embedded sections of oral pre-malignant lesions (OPLs), OSCCs and histologically normal oral tissues and corroborated by Western Blotting. Co-immunoprecipitation assays were carried out to determine its association with NF?B, ?-catenin and Bcl-2. Results Intense immunostaining of 14-3-3? protein was observed in 61/89 (69%) OPLs and 95/120 (79%) OSCCs. Immunohistochemistry showed significant increase in expression of 14-3-3? protein from normal mucosa to OPLs to OSCCs (ptrend < 0.001). Significant increase in expression of 14-3-3? protein was observed as early as in hyperplasia (p = 0.009), with further elevation in moderate and severe dysplasia, that was sustained in OSCCs. These findings were validated by Western blotting. Using Co-immunoprecipitation, we demonstrated that 14-3-3? protein binds to NF?B, ?-catenin and Bcl-2, suggesting its involvement in cellular signaling, leading to proliferation of oral cancer cells. Conclusion Our findings suggest that over-expression of 14-3-3? is an early event in oral tumorigenesis and may have an important role in its development and progression. Thus, 14-3-3? may serve as an important molecular target for designing novel therapy for oral cancer. PMID:17764575

  5. Early Virological and Immunological Events in Asymptomatic Epstein-Barr Virus Infection in African Children

    PubMed Central

    Jayasooriya, Shamanthi; de Silva, Thushan I.; Njie-jobe, Jainaba; Sanyang, Chilel; Leese, Alison M.; Bell, Andrew I.; McAulay, Karen A.; Yanchun, Peng; Long, Heather M.; Dong, Tao; Whittle, Hilton C.; Rickinson, Alan B.; Rowland-Jones, Sarah L.; Hislop, Andrew D.; Flanagan, Katie L.

    2015-01-01

    Epstein-Barr virus (EBV) infection often occurs in early childhood and is asymptomatic. However, if delayed until adolescence, primary infection may manifest as acute infectious mononucleosis (AIM), a febrile illness characterised by global CD8+ T-cell lymphocytosis, much of it reflecting a huge expansion of activated EBV-specific CD8+ T-cells. While the events of AIM have been intensely studied, little is known about how these relate to asymptomatic primary infection. Here Gambian children (14–18 months old, an age at which many acquire the virus) were followed for the ensuing six months, monitoring circulating EBV loads, antibody status against virus capsid antigen (VCA) and both total and virus-specific CD8+ T-cell numbers. Many children were IgG anti-VCA-positive and, though no longer IgM-positive, still retained high virus loads comparable to AIM patients and had detectable EBV-specific T-cells, some still expressing activation markers. Virus loads and the frequency/activation status of specific T-cells decreased over time, consistent with resolution of a relatively recent primary infection. Six children with similarly high EBV loads were IgM anti-VCA-positive, indicating very recent infection. In three of these donors with HLA types allowing MHC-tetramer analysis, highly activated EBV-specific T-cells were detectable in the blood with one individual epitope response reaching 15% of all CD8+ T-cells. That response was culled and the cells lost activation markers over time, just as seen in AIM. However, unlike AIM, these events occurred without marked expansion of total CD8+ numbers. Thus asymptomatic EBV infection in children elicits a virus-specific CD8+ T-cell response that can control the infection without over-expansion; conversely, in AIM it appears the CD8 over-expansion, rather than virus load per se, is the cause of disease symptoms. PMID:25816224

  6. The strontium isotope seawater curve during the early Middle Miocene and its relation to paleoceanographic events

    SciTech Connect

    Hodell, D.A. . Dept. of Geology); Woodruff, F. . Dept. Geological Sciences)

    1992-01-01

    Breaks in slope of the strontium isotope seawater curve signal fundamental changes in either rates of continental weathering, seafloor spreading (i.e., tectonic reorganizations), or submarine dissolution of marine carbonates. The authors conducted a detailed study of the change in slope of the strontium isotopic seawater curve that occurred during the early middle Miocene in three Pacific DSDP sites (289, 574, and 588). The change in slope from the rapid rise in Sr-87/Sr-86 of the early Miocene (60 ppm/Ma) to the less rapid increase of the mid- and late Miocene (22 ppm/Ma) occurred between two periods of maximum [delta]C-13 values dated between 15.5 and 15.2 Ma. This internal was followed by relatively constant Sr-87/Sr-86 values (averaging 0.70878) between 15.2 and 14.2 Ma. Sr-87/Sr-86 ratios began to increase again after 14.2 Ma, but at a reduced rate compared to the early Miocene. The break in slope in Sr-87/Sr-86 preceded the mid-Miocene increase in [delta]O-18 that represents ice growth on Antarctica, which began at 14.9 Ma and increased rapidly after 14.2 Ma. In 2 out of 3 of the sites, the break in Sr-slope between 15.5 and 15.2 Ma is accompanied by a small, but significant, decrease in Sr-87/Sr-86 values. They speculate, that this decrease in Sr-87/Sr-86 may have been related to massive dissolution of older carbonate on the sea floor associated with NH2B (Neogene Hiatus 2 of Keller and Barron, 1983). This event may have important implications for changes in carbonate chemistry of the oceans. Numerical modeling of the strontium isotope budget will be used to test the feasibility of this mechanism and to estimate the volume and age of dissolved carbonate needed to produce the observed decrease in Sr-87/Sr-86.

  7. Imaging of early acceleration phase of the 2013-2014 Boso slow slip event

    NASA Astrophysics Data System (ADS)

    Fukuda, J.; Kato, A.; Obara, K.; Miura, S.; Kato, T.

    2014-12-01

    Based on GPS and seismic data, we examine the spatiotemporal evolution of a slow slip event (SSE) and associated seismic activity that occurred off the Boso peninsula, central Japan, from December 2013 to January 2014. We use GPS data from 71 stations of the GEONET and 6 stations operated by Earthquake Research Institute of the University of Tokyo and Tohoku University around the Boso peninsula. We apply a modified version of the Network Inversion Filter to the GPS time series at the 77 stations to estimate the spatiotemporal evolution of daily cumulative slip and slip rate on the subducting Philippine Sea plate. In addition, we create an improved earthquake catalog by applying a matched filter technique to continuous seismograms and examine the spatiotemporal relations between slow slip and seismicity. We find that the SSE started in early December 2013. The spatiotemporal evolution of slow slip and seismicity is divided into two distinct phases, an earlier slow phase from early to 30 December 2013 (Phase I) and a subsequent faster phase from 30 December 2013 to 9 January 2014 (Phase II). During Phase I, slip accelerated slowly up to a maximum rate of 1.6 m/yr with potentially accelerating?along-strike propagation at speeds on the order of 1 km/day or less and no accompanying seismicity. On the other hand, during Phase II, slip accelerated rapidly up to a maximum rate of 4.5 m/yr and then rapidly decelerated. The slip front propagated along strike at a constant speed of ~10 km/day. During the Phase II, slow slip was accompanied by seismic swarm activity that was highly correlated in space and time with slip rate, suggesting that the swarm activity was triggered by stress loading due to slow slip. Early slow acceleration of slip has not been identified in the past Boso SSEs in 1996, 2002, 2007, and 2011. It is not clear at this point whether the past Boso SSEs started with slow acceleration similarly to the 2013-2014 SSE. The transition from the slow to the faster phase shares some similarities with the nucleation of megathrust earthquakes inferred from foreshock activities, suggesting that SSEs may provide insights into the nucleation of large earthquakes.

  8. BioSystems xxx (2005) xxxxxx A network model of early events in epidermal growth factor receptor

    E-print Network

    Blinov, Michael L.

    2005-01-01

    BioSystems xxx (2005) xxx­xxx A network model of early events in epidermal growth factor receptor.06.014 BIO-2484; No. of Pages 16 #12;2 M.L. Blinov et al. / BioSystems xxx (2005) xxx­xxx lent character

  9. EFFECT OF ARSENICALS ON THE EXPRESSION OF CELL CYCLE PROTEINS AND EARLY SIGNALING EVENTS IN PRIMARY HUMAN KERATINOCYTES.

    EPA Science Inventory

    Effect of Arsenicals on the Expression of Cell Cycle Proteins and Early Signaling Events in Primary Human Keratinocytes.

    Mudipalli, A, Owen R. D. and R. J. Preston, Environmental Carcinogenesis Division, USEPA, RTP, NC 27711.

    Environmental exposure to arsenic is a m...

  10. The asymmetry of telomere replication contributes to replicative senescence heterogeneity.

    PubMed

    Bourgeron, Thibault; Xu, Zhou; Doumic, Marie; Teresa Teixeira, Maria

    2015-01-01

    In eukaryotes, the absence of telomerase results in telomere shortening, eventually leading to replicative senescence, an arrested state that prevents further cell divisions. While replicative senescence is mainly controlled by telomere length, the heterogeneity of its onset is not well understood. This study proposes a mathematical model based on the molecular mechanisms of telomere replication and shortening to decipher the causes of this heterogeneity. Using simulations fitted on experimental data obtained from individual lineages of senescent Saccharomyces cerevisiae cells, we decompose the sources of senescence heterogeneity into interclonal and intraclonal components, and show that the latter is based on the asymmetry of the telomere replication mechanism. We also evidence telomere rank-switching events with distinct frequencies in short-lived versus long-lived lineages, revealing that telomere shortening dynamics display important variations. Thus, the intrinsic heterogeneity of replicative senescence and its consequences find their roots in the asymmetric structure of telomeres. PMID:26468778

  11. The asymmetry of telomere replication contributes to replicative senescence heterogeneity

    PubMed Central

    Bourgeron, Thibault; Xu, Zhou; Doumic, Marie; Teresa Teixeira, Maria

    2015-01-01

    In eukaryotes, the absence of telomerase results in telomere shortening, eventually leading to replicative senescence, an arrested state that prevents further cell divisions. While replicative senescence is mainly controlled by telomere length, the heterogeneity of its onset is not well understood. This study proposes a mathematical model based on the molecular mechanisms of telomere replication and shortening to decipher the causes of this heterogeneity. Using simulations fitted on experimental data obtained from individual lineages of senescent Saccharomyces cerevisiae cells, we decompose the sources of senescence heterogeneity into interclonal and intraclonal components, and show that the latter is based on the asymmetry of the telomere replication mechanism. We also evidence telomere rank-switching events with distinct frequencies in short-lived versus long-lived lineages, revealing that telomere shortening dynamics display important variations. Thus, the intrinsic heterogeneity of replicative senescence and its consequences find their roots in the asymmetric structure of telomeres. PMID:26468778

  12. Early molecular events in the photoactive yellow protein: role of the chromophore photophysics.

    PubMed

    Changenet-Barret, Pascale; Espagne, Agathe; Charier, Sandrine; Baudin, Jean-Bernard; Jullien, Ludovic; Plaza, Pascal; Hellingwerf, Klaas J; Martin, Monique M

    2004-08-01

    We report a comparative study of the isomerization reaction in native and denatured photoactive yellow protein (PYP) and in various chromophore analogues in their trans deprotonated form. The excited-state relaxation dynamics was followed by subpicosecond transient absorption and gain spectroscopy. The free p-hydroxycinnamate (pCA(2-)) and its amide analogue (pCM(-)) are found to display a quite different transient spectroscopy from that of PYP. The excited-state deactivation leads to the formation of the ground-state cis isomer without any detectable intermediate with a mechanism comparable to trans-stilbene photoisomerization. On the contrary, the early stage of the excited-state deactivation of the free thiophenyl-p-hydroxycinnamate (pCT(-)) and of the denatured PYP is similar to that of the native protein. It involves the formation of an intermediate absorbing in the spectral region located between the bleaching and gain bands in less than 2 ps. However, in these two cases, the formation of the cis isomer has not been proved yet. This difference with pCA(-) and pCM(-) might result from the fact that, in the thioester substituted chromophore, simultaneous population of two quasi-degenerate excited states occurs upon excitation. This comparative study highlights the determining role of the chromophore structure and of its intrinsic properties in the primary molecular events in native PYP. PMID:15295641

  13. Visualization of Early Events in Acetic Acid Denaturation of HIV-1 Protease: A Molecular Dynamics Study

    PubMed Central

    Borkar, Aditi Narendra; Rout, Manoj Kumar; Hosur, Ramakrishna V.

    2011-01-01

    Protein denaturation plays a crucial role in cellular processes. In this study, denaturation of HIV-1 Protease (PR) was investigated by all-atom MD simulations in explicit solvent. The PR dimer and monomer were simulated separately in 9 M acetic acid (9 M AcOH) solution and water to study the denaturation process of PR in acetic acid environment. Direct visualization of the denaturation dynamics that is readily available from such simulations has been presented. Our simulations in 9 M AcOH reveal that the PR denaturation begins by separation of dimer into intact monomers and it is only after this separation that the monomer units start denaturing. The denaturation of the monomers is flagged off by the loss of crucial interactions between the ?-helix at C-terminal and surrounding ?-strands. This causes the structure to transit from the equilibrium dynamics to random non-equilibrating dynamics. Residence time calculations indicate that denaturation occurs via direct interaction of the acetic acid molecules with certain regions of the protein in 9 M AcOH. All these observations have helped to decipher a picture of the early events in acetic acid denaturation of PR and have illustrated that the ?-helix and the ?-sheet at the C-terminus of a native and functional PR dimer should maintain both the stability and the function of the enzyme and thus present newer targets for blocking PR function. PMID:21738569

  14. Autophagic degradation of aquaporin-2 is an early event in hypokalemia-induced nephrogenic diabetes insipidus

    PubMed Central

    Khositseth, Sookkasem; Uawithya, Panapat; Somparn, Poorichaya; Charngkaew, Komgrid; Thippamom, Nattakan; Hoffert, Jason D.; Saeed, Fahad; Michael Payne, D.; Chen, Shu-Hui; Fenton, Robert A.; Pisitkun, Trairak

    2015-01-01

    Hypokalemia (low serum potassium level) is a common electrolyte imbalance that can cause a defect in urinary concentrating ability, i.e., nephrogenic diabetes insipidus (NDI), but the molecular mechanism is unknown. We employed proteomic analysis of inner medullary collecting ducts (IMCD) from rats fed with a potassium-free diet for 1 day. IMCD protein quantification was performed by mass spectrometry using a label-free methodology. A total of 131 proteins, including the water channel AQP2, exhibited significant changes in abundance, most of which were decreased. Bioinformatic analysis revealed that many of the down-regulated proteins were associated with the biological processes of generation of precursor metabolites and energy, actin cytoskeleton organization, and cell-cell adhesion. Targeted LC-MS/MS and immunoblotting studies further confirmed the down regulation of 18 selected proteins. Electron microscopy showed autophagosomes/autophagolysosomes in the IMCD cells of rats deprived of potassium for only 1 day. An increased number of autophagosomes was also confirmed by immunofluorescence, demonstrating co-localization of LC3 and Lamp1 with AQP2 and several other down-regulated proteins in IMCD cells. AQP2 was also detected in autophagosomes in IMCD cells of potassium-deprived rats by immunogold electron microscopy. Thus, enhanced autophagic degradation of proteins, most notably including AQP2, is an early event in hypokalemia-induced NDI. PMID:26674602

  15. Early Events, Kinetic Intermediates and the Mechanism of Protein Folding in Cytochrome c

    PubMed Central

    Goldbeck, Robert A.; Chen, Eefei; Kliger, David S.

    2009-01-01

    Kinetic studies of the early events in cytochrome c folding are reviewed with a focus on the evidence for folding intermediates on the submillisecond timescale. Evidence from time-resolved absorption, circular dichroism, magnetic circular dichroism, fluorescence energy and electron transfer, small-angle X-ray scattering and amide hydrogen exchange studies on the t ? 1 ms timescale reveals a picture of cytochrome c folding that starts with the ~ 1-?s conformational diffusion dynamics of the unfolded chains. A fractional population of the unfolded chains collapses on the 1 – 100 ?s timescale to a compact intermediate IC containing some native-like secondary structure. Although the existence and nature of IC as a discrete folding intermediate remains controversial, there is extensive high time-resolution kinetic evidence for the rapid formation of IC as a true intermediate, i.e., a metastable state separated from the unfolded state by a discrete free energy barrier. Final folding to the native state takes place on millisecond and longer timescales, depending on the presence of kinetic traps such as heme misligation and proline mis-isomerization. The high folding rates observed in equilibrium molten globule models suggest that IC may be a productive folding intermediate. Whether it is an obligatory step on the pathway to the high free energy barrier associated with millisecond timescale folding to the native state, however, remains to be determined. PMID:19468320

  16. Autophagic degradation of aquaporin-2 is an early event in hypokalemia-induced nephrogenic diabetes insipidus.

    PubMed

    Khositseth, Sookkasem; Uawithya, Panapat; Somparn, Poorichaya; Charngkaew, Komgrid; Thippamom, Nattakan; Hoffert, Jason D; Saeed, Fahad; Michael Payne, D; Chen, Shu-Hui; Fenton, Robert A; Pisitkun, Trairak

    2015-01-01

    Hypokalemia (low serum potassium level) is a common electrolyte imbalance that can cause a defect in urinary concentrating ability, i.e., nephrogenic diabetes insipidus (NDI), but the molecular mechanism is unknown. We employed proteomic analysis of inner medullary collecting ducts (IMCD) from rats fed with a potassium-free diet for 1 day. IMCD protein quantification was performed by mass spectrometry using a label-free methodology. A total of 131 proteins, including the water channel AQP2, exhibited significant changes in abundance, most of which were decreased. Bioinformatic analysis revealed that many of the down-regulated proteins were associated with the biological processes of generation of precursor metabolites and energy, actin cytoskeleton organization, and cell-cell adhesion. Targeted LC-MS/MS and immunoblotting studies further confirmed the down regulation of 18 selected proteins. Electron microscopy showed autophagosomes/autophagolysosomes in the IMCD cells of rats deprived of potassium for only 1 day. An increased number of autophagosomes was also confirmed by immunofluorescence, demonstrating co-localization of LC3 and Lamp1 with AQP2 and several other down-regulated proteins in IMCD cells. AQP2 was also detected in autophagosomes in IMCD cells of potassium-deprived rats by immunogold electron microscopy. Thus, enhanced autophagic degradation of proteins, most notably including AQP2, is an early event in hypokalemia-induced NDI. PMID:26674602

  17. A Time Scale for Major Events in Early Mars Crustal Evolution

    NASA Technical Reports Server (NTRS)

    Frey, Herbert V.

    2004-01-01

    The population of visible and buried impact basins > 200 km diameter revealed by high resolution gridded MOLA data and the cumulative frequency curves derived for these pvide a basis for a chronology of major events in early martian history. The relative chronology can be given in terms of N(200) crater retention ages; 'absolute ages' can be assigued using the Hartmann-Neukum (H&N) model chronology. In terms of billions of H&N years, the crustal dichotomy formed by large impact basins at 4.12 +/- 0.08 BYA (N(200) = 3.0-3.2) and the global magnetic field died at about or slightly before the same time (4.15 +/- 0.08 BYA (N(200) = 3.5). In this chronology, the buried lowlands are approx. 120 my younger than the buried highlands, approx. 160 my younger than the highlands overall and approx. 340 my younger than the oldest crater retention surface we see, defined by the largest impact basins.

  18. Eye coding mechanisms in early human face event-related potentials.

    PubMed

    Rousselet, Guillaume A; Ince, Robin A A; van Rijsbergen, Nicola J; Schyns, Philippe G

    2014-01-01

    In humans, the N170 event-related potential (ERP) is an integrated measure of cortical activity that varies in amplitude and latency across trials. Researchers often conjecture that N170 variations reflect cortical mechanisms of stimulus coding for recognition. Here, to settle the conjecture and understand cortical information processing mechanisms, we unraveled the coding function of N170 latency and amplitude variations in possibly the simplest socially important natural visual task: face detection. On each experimental trial, 16 observers saw face and noise pictures sparsely sampled with small Gaussian apertures. Reverse-correlation methods coupled with information theory revealed that the presence of the eye specifically covaries with behavioral and neural measurements: the left eye strongly modulates reaction times and lateral electrodes represent mainly the presence of the contralateral eye during the rising part of the N170, with maximum sensitivity before the N170 peak. Furthermore, single-trial N170 latencies code more about the presence of the contralateral eye than N170 amplitudes and early latencies are associated with faster reaction times. The absence of these effects in control images that did not contain a face refutes alternative accounts based on retinal biases or allocation of attention to the eye location on the face. We conclude that the rising part of the N170, roughly 120-170 ms post-stimulus, is a critical time-window in human face processing mechanisms, reflecting predominantly, in a face detection task, the encoding of a single feature: the contralateral eye. PMID:25385898

  19. How the timing of weather events influences early development in a large mammal.

    PubMed

    Hendrichsen, D K; Tyler, N J C

    2014-07-01

    Capturing components of the weather that drive environment-animal interactions is a perennial problem in ecology. Identifying biologically significant elements of weather conditions in sensible statistics suitable for analysis of life history variation and population dynamics is central. Meteorological variables such as temperature, precipitation, and wind modulate rates of heat loss in animals, but analysis of their effects on endothermic species is complicated by the fact that their influence on energy balance is not invariably linear, even across the thermoneutral range. Rather, the thermal load imposed by a given set of weather conditions is a function of organisms' metabolic requirement, which, crucially, may vary spontaneously both seasonally and across different life phases. We propose that the endogenous component of variation in metabolic demand introduces a temporal dimension and that, as a consequence, the specific effect of meteorological variables on energy balance and attendant life history parameters is a function of the timing of weather events with respect to the organism's metabolic rhythm(s). To test this, we examined how a spontaneous increase in metabolic demand influenced the effect of weather on early development in a large mammal. Specifically, we examined interaction between the exponential rise in the energy requirements of pregnancy and depth of snow, which restricts dams' access to forage, on the body mass of reindeer calves (Rangifer tarandus) at weaning. As expected, we detected a significant temporal component: the specific negative effect of snow on weaning mass was not constant, but increased across pregnancy. The life history response was therefore better predicted by interaction between the magnitude and the timing of weather events than by their magnitude alone. To our knowledge, this is the first demonstration of the influence of an endogenous metabolic dynamic on the impact of weather on a life history trait in a free-living mammal. Evaluating weather variables with respect to endogenous variation in metabolic demand adds biological realism and is likely to improve understanding of the influence of environmental variation on life history traits in many ecological contexts. PMID:25163108

  20. Evaluation of an early warning system for glacial lake outburst flood (GLOF) events in Huaraz, Peru

    NASA Astrophysics Data System (ADS)

    McKinney, D. C.; Somos-Valenzuela, M. A.

    2014-12-01

    People in Cordillera Blanca range in Peru have a long history dealing with natural disasters associated to high mountains; particularly Glacier Lakes Outburst Flood (GLOF). Examples in the Cordillera Blanca vary from a GLOF that occurred in 1941 that killed more than 5000 people in the city of Huaraz to recent events from Lake Artison Baja in 2012 and Lake 513 on 2010, which were not devastating thanks to safety systems previously installed in those lakes. However, glaciers continue melting leaving new lakes or changing the characteristics of lakes that were previously controlled making safety systems obsolete that worked successfully in the past protecting communities downstream. Lake Palcacocha has evolved from being safe after the installation of a safety system in 1970 to an imminent source of GLOF risk due to the expansion that has occurred during the last 40 years increasing from a volume of 500,000 to 17 million m3. In response to this risk the community in Huaraz is planning an Early Warning System (EWS) that will allow the population to mobilize to a safe area in case a GLOF occurs. In this work we present an adaptation of the LifeSIM model to calculate the benefits from such an EWS using 2007 census data and a FLO-2D flood simulation model. The outputs are the number of people in Huaraz that could lose their life due to a GLOF. Our results indicate that without an EWS around 19,773 people could lose their life; whereas, if an EWS is installed the number of victims reduces to 7344. Finally, if mobilization of the affected population is improved the value reduces to 2865. The results show the importance of the EWS as well as informing and training the population to how to react if a GLOF occurs.

  1. Early events following maternal exposure to 5-fluorouracil lead to dysmorphology in cultured embryonic tissues.

    PubMed

    Shuey, D L; Buckalew, A R; Wilke, T S; Rogers, J M; Abbott, B D

    1994-12-01

    The chemotherapeutic agent 5-fluorouracil (5-FU) is teratogenic in a number of species, yet the mechanism(s) of its developmental toxicity are not fully understood. Administration of 5-FU to the pregnant CD rat on day 14 of gestation results in dose-dependent growth retardation and numerous malformations in near-term fetuses, including hindlimb defects and cleft palate. Following treatment, a number of rapid biochemical and cellular alterations are detectable in embryonic hindlimbs, craniofacial and other tissues, which include thymidylate synthetase (TS) inhibition and altered cell cycle progression. In order to assess the importance of these early events in 5-FU-induced dysmorphogenesis, embryonic mid-facial tissues and hindlimbs were dissected 3 or 6 hr after administration of 5-FU to the dam and placed in explant culture. After 5 days in culture, craniofacial explants were evaluated morphologically for palatal closure and growth was assessed by measuring total protein and DNA content. Hindlimb explants were stained for cartilage using alcian blue to evaluate development of the digits. Craniofacial explants cultured at either 3 or 6 hr after exposure exhibited dose-dependent growth retardation and defects of palatal fusion at the end of the culture period. Deficits in protein and DNA content were similar to those in craniofacial tissues that continued to develop in utero after treatment, although morphological defects in cultured explants did not correlate well with the incidence of cleft palate in vivo. Dose-dependent deficits in metatarsal and phalanx development were observed in hindlimb explants dissected either 3 or 6 hr after maternal treatment.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7778042

  2. Early interglacial carbonate-dilution events in the South China Sea: Implications for strengthened typhoon activities over subtropical East Asia

    NASA Astrophysics Data System (ADS)

    Huang, Enqing; Tian, Jun; Qiao, Peijun; Wan, Sui; Xie, Xin; Yang, Wenguang

    2015-10-01

    A compilation of many late Quaternary marine sediment records from the northern South China Sea (SCS) continental slope confirms 15-50% reductions in sedimentary calcium carbonate concentrations between 11.0 and 8.5 ka BP in the early Holocene. This low carbonate% event occurred at a time when the regional sea level rose from -50 m to -10 m, which drowned large areas of continental shelves especially those near and within the Taiwan Strait. This event is associated with a significant increase in bulk sedimentation rates on the upper continental slope and the relative abundance of fine-grained detritus. Sediment provenance analyses suggest a dominant terrigenous input from Taiwan and a minor contribution from Luzon during the low carbonate% event, similar to the background terrigenous deposition in other periods of the Holocene. Two comparable low carbonate% events, respectively from the beginning of marine isotope stages 5.5 and 7.3, have also been recognized, pointing to similar causal factors. While carbonate dissolution and carbonate accumulation rate should not have been responsible, increased terrigenous input and dilution is considered as the main cause for the recurrent low carbonate% events in early interglacials. We further hypothesize that, during early interglacials, fluvial sediment discharge from Taiwan and Luzon intensified due to stronger typhoon activities, and massive fine-grained sediments from these two end members may have been transported to the northern SCS continental slope via surface and deep ocean currents. The conjecture of strengthened typhoon activities over East Asia during the early Holocene is supported by high ocean heat contents in the West Pacific Warm Pool area with the prevailing La Niña-like conditions.

  3. The Early Toarcian Oceanic Anoxic Event and its sedimentary record in Switzerland

    NASA Astrophysics Data System (ADS)

    Fantasia, Alicia; Föllmi, Karl B.; Adatte, Thierry; Spangenberg, Jorge E.; Montero-Serrano, Jean-Carlos

    2015-04-01

    In the Jurassic period, the Early Toarcian Oceanic Anoxic Event (T-OAE), about 183 Ma ago, was a global perturbation of paleoclimatic and paleoenvironmental conditions. This episode was associated with a crisis in marine carbonate accumulation, climate warming, an increase in sea level, ocean acidification, enhanced continental weathering, whereas organic-rich sediments are noticeable for example in the Atlantic and in the Tethys. This episode is associated with a negative carbon excursion, which is recorded both in marine and terrestrial environments. The cause(s) of this environmental crisis remain(s) still controversial. Nevertheless, the development of negative ?13C excursions is commonly interpreted as due to the injection of isotopically-light carbon associated with gas hydrate dissociation, the thermal metamorphism of carbon-rich sediments and input of thermogenic and volcanogenic carbon related to the formation of the Karoo-Ferrar basaltic province in southern Gondwana (Hesselbo et al., 2000, 2007; Beerling et al., 2002; Cohen et al., 2004, 2007; McElwain et al., 2005, Beerling and Brentnall, 2007; Svensen et al., 2007; Hermoso et al., 2009, 2012; Mazzini et al., 2010). Several studies of the T-OAE have been conducted on sediments in central and northwest Europe, but only few data are available concerning the Swiss sedimentary records. Therefore, we focused on two sections in the Jura Plateau (canton Aargau): the Rietheim section (Montero-Serrano et al., submitted) and the Gipf section (current study). A multidisciplinary approach has been chosen and the tools to be used are based on sedimentological observations (sedimentary condensation, etc.), biostratigraphy, mineralogy (bulk-rock composition), facies and microfacies analysis (presence or absence of benthos), clay-mineralogy composition (climatic conditions), major and trace-element analyses (productivity, redox conditions, etc.), phosphorus (trophic levels, anoxia), carbon isotopes and organic-matter content (source of organic matter and preservation). The Posidonia Shales in northern Switzerland accumulated in a relatively slowly subsiding transition zone between the southwestern part of the Swabian basin and the eastern part of the Paris basin under fully marine conditions (Reisdorf et al., 2011). The negative carbon isotopic excursion characteristic of the Early Toarcian is well developed in the Gipf section although the bituminous sequence is considerably reduced in thickness relative to the Rietheim section. Indeed, the Plienbachian-Toarcian transition in the Gipf section probably lacks most of the tenuicostatum Zone and the Gipf Bed, which is a peculiar limestone bed showing an erosive base, correlates with the erosion horizons of the Variabilis Zone, Late Toarcian (Rieber, 1973; Reisdorf, 2011). The Gipf Bed is overlain by an alternation of condensed, fossil-rich marl and nodular limestone. The analysis of Swiss sections will assist us in the identification of the mechanisms implied in the condensation and/or erosion of parts of the Lower Toarcian Posidonia Shale. Therefore, it will improve our understanding of the general paleoceanographic conditions leading to the development of widespread oceanic anoxia during the early Toarcian.

  4. Deterioration of the memory for historic events in patients with mild cognitive impairment and early Alzheimer's disease.

    PubMed

    Leyhe, Thomas; Müller, Stephan; Eschweiler, Gerhard W; Saur, Ralf

    2010-12-01

    Retrograde memory decline in Alzheimer's disease (AD) and mild cognitive impairment (MCI) has been evaluated using tests of past public knowledge, such as famous personalities and events, and tests of autobiographical memory. Reports of temporal gradients (TG) in retrograde amnesia have been inconclusive. Here, we compared the remembrance of famous historic events by patients with amnesic MCI and early AD using the newly developed Historic Events Test (HET). The HET demands knowledge about famous public events of the past 60 years divided into five time segments, and consists of three tasks, Recognition, Dating Accuracy, and Contextual Memory. In both patient groups, the performance was worse than in healthy controls. Memory performance of all time segments was uniformly affected by this kind of retrograde amnesia. There was no evidence of a TG, and memory decline was similar in all three tasks of the HET. In contrast, for the same patients tested at the same time, we had previously found a TG for autobiographical memory with better preservation of remote than recent memories (Leyhe, Müller, Milian, Eschweiler, & Saur, 2009). We propose that recall of more frequently retrieved remote autobiographical facts and incidents has become independent of the hippocampus, whereas more seldomly retrieved recent autobiographical memory and knowledge of famous events remain dependent on the hippocampus and will thereby be susceptible to the early neurodegenerative damage of the hippocampus in AD. Our assumption may reconcile the Cortical Reallocation Theory and the Multiple Trace Theory. PMID:20950632

  5. Early events in tissues during infection with pathogenic (SIVmac239) and nonpathogenic (SIVmac1A11) molecular clones of simian immunodeficiency virus.

    PubMed Central

    Lackner, A. A.; Vogel, P.; Ramos, R. A.; Kluge, J. D.; Marthas, M.

    1994-01-01

    The extent of virus replication, tissue distribution, localization of virus within tissues, and the presence of pathological lesions was examined early after experimental infection of rhesus monkeys with simian immunodeficiency virus (SIV). Three strains of SIV were used: molecularly cloned pathogenic SIVmac239; molecularly cloned nonpathogenic SIVmac1A11; and uncloned pathogenic SIVmac. The major targets of infection in all animals at 2 weeks postinoculation were the thymus and spleen. The distribution of virus within lymphoid organs varied with the viral inoculum: nonpathogenic SIVmac1A11 was present primarily within lymphoid follicles and in the thymic cortex; SIVmac239 was present primarily within periarteriolar lymphoid sheaths in the spleen, the paracortex of lymph nodes, and the medulla of the thymus; uncloned SIVmac was present in all these areas but tended to parallel the distribution of SIVmac239. Animals inoculated with nonpathogenic SIVmac1A11 had fewer SIV-positive cells by in situ hybridization and after 13 weeks postinoculation, virus was undetectable in any tissue from these animals. No significant pathological abnormalities were recognized in animals inoculated with this nonpathogenic virus. In contrast, nearly half of the animals inoculated with either SIVmac or SIVmac239 developed significant pathological lesions, including opportunistic infections by 13 weeks postinoculation, highlighting the virulence of these viruses. Our results indicate marked differences in tissue distribution between pathogenic and nonpathogenic molecular clones of SIV during the acute phase of infection. The most striking differences were the absence of SIVmac1A11 from the central nervous system and thymic medulla. The prominent early involvement of the thymus suggests that infection of this organ is a key event in the induction of immune suppression by SIV. Images Figure 1 Figure 2 Figure 3 PMID:8053500

  6. Early virological and immunological events in Epstein-Barr virus infection.

    PubMed

    Hislop, Andrew D

    2015-12-01

    Epstein-Barr virus (EBV) is a ?-herpesvirus which establishes a chronic yet asymptomatic infection in humans. This saliva transmitted virus has a tropism for B lymphocytes, in which it establishes a latent infection, and epithelial cells where the virus replicates to produce infectious particles. Although the majority of infections are apparently benign, primary EBV infection can be associated with an acute febrile syndrome, infectious mononucleosis, while infection is also associated with the development of malignancies of B lymphocyte and epithelial origin. A better understanding how the virus replicates initially in the host and its control at this stage will lead to the development of rationally targeted interventions which potentially would prevent infection or modify infection associated disease. PMID:26322696

  7. Microgravity Effects on the Early Events of Biological Nitrogen Fixation in Medicago Truncatula: Results from the SyNRGE Experiment

    NASA Technical Reports Server (NTRS)

    Stutte, Gary W.; Roberts, Michael

    2012-01-01

    SyNRGE (Symbiotic Nodulation in a Reduced Gravity Environment) was a sortie mission on STS-135 in the Biological Research in Canisters (BRIC) hardware to study the effect of microgravity on a plant-microbe symbiosis resulting in biological nitrogen fixation. Medicago truncatula, a model species for th legume family, was inoculated with its bacterial symbiont, Sinorhizobium meliloti, to observe early biomolecular events associated with infection and nodulation in Petri Dish Fixation Units (PDFU's).

  8. Planktonic foraminiferal biostratigraphy and faunal turnover events during the Late Cretaceous-Early Tertiary along the Red Sea Coast, Egypt

    NASA Astrophysics Data System (ADS)

    Obaidalla, N. A.

    2000-11-01

    Planktonic foraminiferal assemblages from the Late Cretaceous-Early Tertiary sedimentary sequence in Quseir (Hammadat section), Safaga (Wasif section) and Esh El-Mellaha (Esh El-Mellaha section) areas along the Red Sea Coast, provide a database for biostratigraphical subdivisions and marking of faunal changes. Ten planktonic foraminiferal zones were found. There are, from base to top, the Late Cretaceous Globotruncana ægyptiaca and Gansserina gansseri Zones and the Early Tertiary Parasubbotina pseudobulloides, Praemurica trinidadensis, P. uncinata, Morozovella angulata, Igorina pusilla, Globanomalina pseudomenardii, Morozovella velascoensis and M. edgari zones. Two intervals of non-deposition of sediments (hiatuses) in the study areas are recorded, indicating tectonic events. The first hiatus occurred all over the study areas near the Cretaceous/Tertiary boundary. The second hiatus is restricted to the Late Palæocene of the Safaga area. Two global planktonic foraminiferal faunal turnover events are identified, reflecting major palæoceanographic changes. The faunal turnover event I occurred near the M. angulata/I. pusilla boundary near the Palæocene/Eocene boundary. These turnovers are characterised by the appearance and disappearance of species and changes in relative abundance, diversity and richness of species. Oscillation in the mean sea level in the study areas during the Late Cretaceous-Early Tertiary may be related to a true eustatic change in addition to the evidence for local tectonic control.

  9. Low ABCB1 gene expression is an early event in colorectal carcinogenesis.

    PubMed

    Andersen, Vibeke; Vogel, Ulla; Godiksen, Sine; Frenzel, Franz B; Sæbø, Mona; Hamfjord, Julian; Kure, Elin; Vogel, Lotte K

    2013-01-01

    The ABCB1/MDR1 gene product ABCB1/P-glycoprotein is implicated in the development of colorectal cancer (CRC). NFKB1 encodes transcription factors regulating expression of a number of genes including ABCB1. We have previously found association between the ABCB1 C-rs3789243-T polymorphism and CRC risk and interactions between the ABCB1 C-rs3789243-T and C3435T polymorphisms and meat intake in relation to CRC risk (Andersen, BMC Cancer, 2009, 9, 407). ABCB1 and NFKB1 mRNA levels were assessed in intestinal tissue from 122 CRC cases, 101 adenoma cases (12 with severe dysplasia, 89 with mild-moderate dysplasia) and from 18 healthy individuals, together with gene polymorphisms in ABCB1 and NFKB1. ABCB1 mRNA levels were highest in the healthy individuals and significantly lower in mild/moderate and severe dysplasia tissue (P<0.05 for both), morphologically normal tissues close to the tumour (P<0.05), morphologically normal tissue at a distance from the tumour (P<0.05) and CRC tissue (P<0.001). Furthermore, ABCB1 mRNA levels were lower in adenomas and carcinomas compared to morphologically normal tissue from the same individuals (P<0.01). The ABCB1 C-rs3789243-T and NFKB1 -94ins/del homozygous variant genotypes were associated with low ABCB1 mRNA levels in morphologically normal sigmoid tissue from adenoma cases (P<0.05 for both). NFKB1 mRNA levels were lower in both tumour and normal tissue from cancer patients (P<0.001) as compared to healthy individuals but we were unable to show association between NFKB1 -94ins/del genotype and NFKB1 mRNA levels. This study suggests that low ABCB1 mRNA levels are an early event in CRC development and that the two polymorphisms affect ABCB1 mRNA levels whereas low NFKB1 mRNA levels occur later in carcinogenesis. Low ABCB1 protein levels may promote colorectal carcinogenesis through increasing intracellular exposure to carcinogenic ABCB1 substrates. PMID:23977225

  10. Low ABCB1 Gene Expression Is an Early Event in Colorectal Carcinogenesis

    PubMed Central

    Andersen, Vibeke; Vogel, Ulla; Godiksen, Sine; Frenzel, Franz B.; Sæbø, Mona; Hamfjord, Julian

    2013-01-01

    The ABCB1/MDR1 gene product ABCB1/P-glycoprotein is implicated in the development of colorectal cancer (CRC). NFKB1 encodes transcription factors regulating expression of a number of genes including ABCB1. We have previously found association between the ABCB1 C-rs3789243-T polymorphism and CRC risk and interactions between the ABCB1 C-rs3789243-T and C3435T polymorphisms and meat intake in relation to CRC risk (Andersen, BMC Cancer, 2009, 9, 407). ABCB1 and NFKB1 mRNA levels were assessed in intestinal tissue from 122 CRC cases, 101 adenoma cases (12 with severe dysplasia, 89 with mild-moderate dysplasia) and from 18 healthy individuals, together with gene polymorphisms in ABCB1 and NFKB1. ABCB1 mRNA levels were highest in the healthy individuals and significantly lower in mild/moderate and severe dysplasia tissue (P<0.05 for both), morphologically normal tissues close to the tumour (P<0.05), morphologically normal tissue at a distance from the tumour (P<0.05) and CRC tissue (P<0.001). Furthermore, ABCB1 mRNA levels were lower in adenomas and carcinomas compared to morphologically normal tissue from the same individuals (P<0.01). The ABCB1 C-rs3789243-T and NFKB1 -94ins/del homozygous variant genotypes were associated with low ABCB1 mRNA levels in morphologically normal sigmoid tissue from adenoma cases (P<0.05 for both). NFKB1 mRNA levels were lower in both tumour and normal tissue from cancer patients (P<0.001) as compared to healthy individuals but we were unable to show association between NFKB1 -94ins/del genotype and NFKB1 mRNA levels. This study suggests that low ABCB1 mRNA levels are an early event in CRC development and that the two polymorphisms affect ABCB1 mRNA levels whereas low NFKB1 mRNA levels occur later in carcinogenesis. Low ABCB1 protein levels may promote colorectal carcinogenesis through increasing intracellular exposure to carcinogenic ABCB1 substrates. PMID:23977225

  11. The Cenozoic Diversity of Agglutinated Foraminifera - Evidence for a late Oligocene to early Miocene diversification event

    NASA Astrophysics Data System (ADS)

    Kaminski, Michael; Setoyama, Eiichi; Kender, Sev; Cetean, Claudia

    2014-05-01

    The agglutinated foraminifera are among the most abundant micro-organisms in the deep marine environment and have a diversity record extending back to the late Precambrian. We present an updated diversity curve for agglutinated foraminiferal genera based on the stratigraphic ranges of all the agglutinated genera recognized as valid in the classification of Kaminski (2014). The data set for this analysis is based on the stratigraphic ranges of agglutinated genera published in Foraminiferal Genera and their Classification, which has been subsequently updated based on published studies and our new observations. The mean standing diversity of agglutinated foraminiferal genera was compiled by counting the number of boundary crossers rather than the number of genera in each stage. In this study, we report the stratigraphic and geographical occurrence of a benthic foraminiferal diversification event that has previously received little attention. In the latest Oligocene to earliest Miocene a number of trochospiral agglutinated genera with alveolar or canaliculate walls first appeared in the fossil record. Our studies of late Oligocene of the Congo fan, offshore Angola (Kender et al., 2008; Cetean and Kaminski, 2011) have revealed a diverse assemblage that includes new taxa of deep-water agglutinated foraminifera. In a biostratigraphic study of the Miocene foraminiferal assemblages Kender et al. (2008) noted steadily increasing diversity and proportions of infaunal agglutinated foraminiferal morphotypes over the lower Miocene interval. The proportion of infaunal agglutinated foraminifera assigned to the order Textularida increased dramatically in the lower mid-Miocene, suggesting expansion of the oxygen minimum zone into deeper waters. In addition to the trochospiral alveolar genera, several species of Reticulophragmium and Cyclammina display rapid diversification into numerous separate lineages that are at present not reflected in our generic diversity record owing to their poorly established taxonomy. Genera such as Alveovalvulina, Guppyella, Goesella, and Alveovalvulinella, are typical of assemblages found in subtropical oxygen minimum zones, especially in West Africa and the Caribbean. These agglutinated genera are not found in coeval assemblages from the northern high latitudes (Kaminski et al. 2005), suggesting they are restricted to the low-latitude OMZ. It is likely that the global warming of the latest Oligocene to Early Miocene contributed to intensification of dysoxic conditions in low-latitude upwelling regions, possibly from enhanced productivity and reduced deep-sea ventilation, creating an expanded niche for these organisms that flourished in low-oxygen conditions with high particulate organic matter input. We believe a more detailed phylogenetic approach to these agglutinated genera would result in the description of new genera for individual lineages and refinement of the foraminiferal diversity record.

  12. Modeling Temporal Processes in Early Spacecraft Design: Application of Discrete-Event Simulations for Darpa's F6 Program

    NASA Technical Reports Server (NTRS)

    Dubos, Gregory F.; Cornford, Steven

    2012-01-01

    While the ability to model the state of a space system over time is essential during spacecraft operations, the use of time-based simulations remains rare in preliminary design. The absence of the time dimension in most traditional early design tools can however become a hurdle when designing complex systems whose development and operations can be disrupted by various events, such as delays or failures. As the value delivered by a space system is highly affected by such events, exploring the trade space for designs that yield the maximum value calls for the explicit modeling of time.This paper discusses the use of discrete-event models to simulate spacecraft development schedule as well as operational scenarios and on-orbit resources in the presence of uncertainty. It illustrates how such simulations can be utilized to support trade studies, through the example of a tool developed for DARPA's F6 program to assist the design of "fractionated spacecraft".

  13. Molecular replication

    NASA Technical Reports Server (NTRS)

    Orgel, L. E.

    1986-01-01

    The object of our research program is to understand how polynucleotide replication originated on the primitive Earth. This is a central issue in studies of the origins of life, since a process similar to modern DNA and RNA synthesis is likely to have formed the basis for the most primitive system of genetic information transfer. The major conclusion of studies so far is that a preformed polynucleotide template under many different experimental conditions will facilitate the synthesis of a new oligonucleotide with a sequence complementary to that of the template. It has been shown, for example, that poly(C) facilitates the synthesis of long oligo(G)s and that the short template CCGCC facilities the synthesis of its complement GGCGG. Very recently we have shown that template-directed synthesis is not limited to the standard oligonucleotide substrates. Nucleic acid-like molecules with a pyrophosphate group replacing the phosphate of the standard nucleic acid backbone are readily synthesized from deoxynucleotide 3'-5'-diphosphates on appropriate templates.

  14. Middle Devonian to Early Carboniferous event stratigraphy of Devils Gate and Northern Antelope Range sections, Nevada, U.S.A

    USGS Publications Warehouse

    Sandberg, C.A.; Morrow, J.R.; Poole, F.G.; Ziegler, W.

    2003-01-01

    The classic type section of the Devils Gate Limestone at Devils Gate Pass is situated on the eastern slope of a proto-Antler forebulge that resulted from convergence of the west side of the North American continent with an ocean plate. The original Late Devonian forebulge, the site of which is now located between Devils Gate Pass and the Northern Antelope Range, separated the continental-rise to deep-slope Woodruff basin on the west from the backbulge Pilot basin on the east. Two connections between these basins are recorded by deeper water siltstone beds at Devils Gate; the older one is the lower tongue of the Woodruff Formation, which forms the basal unit of the upper member of the type Devils Gate, and the upper one is the overlying, thin lower member of the Pilot Shale. The forebulge and the backbulge Pilot basin originated during the middle Frasnian (early Late Devonian) Early hassi Zone, shortly following the Alamo Impact within the punctata Zone in southern Nevada. Evidence of this impact is recorded by coeval and reworked shocked quartz grains in the Northern Antelope Range and possibly by a unique bypass-channel or megatsunami-uprush sandy diamictite within carbonate-platform rocks of the lower member of the type Devils Gate Limestone. Besides the Alamo Impact and three regional events, two other important global events are recorded in the Devils Gate section. The semichatovae eustatic rise, the maximum Late Devonian flooding event, coincides with the sharp lithogenetic change at the discordant boundary above the lower member of the Devils Gate Limestone. Most significantly, the Devils Gate section contains the thickest and most complete rock record in North America across the late Frasnian linguiformis Zone mass extinction event. Excellent exposures include not only the extinction shale, but also a younger. Early triangularis Zone tsunamite breccia, produced by global collapse of carbonate platforms during a shallowing event that continued into the next younger Famennian Stage. The Northern Antelope Range section is located near the top of the west side of the proto-Antler forebulge. Because of its unusual, tectonically active location, unmatched at any other Nevada localities, this section records only four regional and global events during a timespan slightly longer than that of the Devils Gate section. The global semichatovae rise and late Frasnian mass extinction event are largely masked because of the depositional complexities resulting from this location.

  15. Is epigenetics an important link between early life events and adult disease?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Epigenetic mechanisms provide one potential explanation for how environmental influences in early life cause long-term changes in chronic disease susceptibility. Whereas epigenetic dysregulation is increasingly implicated in various rare developmental syndromes and cancer, the role of epigenetics in...

  16. Early terrestrial impact events: Archean spherule layers in the Barberton Greenstone Belt, South Africa

    NASA Astrophysics Data System (ADS)

    Ozdemir, Seda; Koeberl, Christian; Schulz, Toni; Reimold, W. Uwe; Hofmann, Axel

    2015-04-01

    In addition to the oldest known impact structure on Earth, the 2.02-billion-year-old Vredefort Structure in South Africa, the evidence of Early Earth impact events are Archean spherule beds in South Africa and Australia. These spherules have been interpreted as condensation products from impact plumes and molten impact ejecta or/and impact ejecta that were melted during atmospheric re-entry [e.g., 1,2]. The 3.2-3.5 Ga spherule layers in the Barberton Greenstone Belt in South Africa currently represent the oldest known remnants of impact deposits on Earth. Aiming at identification of extraterrestrial components and to determine the diagenetic and metamorphic history of spherule layer intersections recently recovered in the CT3 drill core from the northeastern part of the Barberton Greenstone Belt, we have studied samples from these layers in terms of petrography and geochemistry. All samples, including spherule layer intersections and intercalating country rocks, were studied for mineral identification by optical and electron microscopy, as well as electron microprobe analysis (EPMA) at Natural History Museum Vienna and Museum für Naturkunde Berlin (MfN). Major and trace element compositions were determined via X-ray fluorescence spectrometry at MfN and instrumental neutron activation analysis (INAA) at University of Vienna. Os isotopes were measured by thermal ionization mass spectrometry (N-TIMS) at University of Vienna. Eighteen spherule beds are distributed over 150 meter drill core in CT3. Spherules are variably, deformed or undeformed. The high number of these layers may have been caused by tectonic duplication. Spherule beds are intercalated with shale, chert, carbonate, and/or sulfide deposits (country rocks). The size range of spherules is 0.5 to 2 mm, and some layers exhibit gradation. Shapes of spherules differ from spherical to ovoid, as well as teardrops, and spherules commonly show off-center vesicles, which have been interpreted as a primary characteristic pointing toward an impact origin [3]. Mineralogical and petrographic studies indicate that most of the mineralogy of the spherule layers is secondary due to secondary overprint by alteration and metamorphism. The mineral assemblages comprise quartz, K-feldspar, various muscovite types, phyllosilicates, Mg-siderite, Ti/Fe-Ti oxides, sulfides such as pyrite, pyrrhotite, chalkopyrite, sphalerite, and galena. INAA data show that some spherule layer intersections have extremely high siderophile element contents, with up to 1.60 wt% Ni, 0.69 wt% Cr, 0.05 wt% Co, 2.06 ppm Ir and 0.02 ppm Au, which is considered extraterrestrial component. This is further supported by their chondritic to slightly supercondritic 187Os/188Os ratios (ranging from 0.11 to 0.19), contrasting more radiogenic values of the spherule layer intercalations in comparison to country rocks, and Os concentrations up to ~4312 ppb. References: [1] Artemieva, N.A., and Simonson, B.M., 2012, LPSC 43, abstract #1372. [2] Johnson, B.C., and Melosh, H.J., 2014, Icarus, 228, 347-363. [3] Glass, B.P. and Simonson, B.M., 2012, Elements 8, 15-60.

  17. Massive Expansion of Marine Archaea During The Early Albian Oceanic Anoxic Event 1B

    NASA Astrophysics Data System (ADS)

    Kuypers, M. M.; Kuypers, M. M.; Blokker, P.; Erbacher, J.; Kinkel, H.; Pancost, R. D.; Pancost, R. D.; Schouten, S.; Sinninghe Damsté, J. S.

    2001-12-01

    Oceanic anoxic events (OAEs), periods of globally enhanced burial of organic matter (OM) in the marine realm, played an important role in the mid-Cretaceous `greenhouse climate' by effectively reducing atmospheric carbon dioxide concentrations. It is generally believed that these OAEs were caused either by decreased remineralisation or increased production of phytoplanktonic OM. Here we show that enhanced organic carbon (OC) burial during the early Albian OAE1b (~112 My) was caused by a different process. Combined biogeochemical and stable carbon isotopic analyses indicate that black shales from this period contain up to 80% of OC derived from archaea. Archaea-derived isoprenoidal tetraether membrane lipids and free and macromolecularly bound isoprenoid alkanes are abundantly present in these black shales. More specifically the presence of certain ether lipids (cyclic biphytane tetraethers) indicates representatives of the pelagic archaea. To the best of our knowledge this is the earliest fossil evidence for marine planktonic archaea, extending their geological record by more than 60 million years. The diversity of archaeal lipids recovered from the OAE1b black shales suggests that they derive from a multitude of archaeal species. However, the specific 13C enrichment of all such lipids indicates a common `heavy' (13C-rich) carbon source for the archaea and/or a common pathway of carbon-fixation with a reduced 13C fractionation effect compared to the Calvin cycle used by algae, cyanobacteria and higher plants. The large differences (up to 12%) in 13C/12C ratios between the algal biomarkers and the much more abundant archaeal molecular fossils suggest that the latter were not living heterotrophically on photoautotrophic biomass. It seems likely that the archaea present during OAE1b used a chemical energy source (possibly ammonium) for carbon fixation since photoautotrophy within the domain of the Archaea is restricted to only a few species from hypersaline environments. We can only speculate about the causes of this unprecedented massive expansion of marine planktonic archaea during the mid-Cretaceous OAE1b. Prolonged periods of enhanced hydrothermal activity would have significantly altered the ocean chemistry during the mid-Cretaceous, providing the necessary reduced compounds like ammonium to sustain a large community of chemoautotrophic archaea. In addition pronounced water stratification and anoxic conditions such as existed during the OAE1b could have provided a competitive advantage for archaea over phytoplankton utilising ammonium, allowing a diverse community of nitrifying non-thermophilic archaea to evolve. In any case our data show that there seems to be no unifying mechanism for black shale deposition during the mid-Cretaceous OAEs. Although there are apparent similarities (distinct lamination, 13C-enrichment of OC) between the black shales of OAE1b and other OAEs, our detailed molecular work shows that the origin of the OM (archaeal versus phytoplanktonic) and causes for 13C-enrichment of OC are completely different.

  18. Modeling and Analysis of Early Events in T-Lymphocyte Antigen ...

    E-print Network

    Greg Buzzard

    become activated through the engagement of antigen receptors (T-cell receptors, TCRs) .... course of kinase activation that dominates the initial signaling events, ..... The switch-like behavior in the equilibrium state of the system shown in Fig.

  19. Major events in the late Precambrian to early Triassic geohistory of the Arabian Peninsula

    SciTech Connect

    Stump, T.E.; Connally, T.C.; Van der Eem, J.G.L.A. )

    1993-09-01

    The late Precambrian to Early Triassic of the Arabian Peninsula occur in five supergroups. Their geohistory resulted from sedimentation along fluvial to midshelf facies tracts, eustatic oscillation and periodic uplift. The first supergroup, Plate Precambrian-Middle Cambrian, includes the Siq/Salib and Yatib formations. Deposited by north-eastward-flowing braided streams, they eroded and buried an Arabian shield topography. The Saq Formation lies in angular unconformity on the Siq which documents early Middle Cambrian uplift. Supergroup two, Middle Cambrian-middle Caradocian, the Burj and Saq formations, the Hanadir, Kahfah, and Ra'an members, Qasim Formation, were deposited on a stable continental margin in fluvio-deltaic to midshelf settings. Coastal onlap occurred in the Middle Cambrian, early Llanvirn, middle Llandeilo and early Caradoc. Middle Caradocian uplift deeply eroded parts of central and southern Arabia. Supergroup three of middle Caradocian-early Llandoverian are the Quwarah Member, Qasim Formation and the Zarqa/Sarah formations. They were deposited in a fluvio-deltaic shallow shelf. Late Ashgill uplift, combined with glacially induced sea level lowering, incised valleys up to 2000 ft (610 m) deep. Supergroup four, early Llandovery-Middle Carboniferous, includes the Qalibah, Tawil, Jauf, Jubah and Berwath formations. They were deposited in a fluvio-deltaic marine, river dominated system. The Quysaiba and Sharawra members, Qalibah Formation, were the offshore clays and prodelta sands, the Tawil-Jubah were the fluvial to delta front, and the Berwath the delta plain facies. Deep pre-Tawil erosion documents late Silurian-Early Devonian uplift. The fifth supergroup are the Juwayl, Unayzah, Khuff and Sudair formations. The first two units were deposited in a glacio-fluvial system which eroded and infilled a Hercynian topography. The Khuff transgression occurred during the Artinsklan-Tartarian and the Early Triassic regressive Sudair documents renewed uplift.

  20. Helicase Loading at Chromosomal Origins of Replication

    PubMed Central

    Bell, Stephen P.; Kaguni, Jon M.

    2013-01-01

    Loading of the replicative DNA helicase at origins of replication is of central importance in DNA replication. As the first of the replication fork proteins assemble at chromosomal origins of replication, the loaded helicase is required for the recruitment of the rest of the replication machinery. In this work, we review the current knowledge of helicase loading at Escherichia coli and eukaryotic origins of replication. In each case, this process requires both an origin recognition protein as well as one or more additional proteins. Comparison of these events shows intriguing similarities that suggest a similar underlying mechanism, as well as critical differences that likely reflect the distinct processes that regulate helicase loading in bacterial and eukaryotic cells. PMID:23613349

  1. Serotonin Transporter-Linked Polymorphic Region (5-HTTLPR) Genotype and Stressful Life Events Interact to Predict Preschool-Onset Depression: A Replication and Developmental Extension

    ERIC Educational Resources Information Center

    Bogdan, Ryan; Agrawal, Arpana; Gaffrey, Michael S.; Tillman, Rebecca; Luby, Joan L.

    2014-01-01

    Background: Scientific enthusiasm about gene × environment interactions, spurred by the 5-HTTLPR (serotonin transporter-linked polymorphic region) × SLEs (stressful life events) interaction predicting depression, have recently been tempered by sober realizations of small effects and meta-analyses reaching opposing conclusions. These mixed findings…

  2. Titration of Four Replication Factors is essential for the Xenopus laevis Mid-Blastula Transition

    PubMed Central

    Collart, Clara; Allen, George E.; Bradshaw, Charles R.; Smith, James C.; Zegerman, Philip

    2014-01-01

    The rapid, reductive early divisions of many metazoan embryos are followed by the mid-blastula transition (MBT), during which the cell cycle elongates and zygotic transcription begins. It has been proposed that the increasing nuclear to cytoplasmic (N/C) ratio is critical for controlling the events of the mid-blastula transition (MBT). We show that four DNA replication factors, Cut5, RecQ4, Treslin, and Drf1, are limiting for replication initiation at increasing N/C ratios in vitro and in vivo in Xenopus laevis . The levels of these factors regulate multiple events of the MBT including the slowing of the cell cycle, the onset of zygotic transcription, and the developmental activation of the kinase Chk1. This work provides a mechanism for how the N/C ratio controls the MBT and shows that the regulation of replication initiation is fundamental for normal embryogenesis. PMID:23907533

  3. Titration of four replication factors is essential for the Xenopus laevis midblastula transition.

    PubMed

    Collart, Clara; Allen, George E; Bradshaw, Charles R; Smith, James C; Zegerman, Philip

    2013-08-23

    The rapid, reductive early divisions of many metazoan embryos are followed by the midblastula transition (MBT), during which the cell cycle elongates and zygotic transcription begins. It has been proposed that the increasing nuclear to cytoplasmic (N/C) ratio is critical for controlling the events of the MBT. We show that four DNA replication factors--Cut5, RecQ4, Treslin, and Drf1--are limiting for replication initiation at increasing N/C ratios in vitro and in vivo in Xenopus laevis. The levels of these factors regulate multiple events of the MBT, including the slowing of the cell cycle, the onset of zygotic transcription, and the developmental activation of the kinase Chk1. This work provides a mechanism for how the N/C ratio controls the MBT and shows that the regulation of replication initiation is fundamental for normal embryogenesis. PMID:23907533

  4. SeismoGeodesy: Combination of High Rate, Real-time GNSS and Accelerometer Observations and Rapid Seismic Event Notification for Earth Quake Early Warning and Volcano Monitoring

    NASA Astrophysics Data System (ADS)

    Jackson, Michael; Zimakov, Leonid; Moessmer, Matthias

    2015-04-01

    Scientific GNSS networks are moving towards a model of real-time data acquisition, epoch-by-epoch storage integrity, and on-board real-time position and displacement calculations. This new paradigm allows the integration of real-time, high-rate GNSS displacement information with acceleration and velocity data to create very high-rate displacement records. The mating of these two instruments allows the creation of a new, very high-rate (200 Hz) displacement observable that has the full-scale displacement characteristics of GNSS and high-precision dynamic motions of seismic technologies. It is envisioned that these new observables can be used for earthquake early warning studies, volcano monitoring, and critical infrastructure monitoring applications. Our presentation will focus on the characteristics of GNSS, seismic, and strong motion sensors in high dynamic environments, including historic earthquakes replicated on a shake table over a range of displacements and frequencies. We will explore the optimum integration of these sensors from a filtering perspective including simple harmonic impulses over varying frequencies and amplitudes and under the dynamic conditions of various earthquake scenarios. We will also explore the tradeoffs between various GNSS processing schemes including real-time precise point positioning (PPP) and real-time kinematic (RTK) as applied to seismogeodesy. In addition we will discuss implementation of a Rapid Seismic Event Notification System that provides quick delivery of digital data from seismic stations to the acquisition and processing center and a full data integrity model for real-time earthquake notification that provides warning prior to significant ground shaking.

  5. Early trimpi events from lightning-induced electric fields in the ionosphere: An alternative explanation. (Reannouncement with new availability information)

    SciTech Connect

    Burke, W.J.

    1992-12-31

    Two classes of Trimpi modulation of VLF signals in the Earth-ionosphere waveguide have been identified in the literature. The more common type occurs 1 s or more after causative lightning strokes, the second in less than 100 ms. The authors explore the possibility that these early Trimpi events result from lightning-generated, electric field impulses lowering the mirror altitudes of trapped electrons. To overcome the mirror force on energetic electrons, upward-directed electric fields with strength of a few tens of mV/m are required. This is well within the range of electric field observed on sounding rockets above thunderstorms.

  6. The "terminal Triassic catastrophic extinction event" in perspective: a review of carboniferous through Early Jurassic terrestrial vertebrate extinction patterns

    USGS Publications Warehouse

    Weems, R.E.

    1992-01-01

    A catastrophic terminal Triassic extinction event among terrestrial vertebrates is not supported by available evidence. The current model for such an extinction is based on at least eight weak or untenable assumptions: (1) a terminal Triassic extinction-inducing asteroid impact occurred, (2) a terminal Triassic synchronous mass extinction of terrestrial vertebrates occurred, (3) a concurrent terminal Triassic marine extinction occurred, (4) all terrestrial vertebrate families have similar diversities and ecologies, (5) changes in familial diversity can be gauged accurately from the known fossil record, (6) extinction of families can be compared through time without normalizing for changes in familial diversity through time, (7) extinction rates can be compared without normalizing for differing lengths of geologic stages, and (8) catastrophic mass extinctions do not select for small size. These assumptions have resulted in unsupportable and (or) erroneous conclusions. Carboniferous through Early Jurassic terrestrial vertebrate families mostly have evolution and extinction patterns unlike the vertebrate evolution and extinction patterns during the terminal Cretaceous event. Only the Serpukhovian (mid Carboniferous) extinction event shows strong analogy to the terminal Cretaceous event. Available data suggest no terminal Triassic extinction anomaly, but rather a prolonged and nearly steady decline in the global terrestrial vertebrate extinction rate throughout the Triassic and earliest Jurassic. ?? 1992.

  7. Inhibition of iridovirus protein synthesis and virus replication by antisense morpholino oligonucleotides targeted to the major capsid protein, the 18 kDa immediate-early protein, and a viral homolog of RNA polymerase II

    SciTech Connect

    Sample, Robert; Bryan, Locke; Long, Scott; Majji, Sai; Hoskins, Glenn; Sinning, Allan; Olivier, Jake; Chinchar, V. Gregory . E-mail: vchinchar@microbio.umsmed.edu

    2007-02-20

    Frog virus 3 (FV3) is a large DNA virus that encodes {approx} 100 proteins. Although the general features of FV3 replication are known, the specific roles that most viral proteins play in the virus life cycle have not yet been elucidated. To address the question of viral gene function, antisense morpholino oligonucleotides (asMOs) were used to transiently knock-down expression of specific viral genes and thus infer their role in virus replication. We designed asMOs directed against the major capsid protein (MCP), an 18 kDa immediate-early protein (18K) that was thought to be a viral regulatory protein, and the viral homologue of the largest subunit of RNA polymerase II (vPol-II{alpha}). All three asMOs successfully inhibited translation of the targeted protein, and two of the three asMOs resulted in marked phenotypic changes. Knock-down of the MCP resulted in a marked reduction in viral titer without a corresponding drop in the synthesis of other late viral proteins. Transmission electron microscopy (TEM) showed that in cells treated with the anti-MCP MO assembly sites were devoid of viral particles and contained numerous aberrant structures. In contrast, inhibition of 18K synthesis did not block virion formation, suggesting that the 18K protein was not essential for replication of FV3 in fathead minnow (FHM) cells. Finally, consistent with the view that late viral gene expression is catalyzed by a virus-encoded or virus-modified Pol-II-like protein, knock-down of vPol-II{alpha} triggered a global decline in late gene expression and virus yields without affecting the synthesis of early viral genes. Collectively, these results demonstrate the utility of using asMOs to elucidate the function of FV3 proteins.

  8. Paleomagnetic and Geochronologic Data from Central Asia: Inferences for Early Paleozoic Tectonic Evolution and Timing of Worldwide Glacial Events

    NASA Astrophysics Data System (ADS)

    Gregory, L. C.; Meert, J. G.; Levashova, N.; Grice, W. C.; Gibsher, A.; Rybanin, A.

    2007-12-01

    The Neoproterozoic to early Paleozoic Ural-Mongol belt that runs through Central Asia is crucial for determining the enigmatic amalgamation of microcontinents that make up the Eurasian subcontinent. Two unique models have been proposed for the evolution of Ural-Mongol belt. One involves a complex assemblage of cratonic blocks that have collided and rifted apart during diachronous opening and closing of Neoproterozoic to Devonian aged ocean basins. The opposing model of Sengor and Natal"in proposes a long-standing volcanic arc system that connected Central Asian blocks with the Baltica continent. The Aktau-Mointy and Dzabkhan microcontinents in Kazakhstan and Central Mongolia make up the central section of the Ural-Mongol belt, and both contain glacial sequences characteristic of the hypothesized snowball earth event. These worldwide glaciations are currently under considerable debate, and paleomagnetic data from these microcontients are a useful contribution to the snowball controversy. We have sampled volcanic and sedimentary sequences in Central Mongolia, Kazakhstan and Kyrgyzstan for paleomagnetic and geochronologic study. U-Pb data, 13C curves and abundant fossil records place age constraints on sequences that contain glacial deposits of the hypothesized snowball earth events. Carbonates in the Zavkhan Basin in Mongolia are likely remagnetized, but fossil evidence within the sequence suggests a readjusted age control on two glacial events that were previously labeled as Sturtian and Marinoan. U-Pb ages from both Kazakhstan and Mongolian volcanic sequences imply a similar evolution history of the areas as part of the Ural-Mongol fold belt, and these ages paired with paleomagnetic and 13C records have important tectonic implications. We will present these data in order to place better constraints on the Precambrian to early Paleozoic tectonic evolution of Central Asia and the timing of glacial events recorded in the area.

  9. Introduction: Cortical event-related potentials and early language development: Variations with age and nutrition

    Technology Transfer Automated Retrieval System (TEKTRAN)

    There is increasing evidence in the form of language-relevant sensory processing and discrimination that the foundations for speech perception are present at birth and are subject to significant modification during the first year of life. However, charting the course of early language development is...

  10. Early Processing of Emotional Faces in Children with Autism: An Event-Related Potential Study

    ERIC Educational Resources Information Center

    Batty, Magali; Meaux, Emilie; Wittemeyer, Kerstin; Roge, Bernadette; Taylor, Margot J.

    2011-01-01

    Social deficits are one of the most striking manifestations of autism spectrum disorders (ASDs). Among these social deficits, the recognition and understanding of emotional facial expressions has been widely reported to be affected in ASDs. We investigated emotional face processing in children with and without autism using event-related potentials…

  11. Traumatic and Stressful Events in Early Childhood: Can Treatment Help Those at Highest Risk?

    ERIC Educational Resources Information Center

    Ippen, Chandra Ghosh; Harris, William W.; Van Horn, Patricia; Lieberman, Alicia F.

    2011-01-01

    Objective: This study involves a reanalysis of data from a randomized controlled trial to examine whether child-parent psychotherapy (CPP), an empirically based treatment focusing on the parent-child relationship as the vehicle for child improvement, is efficacious for children who experienced multiple traumatic and stressful life events (TSEs).…

  12. Risk Factors for Preschool Depression: The Mediating Role of Early Stressful Life Events

    ERIC Educational Resources Information Center

    Luby, Joan L.; Belden, Andy C.; Spitznagel, Edward

    2006-01-01

    Background: Family history of mood disorders and stressful life events are both established risk factors for childhood depression. However, the role of mediators in risk trajectories, which are potential targets for intervention, remains understudied. To date, there have been no investigations of mediating relationships between risk factors and…

  13. Mood Reactivity to Daily Negative Events in Early Adolescence: Relationship to Risk for Psychopathology

    ERIC Educational Resources Information Center

    Schneiders, Josien; Nicolson, Nancy A.; Berkhof, Johannes; Feron, Frans J.; van Os, Jim; deVries, Marten W.

    2006-01-01

    Emotional responses to negative daily experiences in young adolescents may provide important clues to the development of psychopathology, but research is lacking. This study assessed momentary mood reactivity to daily events as a function of risk profile in a school sample, ages 11-14. High-risk (HR, n = 25) and low-risk (LR, n = 106) subgroups…

  14. Riding the Wave to Reach the Masses: Natural Events in Early Twentieth Century Portuguese Daily Press

    ERIC Educational Resources Information Center

    Simoes, Ana; Carneiro, Ana; Diogo, Maria Paula

    2012-01-01

    This paper brings together science communicated in newspapers in Portugal by looking at how news on natural events were communicated in two different newspapers--the capital newspaper "Diario de Noticias" ("Daily News") and the "Diario dos Acores" ("Azores Daily"). In particular, we look at how the 1900 solar eclipse, a hot topic throughout…

  15. Glycoprotein from street rabies virus BD06 induces early and robust immune responses when expressed from a non-replicative adenovirus recombinant.

    PubMed

    Wang, Shuchao; Sun, Chenglong; Zhang, Shoufeng; Zhang, Xiaozhuo; Liu, Ye; Wang, Ying; Zhang, Fei; Wu, Xianfu; Hu, Rongliang

    2015-09-01

    The rabies virus (RABV) glycoprotein (G) is responsible for inducing neutralizing antibodies against rabies virus. Development of recombinant vaccines using the G genes from attenuated strains rather than street viruses is a regular practice. In contrast to this scenario, we generated three human adenovirus type 5 recombinants using the G genes from the vaccine strains SRV9 and Flury-LEP, and the street RABV strain BD06 (nrAd5-SRV9-G, nrAd5-Flury-LEP-G, and nrAd5-BD06-G). These recombinants were non-replicative, but could grow up to ~10(8) TCID50/ml in helper HEK293AD cells. Expression of the G protein was verified by immunostaining, quantitative PCR and cytometry. Animal experiments revealed that immunization with nrAd5-BD06-G can induce a higher seroconversion rate, a higher neutralizing antibody level, and a longer survival time after rabies virus challenge in mice when compared with the other two recombinants. Moreover, the expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) was significantly higher in mice immunized with nrAd5-BD06-G, which might also contribute to the increased protection. These results show that the use of street RABV G for non-replicative systems may be an alternative for developing effective recombinant rabies vaccines. PMID:26143474

  16. Ar-Ar Dating of Martian Meteorite, Dhofar 378: An Early Shock Event?

    NASA Technical Reports Server (NTRS)

    Park, J.; Bogard, D. D.

    2006-01-01

    Martian meteorite, Dhofar 378 (Dho378) is a basaltic shergottite from Oman, weighing 15 g, and possessing a black fusion crust. Chemical similarities between Dho378 and the Los Angeles 001 shergottite suggests that they might have derived from the same Mars locale. The plagioclase in other shergottites has been converted to maskelenite by shock, but Dho378 apparently experienced even more intense shock heating, estimated at 55-75 GPa. Dho378 feldspar (approximately 43 modal %) melted, partially flowed and vesiculated, and then partially recrystallized. Areas of feldspathic glass are appreciably enriched in K, whereas individual plagioclases show a range in the Or/An ratio of approximately 0.18-0.017. Radiometric dating of martian shergottites indicate variable formation times of 160-475 Myr, whereas cosmic ray exposure (CRE) ages of shergottites indicate most were ejected from Mars within the past few Myr. Most determined Ar-39-Ar-40 ages of shergottites appear older than other radiometric ages because of the presence of large amounts of martian atmosphere or interior Ar-40. Among all types of meteorites and returned lunar rocks, the impact event that initiated the CRE age very rarely reset the Ar-Ar age. This is because a minimum time and temperature is required to facilitate Ar diffusion loss. It is generally assumed that the shock-texture characteristics in martian meteorites were produced by the impact events that ejected the rocks from Mars, although the time of these shock events (as opposed to CRE ages) are not directly dated. Here we report Ar-39-Ar-40 dating of Dho378 plagioclase. We suggest that the determined age dates the intense shock heating event this meteorite experienced, but that it was not the impact that initiated the CRE age.

  17. An early warning indicator for atmospheric blocking events using transfer operators

    E-print Network

    Alexis Tantet; Fiona R. van der Burgt; Henk A. Dijkstra

    2015-03-14

    The existence of persistent midlatitude atmospheric flow regimes with time-scales larger than 5-10 days and indications of preferred transitions between them motivates to develop early warning indicators for such regime transitions. In this paper, we use a hemispheric barotropic model together with estimates of transfer operators on a reduced phase space to develop an early warning indicator of the zonal to blocked flow transition in this model. It is shown that, the spectrum of the transfer operators can be used to study the slow dynamics of the flow as well as the non-Markovian character of the reduction. The slowest motions are thereby found to have time scales of three to six weeks and to be associated with meta-stable regimes (and their transitions) which can be detected as almost-invariant sets of the transfer operator. From the energy budget of the model, we are able to explain the meta-stability of the regimes and the existence of preferred transition paths. Even though the model is highly simplified, the skill of the early warning indicator is promising, suggesting that the transfer operator approach can be used in parallel to an operational deterministic model for stochastic prediction or to assess forecast uncertainty.

  18. Age Dating Merger Events in Early Type Galaxies via the Detection of AGB Light

    NASA Technical Reports Server (NTRS)

    Bothun, G.

    2005-01-01

    A thorough statistical analysis of the J-H vs. H-K color plane of all detected early type galaxies in the 2MASS catalog with velocities less than 5000 km/s has been performed. This all sky survey is not sensitive to one particular galactic environment and therefore a representative range of early type galaxy environments have been sampled. Virtually all N-body simulation so major mergers produces a central starburst due to rapid collection of gas. This central starburst is of sufficient amplitude to change the stellar population in the central regions of the galaxy. Intermediate age populations are given away by the presence of AGB stars which will drive the central colors redder in H-K relative to the J- H baseline. This color anomaly has a lifetime of 2-5 billion years depending on the amplitude of the initial starburst Employing this technique on the entire 2MASS sample (several hundred galaxies) reveals that the AGB signature occurs less than 1% of the time. This is a straightforward indication that virtually all nearby early type galaxies have not had a major merger occur within the last few billion years.

  19. Risk of Cerebrovascular Events in Elderly Patients After Radiation Therapy Versus Surgery for Early-Stage Glottic Cancer

    SciTech Connect

    Hong, Julian C.; Kruser, Tim J.; Gondi, Vinai; Mohindra, Pranshu; Cannon, Donald M.; Harari, Paul M.; Bentzen, Søren M.

    2013-10-01

    Purpose: Comprehensive neck radiation therapy (RT) has been shown to increase cerebrovascular disease (CVD) risk in advanced-stage head-and-neck cancer. We assessed whether more limited neck RT used for early-stage (T1-T2 N0) glottic cancer is associated with increased CVD risk, using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Methods and Materials: We identified patients ?66 years of age with early-stage glottic laryngeal cancer from SEER diagnosed from 1992 to 2007. Patients treated with combined surgery and RT were excluded. Medicare CPT codes for carotid interventions, Medicare ICD-9 codes for cerebrovascular events, and SEER data for stroke as the cause of death were collected. Similarly, Medicare CPT and ICD-9 codes for peripheral vascular disease (PVD) were assessed to serve as an internal control between treatment groups. Results: A total of 1413 assessable patients (RT, n=1055; surgery, n=358) were analyzed. The actuarial 10-year risk of CVD was 56.5% (95% confidence interval 51.5%-61.5%) for the RT cohort versus 48.7% (41.1%-56.3%) in the surgery cohort (P=.27). The actuarial 10-year risk of PVD did not differ between the RT (52.7% [48.1%-57.3%]) and surgery cohorts (52.6% [45.2%-60.0%]) (P=.89). Univariate analysis showed an increased association of CVD with more recent diagnosis (P=.001) and increasing age (P=.001). On multivariate Cox analysis, increasing age (P<.001) and recent diagnosis (P=.002) remained significantly associated with a higher CVD risk, whereas the association of RT and CVD remained not statistically significant (HR=1.11 [0.91-1.37,] P=.31). Conclusions: Elderly patients with early-stage laryngeal cancer have a high burden of cerebrovascular events after surgical management or RT. RT and surgery are associated with comparable risk for subsequent CVD development after treatment in elderly patients.

  20. Climate forcing due to the 8200 cal yr BP event observed at Early Neolithic sites in the eastern Mediterranean

    NASA Astrophysics Data System (ADS)

    Weninger, Bernhard; Alram-Stern, Eva; Bauer, Eva; Clare, Lee; Danzeglocke, Uwe; Jöris, Olaf; Kubatzki, Claudia; Rollefson, Gary; Todorova, Henrieta; van Andel, Tjeerd

    2006-11-01

    We explore the hypothesis that the abrupt drainage of Laurentide lakes and associated rapid switch of the North Atlantic thermohaline circulation 8200 yr ago had a catastrophic influence on Neolithic civilisation in large parts of southeastern Europe, Anatolia, Cyprus, and the Near East. The event at 8200 cal yr BP is observed in a large number of high-resolution climate proxies in the Northern Hemisphere, and in many cases corresponds to markedly cold and arid conditions. We identify the relevant archaeological levels of major Neolithic settlements in Central Anatolia, Cyprus, Greece and Bulgaria, and examine published stratigraphic, architectural, cultural and geoarchaeological studies for these sites. The specific archaeological events and processes we observe at a number of these sites during the study interval 8400-8000 cal yr BP lead us to refine some previously established Neolithisation models. The introduction of farming to South-East Europe occurs in all study regions (Thrace, Macedonia, Thessaly, Bulgaria) near 8200 cal yr BP. We observe major disruptions of Neolithic cultures in the Levant, North Syria, South-East Anatolia, Central Anatolia and Cyprus, at the same time. We conclude that the 8200 cal yr BP aridity event triggered the spread of early farmers, by different routes, out of West Asia and the Near East into Greece and Bulgaria.

  1. Early genetic and functional events in the pathogenesis of oral cancer.

    PubMed

    Prime, S S; Eveson, J W; Guest, P G; Parkinson, E K; Paterson, I C

    1997-01-01

    Oral squamous cell carcinoma (SCC) is a major world health problem, but the changes leading to the development of malignancy remain essentially unknown. Early changes are thought to include the loss of tumour suppressor genes on chromosomes 3p, 9p, and 17p. Although what genes are involved on chromosome 3 remains speculative, p16 (9p21) and p53 (17p13) are inactivated in a high proportion of oral dysplastic lesions and carcinomas. SCC-derived cell lines are immortal, have decreased growth requirements in vitro, and show a variable capacity to form tumours in athymic mice. Normal oral keratinocytes and cells from potentially malignant lesions invariably senesce at early culture passage, have strict growth requirements in vitro, and are nontumorigenic in vivo. By contrast to normal oral keratinocytes, cells from potentially malignant lesions are defective in their capacity to terminally differentiate in suspension culture. Loss of cellular senescence and gain of the immortal phenotype is associated with inactivation of p16 and p53. PMID:9303062

  2. Early Paleozoic magmatic events in the eastern Klamath Mountains, northern California

    NASA Astrophysics Data System (ADS)

    Wallin, E. Timothy; Mattinson, James M.; Potter, A. W.

    1988-02-01

    New U-Pb zircon ages for nine samples of tonalite and pegmatitic trondhjemite from the Trinity ophiolite and associated melange reveal a complex history of magmatic activity extending back into the earliest Cambrian, much older than previously believed. Earlier investigations, based on limited data, recognized lower Paleozoic crustal elements in the eastern Klamath terrane (EKT) ranging in age from Middle Ordovician to Early to Middle Devonian. The new work in the Yreka-Callahan area of the EKT confirms the Ordovician (440-475 Ma) and younger ages, but reveals for the first time the presence of tonalitic rocks that crystallized during a narrow time interval at about 565-570 Ma. We also recognize younger, Late Silurian magmatism at 412 Ma. In the context of available mapping, these ages indicate that the Trinity ophiolite is broadly polygenetic because parts of it yield crystallization ages that span approximately 150 m.y. Superjacent dismembered units of probable early Paleozoic age may be tectonostratigraphically equivalent to the Sierra City melange in the northern Sierra Nevada.

  3. Dynamic changes in 5-hydroxymethylation signatures underpin early and late events in drug exposed liver

    PubMed Central

    Thomson, John P.; Hunter, Jennifer M.; Lempiäinen, Harri; Müller, Arne; Terranova, Rémi; Moggs, Jonathan G.; Meehan, Richard R.

    2013-01-01

    Aberrant DNA methylation is a common feature of neoplastic lesions, and early detection of such changes may provide powerful mechanistic insights and biomarkers for carcinogenesis. Here, we investigate dynamic changes in the mouse liver DNA methylome associated with short (1 day) and prolonged (7, 28 and 91 days) exposure to the rodent liver non-genotoxic carcinogen, phenobarbital (PB). We find that the distribution of 5mC/5hmC is highly consistent between untreated individuals of a similar age; yet, changes during liver maturation in a transcriptionally dependent manner. Following drug treatment, we identify and validate a series of differentially methylated or hydroxymethylated regions: exposure results in staged transcriptional responses with distinct kinetic profiles that strongly correlate with promoter proximal region 5hmC levels. Furthermore, reciprocal changes for both 5mC and 5hmC in response to PB suggest that active demethylation may be taking place at each set of these loci via a 5hmC intermediate. Finally, we identify potential early biomarkers for non-genotoxic carcinogenesis, including several genes aberrantly expressed in liver cancer. Our work suggests that 5hmC profiling can be used as an indicator of cell states during organ maturation and drug-induced responses and provides novel epigenetic signatures for non-genotoxic carcinogen exposure. PMID:23598998

  4. Knockin' on pollen's door: live cell imaging of early polarization events in germinating Arabidopsis pollen

    PubMed Central

    Vogler, Frank; Konrad, Sebastian S. A.; Sprunck, Stefanie

    2015-01-01

    Pollen tubes are an excellent system for studying the cellular dynamics and complex signaling pathways that coordinate polarized tip growth. Although several signaling mechanisms acting in the tip-growing pollen tube have been described, our knowledge on the subcellular and molecular events during pollen germination and growth site selection at the pollen plasma membrane is rather scarce. To simultaneously track germinating pollen from up to 12 genetically different plants we developed an inexpensive and easy mounting technique, suitable for every standard microscope setup. We performed high magnification live-cell imaging during Arabidopsis pollen activation, germination, and the establishment of pollen tube tip growth by using fluorescent marker lines labeling either the pollen cytoplasm, vesicles, the actin cytoskeleton or the sperm cell nuclei and membranes. Our studies revealed distinctive vesicle and F-actin polarization during pollen activation and characteristic growth kinetics during pollen germination and pollen tube formation. Initially, the germinating Arabidopsis pollen tube grows slowly and forms a uniform roundish bulge, followed by a transition phase with vesicles heavily accumulating at the growth site before switching to rapid tip growth. Furthermore, we found the two sperm cells to be transported into the pollen tube after the phase of rapid tip growth has been initiated. The method presented here is suitable to quantitatively study subcellular events during Arabidopsis pollen germination and growth, and for the detailed analysis of pollen mutants with respect to pollen polarization, bulging, or growth site selection at the pollen plasma membrane. PMID:25954283

  5. Replication of kinetoplast minicircle DNA

    SciTech Connect

    Sheline, C.T.

    1989-01-01

    These studies describe the isolation and characterization of early minicircle replication intermediates from Crithidia fasciculata, and Leishmania tarentolae, the mitochondrial localization of a type II topoisomerase (TIImt) in C. fasciculata, and the implication of the aforementioned TIImt in minicircle replication in L. tarentolae. Early minicircle replication intermediates from C. fasciculata were identified and characterized using isolated kinetoplasts to incorporate radiolabeled nucleotides into its DNA. The pulse-label in an apparent theta-type intermediate chase into two daughter molecules. A uniquely gapped, ribonucleotide primed, knotted molecule represents the leading strand in the model proposed, and a highly gapped molecule represents the lagging strand. This theta intermediate is repaired in vitro to a doubly nicked catenated dimer which was shown to result from the replication of a single parental molecule. Very similar intermediates were found in the heterogeneous population of minicircles of L. tarentolae. The sites of the Leishmania specific discontinuities were mapped and shown to lie within the universally conserved sequence blocks in identical positions as compared to C. fasciculata and Trypanosoma equiperdum.

  6. Replication in Practice: Lessons from Five Lead Agencies

    ERIC Educational Resources Information Center

    McGonigel, Mary

    2005-01-01

    This article describes the replication efforts of five programs funded by the Pritzker Early Childhood Foundation and determines what methods are key to replication success. Before replication can take place, the lead agency must have substantial evidence of its effectiveness and know its core elements. It must also think carefully about how its…

  7. Developmental differences in memory during early childhood: insights from event-related potentials.

    PubMed

    Riggins, Tracy; Rollins, Leslie

    2015-01-01

    Age-related differences in behavioral and electrophysiological indices of memory were examined in 3- to 6-year-old children (N = 76). Behaviorally, no differences were observed in children's ability to identify old items; however, 3-year-old children were less accurate in correctly rejecting new items, and 3- and 4-year-old children recalled fewer contextual details compared to 5- and 6-year-old children. Age-related differences in electrophysiological measures (800-1,000 ms after stimulus onset) were observed both to items recalled with contextual details, which increased between 3 and 4 years, and items recalled without contextual details, which were greatest in 5-year-old children, even after adjusting for global age-related differences. These findings, interpreted within a dual-process framework, may suggest changes in both recollection and familiarity processes during early childhood. PMID:25677124

  8. Long-term impact of early life events on physiology and behaviour.

    PubMed

    Boersma, G J; Bale, T L; Casanello, P; Lara, H E; Lucion, A B; Suchecki, D; Tamashiro, K L

    2014-09-01

    This review discusses the effects of stress and nutrition throughout development and summarises studies investigating how exposure to stress or alterations in nutrition during the pre-conception, prenatal and early postnatal periods can affect the long-term health of an individual. In general, the data presented here suggest that that anything signalling potential adverse conditions later in life, such as high levels of stress or low levels of food availability, will lead to alterations in the offspring, possibly of an epigenetic nature, preparing the offspring for these conditions later in life. However, when similar environmental conditions are not met in adulthood, these alterations may have maladaptive consequences, resulting in obesity and heightened stress sensitivity. The data also suggest that the mechanism underlying these adult phenotypes might be dependent on the type and the timing of exposure. PMID:24690036

  9. MSH6 and MUTYH Deficiency Is a Frequent Event in Early-Onset Colorectal Cancer

    PubMed Central

    Giráldez, María Dolores; Balaguer, Francesc; Bujanda, Luis; Cuatrecasas, Miriam; Muñoz, Jenifer; Alonso-Espinaco, Virginia; Larzabal, Mikel; Petit, Anna; Gonzalo, Victoria; Ocaña, Teresa; Moreira, Leticia; Enríquez-Navascués, José María; Boland, C. Richard; Goel, Ajay; Castells, Antoni; Castellví-Bel, Sergi

    2011-01-01

    Purpose Early-onset colorectal cancer (CRC) is suggestive of a hereditary predisposition. Lynch syndrome is the most frequent CRC hereditary cause. The MUTYH gene has also been related to hereditary CRC. A systematic characterization of these two diseases has not been reported previously in this population. Experimental Design We studied a retrospectively collected series of 140 patients ?50 years old diagnosed with nonpolyposis CRC. Demographic, clinical, and familial features were obtained. Mismatch repair (MMR) deficiency was determined by microsatellite instability (MSI) analysis, and immunostaining for MLH1, MSH2, MSH6, and PMS2 proteins. Germline MMR mutations were evaluated in all MMR-deficient cases. Tumor samples with loss of MLH1 or MSH2 protein expression were analyzed for somatic methylation. Germline MUTYH mutations were evaluated in all cases. BRAF V600E and KRAS somatic mutational status was also determined. Results Fifteen tumors (11.4%) were MSI, and 20 (14.3%) showed loss of protein expression (7 for MLH1/PMS2, 2 for isolated MLH1, 3 for MSH2/MSH6, 7 for isolated MSH6, and 1 for MSH6/PMS2). We identified 11 (7.8%) germline MMR mutations, 4 in MLH1, 1 in MSH2, and 6 in MSH6. Methylation analysis revealed one case with somatic MLH1 methylation. Biallelic MUTYH mutations were detected in four (2.8%) cases. KRAS and BRAF V600E mutations were present in 39 (27.9%) and 5 (3.6%) cases, respectively. Conclusions Loss of MSH6 expression is the predominant cause of MMR deficiency in early-onset CRC. Our findings prompt the inclusion of MSH6 and MUTYH screening as part of the genetic counseling of these patients and their relatives. PMID:20924129

  10. Phosphoproteomic Analyses Reveal Early Signaling Events in the Osmotic Stress Response1[W][OPEN

    PubMed Central

    E. Stecker, Kelly; Minkoff, Benjamin B.; Sussman, Michael R.

    2014-01-01

    Elucidating how plants sense and respond to water loss is important for identifying genetic and chemical interventions that may help sustain crop yields in water-limiting environments. Currently, the molecular mechanisms involved in the initial perception and response to dehydration are not well understood. Modern mass spectrometric methods for quantifying changes in the phosphoproteome provide an opportunity to identify key phosphorylation events involved in this process. Here, we have used both untargeted and targeted isotope-assisted mass spectrometric methods of phosphopeptide quantitation to characterize proteins in Arabidopsis (Arabidopsis thaliana) whose degree of phosphorylation is rapidly altered by hyperosmotic treatment. Thus, protein phosphorylation events responsive to 5 min of 0.3 m mannitol treatment were first identified using 15N metabolic labeling and untargeted mass spectrometry with a high-resolution ion-trap instrument. The results from these discovery experiments were then validated using targeted Selected Reaction Monitoring mass spectrometry with a triple quadrupole. Targeted Selected Reaction Monitoring experiments were conducted with plants treated under nine different environmental perturbations to determine whether the phosphorylation changes were specific for osmosignaling or involved cross talk with other signaling pathways. The results indicate that regulatory proteins such as members of the mitogen-activated protein kinase family are specifically phosphorylated in response to osmotic stress. Proteins involved in 5? messenger RNA decapping and phosphatidylinositol 3,5-bisphosphate synthesis were also identified as targets of dehydration-induced phosphoregulation. The results of these experiments demonstrate the utility of targeted phosphoproteomic analysis in understanding protein regulation networks and provide new insight into cellular processes involved in the osmotic stress response. PMID:24808101

  11. Phosphoproteomic Analyses Reveal Early Signaling Events in the Osmotic Stress Response.

    PubMed

    E Stecker, Kelly; Minkoff, Benjamin B; Sussman, Michael R

    2014-05-01

    Elucidating how plants sense and respond to water loss is important for identifying genetic and chemical interventions that may help sustain crop yields in water-limiting environments. Currently, the molecular mechanisms involved in the initial perception and response to dehydration are not well understood. Modern mass spectrometric methods for quantifying changes in the phosphoproteome provide an opportunity to identify key phosphorylation events involved in this process. Here, we have used both untargeted and targeted isotope-assisted mass spectrometric methods of phosphopeptide quantitation to characterize proteins in Arabidopsis (Arabidopsis thaliana) whose degree of phosphorylation is rapidly altered by hyperosmotic treatment. Thus, protein phosphorylation events responsive to 5 min of 0.3 m mannitol treatment were first identified using (15)N metabolic labeling and untargeted mass spectrometry with a high-resolution ion-trap instrument. The results from these discovery experiments were then validated using targeted Selected Reaction Monitoring mass spectrometry with a triple quadrupole. Targeted Selected Reaction Monitoring experiments were conducted with plants treated under nine different environmental perturbations to determine whether the phosphorylation changes were specific for osmosignaling or involved cross talk with other signaling pathways. The results indicate that regulatory proteins such as members of the mitogen-activated protein kinase family are specifically phosphorylated in response to osmotic stress. Proteins involved in 5' messenger RNA decapping and phosphatidylinositol 3,5-bisphosphate synthesis were also identified as targets of dehydration-induced phosphoregulation. The results of these experiments demonstrate the utility of targeted phosphoproteomic analysis in understanding protein regulation networks and provide new insight into cellular processes involved in the osmotic stress response. PMID:24808101

  12. The PRESSCA operational early warning system for landslide forecasting: the 11-12 November 2013 rainfall event in Central Italy.

    NASA Astrophysics Data System (ADS)

    Ciabatta, Luca; Brocca, Luca; Ponziani, Francesco; Berni, Nicola; Stelluti, Marco; Moramarco, Tommaso

    2014-05-01

    The Umbria Region, located in Central Italy, is one of the most landslide risk prone area in Italy, almost yearly affected by landslides events at different spatial scales. For early warning procedures aimed at the assessment of the hydrogeological risk, the rainfall thresholds represent the main tool for the Italian Civil Protection System. As shown in previous studies, soil moisture plays a key-role in landslides triggering. In fact, acting on the pore water pressure, soil moisture influences the rainfall amount needed for activating a landslide. In this work, an operational physically-based early warning system, named PRESSCA, that takes into account soil moisture for the definition of rainfall thresholds is presented. Specifically, the soil moisture conditions are evaluated in PRESSCA by using a distributed soil water balance model that is recently coupled with near real-time satellite soil moisture product obtained from ASCAT (Advanced SCATterometer) and from in-situ monitoring data. The integration of three different sources of soil moisture information allows to estimate the most accurate possible soil moisture condition. Then, both observed and forecasted rainfall data are compared with the soil moisture-based thresholds in order to obtain risk indicators over a grid of ~ 5 km. These indicators are then used for the daily hydrogeological risk evaluation and management by the Civil Protection regional service, through the sharing/delivering of near real-time landslide risk scenarios (also through an open source web platform: www.cfumbria.it). On the 11th-12th November, 2013, Umbria Region was hit by an exceptional rainfall event with up to 430mm/72hours that resulted in significant economic damages, but fortunately no casualties among the population. In this study, the results during the rainfall event of PRESSCA system are described, by underlining the model capability to reproduce, two days in advance, landslide risk scenarios in good spatial and temporal agreement with the occurred actual conditions. High-resolution risk scenarios (100mx100m), obtained by coupling PRESSCA forecasts with susceptibility and vulnerability layers, are also produced. The results show good relationship between the PRESSCA forecast and the reported landslides to the Civil Protection Service during the rainfall event, confirming the system robustness. The good forecasts of PRESSCA system have surely contributed to start well in advance the Civil Protection operations (alerting local authorities and population).

  13. A comparative study of diversification events: the early Paleozoic versus the Mesozoic

    NASA Technical Reports Server (NTRS)

    Erwin, D. H.; Valentine, J. W.; Sepkoski, J. J. Jr; Sepkoski JJ, J. r. (Principal Investigator)

    1987-01-01

    We compare two major long-term diversifications of marine animal families that began during periods of low diversity but produced strikingly different numbers of phyla, classes, and orders. The first is the early-Paleozoic diversification (late Vendian-Ordovician; 182 MY duration) and the other the Mesozoic phase of the post-Paleozoic diversification (183 MY duration). The earlier diversification was associated with a great burst of morphological invention producing many phyla, classes, and orders and displaying high per taxon rates of family origination. The later diversification lacked novel morphologies recognized as phyla and classes, produced fewer orders, and displayed lower per taxon rates of family appearances. The chief difference between the diversifications appears to be that the earlier one proceeded from relatively narrow portions of adaptive space, whereas the latter proceeded from species widely scattered among adaptive zones and representing a variety of body plans. This difference is believed to explain the major differences in the products of these great radiations. Our data support those models that hold that evolutionary opportunity is a major factor in the outcome of evolutionary processes.

  14. Epigenetic aberrations in acute myeloid leukemia: Early key events during leukemogenesis.

    PubMed

    Eriksson, Anna; Lennartsson, Andreas; Lehmann, Sören

    2015-08-01

    As a result of the introduction of new sequencing technologies, the molecular landscape of acute myeloid leukemia (AML) is rapidly evolving. From karyotyping, which detects only large genomic aberrations of metaphase chromosomes, we have moved into an era when sequencing of each base pair allows us to define the AML genome at highest resolution. This has revealed a new complex landscape of genetic aberrations where addition of mutations in epigenetic regulators has been one of the most important contributions to the understanding of the pathogenesis of AML. These findings, together with new insights into epigenetic mechanisms, have placed dysregulated epigenetic mechanisms at the forefront of AML development. Not only have several new mutations in genes directly involved in epigenetic regulatory mechanisms been discovered, but also previously well-known gene fusions have been found to exert aberrant effects through epigenetic mechanisms. In addition, mutations in epigenetic regulators such as DNMT3A, TET2, and ASXL1 have recently been found to be the earliest known events during AML evolution and to be present as preleukemic lesions before the onset of AML. In this article, we review epigenetic changes in AML also in relation to what is known about their mechanism of action and their prognostic role. PMID:26118500

  15. Fibroblast growth factor receptor 1 is a key regulator of early adipogenic events in human preadipocytes.

    PubMed

    Widberg, C H; Newell, F S; Bachmann, A W; Ramnoruth, S N; Spelta, M C; Whitehead, J P; Hutley, L J; Prins, J B

    2009-01-01

    Cell number is an important determinant of adipose tissue mass, and the coordinated proliferation and differentiation of preadipocytes into mature lipid-laden adipocytes underpins the increased adipose tissue mass associated with obesity. Despite this, the molecular cues governing such adipose tissue expansion are poorly understood. We previously reported that fibroblast growth factor-1 (FGF-1) promotes both proliferation and differentiation of human preadipocytes and that the major adipogenic effect of FGF-1 occurs during proliferation, priming the cells for adipose conversion. In the current study, we examined whether this effect was linked to the mitogenic action of FGF-1 by investigating the mitogenic and adipogenic potential of other growth factors, platelet-derived growth factor (PDGF; AA and BB) and vascular endothelial growth factor. Although PDGF-AA and PDGF-BB showed comparable mitogenic potential to FGF-1, only FGF-1 treatment resulted in priming and subsequent differentiation. Pharmacological inhibition of FGF receptor (FGFR) tyrosine kinase activity, using the FGFR-specific inhibitors PD-173074 and SU-5402, revealed an obligate requirement for FGFR activity in these processes. A combination of biochemical and genetic approaches revealed an important role for FGFR1. Knock down of FGFR1 expression by small-interfering RNA reduced FGF-1-stimulated signaling events, proliferation, and priming. Together these data highlight the unique nature of the role of FGF-1 during the earliest stages of adipogenesis and establish a role for FGFR1 in human adipogenesis, identifying FGFR1 as a potential therapeutic target to reduce obesity. PMID:18940940

  16. Higher-order unfolding of satellite heterochromatin is a consistent and early event in cell senescence.

    PubMed

    Swanson, Eric C; Manning, Benjamin; Zhang, Hong; Lawrence, Jeanne B

    2013-12-23

    Epigenetic changes to chromatin are thought to be essential to cell senescence, which is key to tumorigenesis and aging. Although many studies focus on heterochromatin gain, this work demonstrates large-scale unraveling of peri/centromeric satellites, which occurs in all models of human and mouse senescence examined. This was not seen in cancer cells, except in a benign senescent tumor in vivo. Senescence-associated distension of satellites (SADS) occurs earlier and more consistently than heterochromatin foci formation, and SADS is not exclusive to either the p16 or p21 pathways. Because Hutchinson Guilford progeria syndrome patient cells do not form excess heterochromatin, the question remained whether or not proliferative arrest in this aging syndrome involved distinct epigenetic mechanisms. Here, we show that SADS provides a unifying event in both progeria and normal senescence. Additionally, SADS represents a novel, cytological-scale unfolding of chromatin, which is not concomitant with change to several canonical histone marks nor a result of DNA hypomethylation. Rather, SADS is likely mediated by changes to higher-order nuclear structural proteins, such as LaminB1. PMID:24344186

  17. FOXO3a loss is a frequent early event in high-grade pelvic serous carcinogenesis.

    PubMed

    Levanon, K; Sapoznik, S; Bahar-Shany, K; Brand, H; Shapira-Frommer, R; Korach, J; Hirsch, M S; Roh, M H; Miron, A; Liu, J F; Vena, N; Ligon, A H; Fotheringham, S; Bailey, D; Flavin, R J; Birrer, M J; Drapkin, R I

    2014-08-28

    Serous ovarian carcinoma is the most lethal gynecological malignancy in Western countries. The molecular events that underlie the development of the disease have been elusive for many years. The recent identification of the fallopian tube secretory epithelial cells (FTSECs) as the cell-of-origin for most cases of this disease has led to studies aimed at elucidating new candidate therapeutic pathways through profiling of normal FTSECs and serous carcinomas. Here we describe the results of transcriptional profiles that identify the loss of the tumor suppressive transcription factor FOXO3a in a vast majority of high-grade serous ovarian carcinomas. We show that FOXO3a loss is a hallmark of the earliest stages of serous carcinogenesis and occurs both at the DNA, RNA and protein levels. We describe several mechanisms responsible for FOXO3a inactivity, including chromosomal deletion (chromosome 6q21), upregulation of miRNA-182 and destabilization by activated PI3K and MEK. The identification of pathways involved in the pathogenesis of ovarian cancer can advance the management of this disease from being dependant on surgery and cytotoxic chemotherapy alone to the era of targeted therapy. Our data strongly suggest FOXO3a as a possible target for clinical intervention. PMID:24077281

  18. A Threshold-Based Earthquake Early-Warning System for Offshore Events in Southern Iberia

    NASA Astrophysics Data System (ADS)

    Picozzi, M.; Colombelli, S.; Zollo, A.; Carranza, M.; Buforn, E.

    2015-09-01

    The south of the Iberian Peninsula is situated at the convergence of the Eurasian and African plates. This region experiences large earthquakes with long separation in time, the best known of which was the great 1755 Lisbon Earthquake, which occurred SW of San Vicente Cape (SW Iberian Peninsula). The high risk of damaging earthquakes has recently led Carranza et al. (Geophys. Res. Lett. 40, 2013) to investigate the feasibility of an EEWS in this region. Analysis of the geometry for the Iberian seismic networks and the San Vicente Cape area led the authors to conclude that a threshold-based approach, which would not require real-time location of the earthquake, might be the best option for an EEWS in SW Iberia. In this work we investigate this hypothesis and propose a new EEW approach that extends standard P-wave threshold-based single-station analysis to the whole network. The proposed method enables real-time estimation of the potential damage at stations that are triggered by P-waves and those which are not triggered, with the advantage of greater lead-times for release of alerts. Results of tests made with synthetic data mimicking the scenario of the great 1755 Lisbon Earthquake, and those conducted by applying the new approach to available recordings, indicate that an EEW estimation of the potential damage associated with an event in the San Vicente Cape area can be obtained for a very large part of the Iberian Peninsula.

  19. Early psychosocial interventions after disasters, terrorism and other shocking events: is there a gap between norms and practice in Europe?

    PubMed Central

    Te Brake, Hans

    2013-01-01

    Background Internationally, several initiatives exist to describe standards for post-disaster psychosocial care. Objective This study explored the level of consensus of experts within Europe on a set of recommendations on early psychosocial intervention after shocking events (Dutch guidelines), and to what degree these standards are implemented into mental health care practice. Methods Two hundred and six (mental) health care professionals filled out a questionnaire to assess the extent to which they consider the guidelines’ scope and recommendations relevant and part of the regular practice in their own country. Forty-five European experts from 24 EU countries discussed the guidelines at an international seminar. Results The data suggest overall agreement on the standards although many of the recommendations appear not (yet) to be embedded in everyday practice. Conclusions Although large consensus exists on standards for early psychosocial care, a chasm between norms and practice appears to exist throughout the EU, stressing the general need for investments in guideline development and implementation. PMID:23393613

  20. Differential Network Analyses of Alzheimer’s Disease Identify Early Events in Alzheimer’s Disease Pathology

    DOE PAGESBeta

    Xia, Jing; Rocke, David M.; Perry, George; Ray, Monika

    2014-01-01

    In late-onset Alzheimer’s disease (AD), multiple brain regions are not affected simultaneously. Comparing the gene expression of the affected regions to identify the differences in the biological processes perturbed can lead to greater insight into AD pathogenesis and early characteristics. We identified differentially expressed (DE) genes from single cell microarray data of four AD affected brain regions: entorhinal cortex (EC), hippocampus (HIP), posterior cingulate cortex (PCC), and middle temporal gyrus (MTG). We organized the DE genes in the four brain regions into region-specific gene coexpression networks. Differential neighborhood analyses in the coexpression networks were performed to identify genes with lowmore »topological overlap (TO) of their direct neighbors. The low TO genes were used to characterize the biological differences between two regions. Our analyses show that increased oxidative stress, along with alterations in lipid metabolism in neurons, may be some of the very early events occurring in AD pathology. Cellular defense mechanisms try to intervene but fail, finally resulting in AD pathology as the disease progresses. Furthermore, disease annotation of the low TO genes in two independent protein interaction networks has resulted in association between cancer, diabetes, renal diseases, and cardiovascular diseases.« less

  1. Molecular events during the early stages of aggregation of GNNQQNY: An all atom MD simulation study of randomly dispersed peptides.

    PubMed

    Srivastava, Alka; Balaji, Petety V

    2015-12-01

    This study probes the early events during lag phase of aggregation of GNNQQNY using all atom MD simulations in explicit solvent. Simulations were performed by varying system size, temperature and starting configuration. Peptides dispersed randomly in the simulation box come together early on in the simulation and form aggregates. These aggregates are dynamic implying the absence of stabilizing interactions. This facilitates the exploration of alternate arrangements. The constituent peptides sample a variety of conformations, frequently re-orient and re-arrange with respect to each other and dissociate from/re-associate with the aggregate. The size and lifetime of aggregates vary depending upon the number of inter-peptide backbone H-bonds. Most of the aggregates formed are amorphous but crystalline aggregates of smaller size (mainly 2-mers) do appear and sustain for varying durations of time. The peptides in crystalline 2-mers are mostly anti-parallel. The largest crystalline aggregate that appears is a 4-mer in a single sheet and a 4-, 5-, or 6-mer in double layered arrangement. Crystalline aggregates grow either by the sequential addition of peptides, or by the head-on or lateral collision-adhesion of 2-mers. The formation of various smaller aggregates suggests the polymorphic nature of oligomers and heterogeneity in the lag phase. PMID:26433030

  2. Co-ordination of early and late ripening events in apples is regulated through differential sensitivities to ethylene

    PubMed Central

    Johnston, Jason W.; Gunaseelan, Kularajathaven; Pidakala, Paul; Wang, Mindy; Schaffer, Robert J.

    2009-01-01

    In this study, it is shown that anti-sense suppression of Malus domestica 1-AMINO-CYCLOPROPANE-CARBOXYLASE OXIDASE (MdACO1) resulted in fruit with an ethylene production sufficiently low to be able to assess ripening in the absence of ethylene. Exposure of these fruit to different concentrations of exogenous ethylene showed that flesh softening, volatile biosynthesis, and starch degradation, had differing ethylene sensitivity and dependency. Early ripening events such as the conversion of starch to sugars showed a low dependency for ethylene, but a high sensitivity to low concentrations of ethylene (0.01 ?l l?1). By contrast, later ripening events such as flesh softening and ester volatile production showed a high dependency for ethylene but were less sensitive to low concentrations (needing 0.1 ?l l?1 for a response). A sustained exposure to ethylene was required to maintain ripening, indicating that the role of ethylene may go beyond that of ripening initiation. These results suggest a conceptual model for the control of individual ripening characters in apple, based on both ethylene dependency and sensitivity. PMID:19429839

  3. Early disrupted neurovascular coupling and changed event level hemodynamic response function in type 2 diabetes: an fMRI study.

    PubMed

    Duarte, João V; Pereira, João M S; Quendera, Bruno; Raimundo, Miguel; Moreno, Carolina; Gomes, Leonor; Carrilho, Francisco; Castelo-Branco, Miguel

    2015-10-01

    Type 2 diabetes (T2DM) patients develop vascular complications and have increased risk for neurophysiological impairment. Vascular pathophysiology may alter the blood flow regulation in cerebral microvasculature, affecting neurovascular coupling. Reduced fMRI signal can result from decreased neuronal activation or disrupted neurovascular coupling. The uncertainty about pathophysiological mechanisms (neurodegenerative, vascular, or both) underlying brain function impairments remains. In this cross-sectional study, we investigated if the hemodynamic response function (HRF) in lesion-free brains of patients is altered by measuring BOLD (Blood Oxygenation Level-Dependent) response to visual motion stimuli. We used a standard block design to examine the BOLD response and an event-related deconvolution approach. Importantly, the latter allowed for the first time to directly extract the true shape of HRF without any assumption and probe neurovascular coupling, using performance-matched stimuli. We discovered a change in HRF in early stages of diabetes. T2DM patients show significantly different fMRI response profiles. Our visual paradigm therefore demonstrated impaired neurovascular coupling in intact brain tissue. This implies that functional studies in T2DM require the definition of HRF, only achievable with deconvolution in event-related experiments. Further investigation of the mechanisms underlying impaired neurovascular coupling is needed to understand and potentially prevent the progression of brain function decrements in diabetes. PMID:26058698

  4. Space-time clusters of adverse health events as a means of early detection of departure from planned containment

    SciTech Connect

    Aldrich, T.E.; Easterly, C.E.

    1987-01-01

    Studies of rare health events offer a novel means for assessing community health impacts from excursions of hazardous contaminants into the ambient environment. Clusters of these infrequent, adverse health occurrences provide sentinel phenomena to epidemiologists for the purpose of formulating preventive strategies and decision rules. The goal of early identification and interpretation of these case clusters has led to the development of a variety of statistical methods. This presentation provides an overview of these techniques, many of which assume infectious disease processes that may reasonably be translated as a common source exposure. Population-based disease registries are substantial sources of data for conducting studies of small area case clusters near contaminated waste sites. The strategy of population surveillance has found initial acceptance as a means of directing environmental health actions and providing a safeguard for public health. The methods discussed are possible choices for analyses directed to cancer or birth defect data in order to identify possible case clusters of rare events. Suggestions are offered for interpreting case clusters of disease and a model, semiquantitative decision process is proposed for use in determining public health action or policy. 26 refs., 1 fig., 1 tab.

  5. Complement inhibition decreases early fibrogenic events in the lung of septic baboons

    PubMed Central

    Silasi-Mansat, Robert; Zhu, Hua; Georgescu, Constantin; Popescu, Narcis; Keshari, Ravi S; Peer, Glenn; Lupu, Cristina; Taylor, Fletcher B; Pereira, Heloise Anne; Kinasewitz, Gary; Lambris, John D; Lupu, Florea

    2015-01-01

    Acute respiratory distress syndrome (ARDS) induced by severe sepsis can trigger persistent inflammation and fibrosis. We have shown that experimental sepsis in baboons recapitulates ARDS progression in humans, including chronic inflammation and long-lasting fibrosis in the lung. Complement activation products may contribute to the fibroproliferative response, suggesting that complement inhibitors are potential therapeutic agents. We have been suggested that treatment of septic baboons with compstatin, a C3 convertase inhibitor protects against ARDS-induced fibroproliferation. Baboons challenged with 109 cfu/kg (LD50) live E. coli by intravenous infusion were treated or not with compstatin at the time of challenge or 5 hrs thereafter. Changes in the fibroproliferative response at 24 hrs post-challenge were analysed at both transcript and protein levels. Gene expression analysis showed that sepsis induced fibrotic responses in the lung as early as 24 hrs post-bacterial challenge. Immunochemical and biochemical analysis revealed enhanced collagen synthesis, induction of profibrotic factors and increased cell recruitment and proliferation. Specific inhibition of complement with compstatin down-regulated sepsis-induced fibrosis genes, including transforming growth factor-beta (TGF-?), connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinase 1 (TIMP1), various collagens and chemokines responsible for fibrocyte recruitment (e.g. chemokine (C-C motif) ligand 2 (CCL2) and 12 (CCL12)). Compstatin decreased the accumulation of myofibroblasts and proliferating cells, reduced the production of fibrosis mediators (TGF-?, phospho-Smad-2 and CTGF) and inhibited collagen deposition. Our data demonstrate that complement inhibition effectively attenuates collagen deposition and fibrotic responses in the lung after severe sepsis. Inhibiting complement could prove an attractive strategy for preventing sepsis-induced fibrosis of the lung. PMID:26337158

  6. Complement inhibition decreases early fibrogenic events in the lung of septic baboons.

    PubMed

    Silasi-Mansat, Robert; Zhu, Hua; Georgescu, Constantin; Popescu, Narcis; Keshari, Ravi S; Peer, Glenn; Lupu, Cristina; Taylor, Fletcher B; Pereira, Heloise Anne; Kinasewitz, Gary; Lambris, John D; Lupu, Florea

    2015-11-01

    Acute respiratory distress syndrome (ARDS) induced by severe sepsis can trigger persistent inflammation and fibrosis. We have shown that experimental sepsis in baboons recapitulates ARDS progression in humans, including chronic inflammation and long-lasting fibrosis in the lung. Complement activation products may contribute to the fibroproliferative response, suggesting that complement inhibitors are potential therapeutic agents. We have been suggested that treatment of septic baboons with compstatin, a C3 convertase inhibitor protects against ARDS-induced fibroproliferation. Baboons challenged with 10(9)  cfu/kg (LD50) live E. coli by intravenous infusion were treated or not with compstatin at the time of challenge or 5 hrs thereafter. Changes in the fibroproliferative response at 24 hrs post-challenge were analysed at both transcript and protein levels. Gene expression analysis showed that sepsis induced fibrotic responses in the lung as early as 24 hrs post-bacterial challenge. Immunochemical and biochemical analysis revealed enhanced collagen synthesis, induction of profibrotic factors and increased cell recruitment and proliferation. Specific inhibition of complement with compstatin down-regulated sepsis-induced fibrosis genes, including transforming growth factor-beta (TGF-?), connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinase 1 (TIMP1), various collagens and chemokines responsible for fibrocyte recruitment (e.g. chemokine (C-C motif) ligand 2 (CCL2) and 12 (CCL12)). Compstatin decreased the accumulation of myofibroblasts and proliferating cells, reduced the production of fibrosis mediators (TGF-?, phospho-Smad-2 and CTGF) and inhibited collagen deposition. Our data demonstrate that complement inhibition effectively attenuates collagen deposition and fibrotic responses in the lung after severe sepsis. Inhibiting complement could prove an attractive strategy for preventing sepsis-induced fibrosis of the lung. PMID:26337158

  7. High-content analysis of sequential events during the early phase of influenza A virus infection.

    PubMed

    Banerjee, Indranil; Yamauchi, Yohei; Helenius, Ari; Horvath, Peter

    2013-01-01

    Influenza A virus (IAV) represents a worldwide threat to public health by causing severe morbidity and mortality every year. Due to high mutation rate, new strains of IAV emerge frequently. These IAVs are often drug-resistant and require vaccine reformulation. A promising approach to circumvent this problem is to target host cell determinants crucial for IAV infection, but dispensable for the cell. Several RNAi-based screens have identified about one thousand cellular factors that promote IAV infection. However, systematic analyses to determine their specific functions are lacking. To address this issue, we developed quantitative, imaging-based assays to dissect seven consecutive steps in the early phases of IAV infection in tissue culture cells. The entry steps for which we developed the assays were: virus binding to the cell membrane, endocytosis, exposure to low pH in endocytic vacuoles, acid-activated fusion of viral envelope with the vacuolar membrane, nucleocapsid uncoating in the cytosol, nuclear import of viral ribonucleoproteins, and expression of the viral nucleoprotein. We adapted the assays to automated microscopy and optimized them for high-content screening. To quantify the image data, we performed both single and multi-parametric analyses, in combination with machine learning. By time-course experiments, we determined the optimal time points for each assay. Our quality control experiments showed that the assays were sufficiently robust for high-content analysis. The methods we describe in this study provide a powerful high-throughput platform to understand the host cell processes, which can eventually lead to the discovery of novel anti-pathogen strategies. PMID:23874633

  8. Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats

    SciTech Connect

    Yamazaki, Makoto; Miyake, Manami; Sato, Hiroko; Masutomi, Naoya; Tsutsui, Naohisa; Adam, Klaus-Peter; Alexander, Danny C.; Lawton, Kay A.; Milburn, Michael V.; Ryals, John A.; Wulff, Jacob E.; Guo, Lining

    2013-04-01

    Drug-induced liver injury (DILI) is a significant consideration for drug development. Current preclinical DILI assessment relying on histopathology and clinical chemistry has limitations in sensitivity and discordance with human. To gain insights on DILI pathogenesis and identify potential biomarkers for improved DILI detection, we performed untargeted metabolomic analyses on rats treated with thirteen known hepatotoxins causing various types of DILI: necrosis (acetaminophen, bendazac, cyclosporine A, carbon tetrachloride, ethionine), cholestasis (methapyrilene and naphthylisothiocyanate), steatosis (tetracycline and ticlopidine), and idiosyncratic (carbamazepine, chlorzoxasone, flutamide, and nimesulide) at two doses and two time points. Statistical analysis and pathway mapping of the nearly 1900 metabolites profiled in the plasma, urine, and liver revealed diverse time and dose dependent metabolic cascades leading to DILI by the hepatotoxins. The most consistent change induced by the hepatotoxins, detectable even at the early time point/low dose, was the significant elevations of a panel of bile acids in the plasma and urine, suggesting that DILI impaired hepatic bile acid uptake from the circulation. Furthermore, bile acid amidation in the hepatocytes was altered depending on the severity of the hepatotoxin-induced oxidative stress. The alteration of the bile acids was most evident by the necrosis and cholestasis hepatotoxins, with more subtle effects by the steatosis and idiosyncratic hepatotoxins. Taking together, our data suggest that the perturbation of bile acid homeostasis is an early event of DILI. Upon further validation, selected bile acids in the circulation could be potentially used as sensitive and early DILI preclinical biomarkers. - Highlights: ? We used metabolomics to gain insights on drug induced liver injury (DILI) in rats. ? We profiled rats treated with thirteen hepatotoxins at two doses and two time points. ? The toxins decreased the liver's ability to uptake bile acid from the circulation. ? Oxidative stress induced by the toxins altered bile acid biosynthesis in the liver. ? Selected bile acids in the plasma and urine could be sensitive DILI biomarkers.

  9. Who Needs Replication?

    ERIC Educational Resources Information Center

    Porte, Graeme

    2013-01-01

    In this paper, the editor of a recent Cambridge University Press book on research methods discusses replicating previous key studies to throw more light on their reliability and generalizability. Replication research is presented as an accepted method of validating previous research by providing comparability between the original and replicated

  10. Early impact event and fluid activity on H chondrite parent body registered in the Pu?tusk meteorite

    NASA Astrophysics Data System (ADS)

    Krzesinska, Agata

    2015-04-01

    Impact is one of the most important processes affecting asteroids, but it is neglected as a source for heat of these bodies. Recent modeling work show, however, that impact into warm planetesimals is able to cause global-scale temperature increase to the point of melting of silicates [1]. An obvious consequence of this fact is that the impact activity in early evolution of asteroids may promote formation of melt and its differentiation. H chondrites provide some lines of evidence for an early, 4.4 Ga impact event on their parent body. The event resulted in formation of heavily shocked and melted H chondrites with old gas retention ages [2, 3], including Portales Valley, an unique metal-rich breccia [e.g. 4]. The impact led also, very likely, to unmixing of silicate and metal-sulfide melts and to formation of silicate-iron non-magmatic IIE meteorites [5]. Additional evidence for this event, and for melting it caused, may come from highly equilibrated and recrystallized fragments of the Pu?tusk meteorite containing vein-like metal accumulations [6]. In the Pu?tusk, vein-like metal accumulations are kamacite-rich, and basically depleted in sulfides. They form many tendrils into the equilibrated, well recrystallized chondritic rock. Marked feature of the chondritic rock at the contact with accumulations is presence of unusually large phosphate and feldspar grains. The minerals bear record of crystallization from melt. Both vein-like metal accumulations and chondritic rock record, however, slow cooling rate. Phopshates are in the meteorite represented by merrillite and apatite, predominantly intergrown with each other. Merrillite poikilitically encloses silicate grains. It is probably of magmatic origin, since it contains detectable amount of potassium and high content of sodium. Apatite contains varying concentrations of chlorine, fluorine and missing structural component. Content of Cl and F are negatively correlated and both elements are heterogeneously distributed in the mineral, forming complex, patchy compositional zoning. Formation of vein-like metal accumulations in the Pu?tusk requires impact activity, since under static conditions metal would have formed isolated patches or globules, rather than veins. The impact event must have affected warm parent body in its early evolution, what resulted in slow cooling. Association of phosphate minerals with metal accumulations suggests that they were also formed in response to impact activity. The most likely source of phosphorous to form merrillite was oxidation of P from metal alloys. Merrillite was magmatic rather than metamorphic in origin, whereas apatite overgrowing it was probably formed by interaction between merrillite and a halogen-rich residual fluid or vapor derived from an impact melt. References: [1] Ciesla F.J. et al., 2013. MaPS 48: 2559-2576. [2] Swindle T.D. et al., 2009. MaPS 44: 747-762. [3] Wittmann A. et al., 2010. JGR 115: E07009. [4] Ruzicka A. et al., 2005. MaPS 40: 261-295. [5] Ruzicka A., 2014. Chem der Erde 74: 3-48. [6] Krzesi?ska A., 2011. Meteorites 1: 3-12.

  11. The Intense Arctic Cyclone of Early August 2012: A Dynamically Driven Cyclogenesis Event

    NASA Astrophysics Data System (ADS)

    Bosart, L. F.; Turchioe, A.; Adamchcik, E.

    2013-12-01

    A series of surface cyclones formed along an anomalously strong northeast-southwest oriented baroclinic zone over north-central Russia on 1-3 August 2012. These cyclones moved northeastward, intensified slowly, and crossed the coast of Russia by 4 August. The last cyclone in the series strengthened rapidly as it moved poleward over the Arctic Ocean on 5-6 August, achieved a minimum sea level pressure of < 965 hPa by 6 August, and was arguably the most intense storm system to impact the Arctic Ocean in the modern data record going back to the International Geophysical Year in 1957-1958. The purpose of this presentation is to illustrate the structure and life cycle of this Arctic Ocean cyclone from a multiscale perspective. Anticyclonic wave breaking in the upper troposphere across Russia in late July and very early August 2012 created an anomalously strong baroclinic zone across northern Asia between 60-80°N. During 1-5 August, negative 850 hPa temperature anomalies between -2° and -4°C were found poleward of 70-75°N between 90°E and the Dateline over the Arctic Ocean while positive 850 hPa temperature anomalies of 8-9°C were found over eastern Russia near 60°N. The associated anomalously strong 850 hPa meridional temperature gradient of ~10°C (2000 km)-1 helped to sustain an anomalously strong (20-30 m s-1) 250 hPa jet along the coast of northeastern Russia. A local wind speed maximum (~50 m s-1 ) embedded in this 250 hPa jet corridor contributed to the extreme intensity of the trailing (last) surface cyclone in the series. Although the dominant surface cyclone in the series of surface cyclones intensified most rapidly over the relatively ice free Arctic Ocean, the impact of surface heat and moisture fluxes appeared to be secondary to jet-driven dynamical processes in the deepening process. Anomalously high observed 1000-500 hPa thickness values between 564-570 dam, precipitable water values between 30-40 mm, and CAPE values between 500-1000 J kg-1 in the warm sector of the developing cyclone over north-central Russia were indicative of the enhanced baroclinicity and instability in the cyclone warm sector and the ability of lower tropospheric warm-air advection to sustain deep ascent in the intensifying cyclone. The relative importance of dynamical versus thermodynamical forcing to the cyclogenesis process as well as the bulk upscale effects of the intense cyclone on the larger scale higher-latitude circulation and the distribution of sea ice will be discussed. A noteworthy aspect of the post-storm polar environment was the upscale growth of a midlevel cyclonic circulation to include most of the Arctic Ocean. The off-pole displacement of this midlevel cyclonic circulation toward northern Canada by mid-August may have contributed to the termination of the 2012 summer-long intensive heat wave over most of the continental United States.

  12. Replication-transcription switch in human mitochondria

    PubMed Central

    Agaronyan, Karen; Morozov, Yaroslav I.; Anikin, Michael; Temiakov, Dmitry

    2015-01-01

    Coordinated replication and expression of mitochondrial genome is critical for metabolically active cells during various stages of development. However, it is not known whether replication and transcription can occur simultaneously without interfering with each other and whether mtDNA copy number can be regulated by the transcription machinery. We found that interaction of human transcription elongation factor, TEFM with mitochondrial RNA polymerase (mtRNAP) and nascent transcript prevents generation of replication primers and increases transcription processivity thereby serving as a molecular switch between replication and transcription, which appear to be mutually exclusive processes in mitochondria. TEFM may allow mitochondria to increase transcription rates and, as consequence, respiration and ATP production without the need to replicate mtDNA, which has been observed during spermatogenesis and early stages of embryogenesis. PMID:25635099

  13. Subsurface warming in the subpolar North Atlantic during rapid climate events in the Early and Mid-Pleistocene

    NASA Astrophysics Data System (ADS)

    Hernández-Almeida, Iván; Sierro, Francisco; Cacho, Isabel; Abel Flores, José

    2014-05-01

    A new high-resolution reconstruction of the temperature and salinity of the subsurface waters using paired Mg/Ca-?18O measurements on the planktonic foraminifera Neogloboquadrina pachyderma sinistrorsa (sin.) was conducted on a deep-sea sediment core in the subpolar North Atlantic (Site U1314). This study aims to reconstruct millennial-scale subsurface hydrography variations during the Early and Mid-Pleistocene (MIS 31-19). These rapid climate events are characterized by abrupt shifts between warm/cold conditions, and ice-sheet oscillations, as evidenced by major ice rafting events recorded in the North Atlantic sediments (Hernández-Almeida et al., 2012), similar to those found during the Last Glacial period (Marcott et al, 2011). The Mg/Ca derived paleotemperature and salinity oscillations prior and during IRD discharges at Site U1314 are related to changes in intermediate circulation. The increases in Mg/Ca paleotemperatures and salinities during the IRD event are preceded by short episodes of cooling and freshening of subsurface waters. The response of the AMOC to this perturbation is an increased of warm and salty water coming from the south, transported to high latitudes in the North Atlantic beneath the thermocline. This process is accompanied by a southward shift in the convection cell from the Nordic Seas to the subpolar North Atlantic and better ventilation of the North Atlantic at mid-depths. Poleward transport of warm and salty subsurface subtropical waters causes intense basal melting and thinning of marine ice-shelves, that culminates in large-scale instability of the ice sheets, retreat of the grounding line and iceberg discharge. The mechanism proposed involves the coupling of the AMOC with ice-sheet dynamics, and would explain the presence of these fluctuations before the establishment of high-amplitude 100-kyr glacial cycles. Hernández-Almeida, I., Sierro, F.J., Cacho, I., Flores, J.A., 2012. Impact of suborbital climate changes in the North Atlantic on ice sheet dynamics at the Mid-Pleistocene Transition. Paleoceanography 27, PA3214. Marcott, S.A., Clark, P.U., Padman, L., Klinkhammer, G.P., Springer, S.R., Liu, Z., Otto-Bliesner, B.L., Carlson, A.E., Ungerer, A., Padman, J., He, F., Cheng, J., Schmittner, A., 2011. Ice-shelf collapse from subsurface warming as a trigger for Heinrich events. Proceedings of the National Academy of Sciences 108, 13415-13419

  14. Mammalian cell DNA replication.

    PubMed

    Hickey, R J; Malkas, L H

    1997-01-01

    The precise mechanisms involved in the regulation of the mammalian cell DNA-synthesizing machinery are poorly understood. In vitro DNA replication systems, in particular the employment of the simian virus 40 (SV40)-based cell-free DNA replication system, has identified several mammalian enzymes and proteins required for DNA synthesis. Although these proteins have been identified as playing a role in DNA replication, their functional organization allowing for the efficient replication of DNA has not been well defined. This review describes the proteins that have currently been defined as having a role in mammalian DNA replication and their proposed mechanisms of action. How these proteins may organize themselves to form multiprotein complexes, or larger DNA replication factories, allowing for efficient chromosomal DNA synthesis is discussed. In addition, the cell cycle regulation of mammalian DNA synthesis and the current status concerning mammalian DNA replication origins is described. PMID:9034719

  15. Single-Cell and Single-Cycle Analysis of HIV-1 Replication

    PubMed Central

    Holmes, Mowgli; Zhang, Fengwen; Bieniasz, Paul D.

    2015-01-01

    The dynamics of the late stages of the HIV-1 life cycle are poorly documented. Viral replication dynamics are typically measured in populations of infected cells, but asynchrony that is introduced during the early steps of HIV-1 replication complicates the measurement of the progression of subsequent steps and can mask replication dynamics and their variation in individual infected cells. We established microscopy-based methods to dynamically measure HIV-1-encoded reporter gene and antiviral gene expression in individual infected cells. We coupled these measurements with conventional analyses to quantify delays in the HIV-1 replication cycle imposed by the biphasic nature of HIV-1 gene expression and by the assembly-inhibiting property of the matrix domain of Gag. We further related the dynamics of restriction factor (APOBEC3G) removal to the dynamics of HIV-1 replication in individual cells. These studies provide a timeline for key events in the HIV-1 replication cycle, and reveal that the interval between the onset of early and late HIV-1 gene expression is only ~3h, but matrix causes a ~6–12h delay in the generation of extracellular virions. Interestingly, matrix delays particle assembly to a time at which APOBEC3G has largely been removed from the cell. Thus, a need to prepare infected cells to be efficient producers of infectious HIV-1 may provide an impetus for programmed delays in HIV-1 virion genesis. Our findings also emphasize the significant heterogeneity in the length of the HIV-1 replication cycle in homogenous cell populations and suggest that a typical infected cell generates new virions for only a few hours at the end of a 48h lifespan. Therefore, small changes in the lifespan of infected cells might have a large effect on viral yield in a single cycle and the overall clinical course in infected individuals. PMID:26086614

  16. Early Results of Three-Year Monitoring of Red Wood Ants’ Behavioral Changes and Their Possible Correlation with Earthquake Events

    PubMed Central

    Berberich, Gabriele; Berberich, Martin; Grumpe, Arne; Wöhler, Christian; Schreiber, Ulrich

    2013-01-01

    Simple Summary For three years (2009–2012), two red wood ant mounds (Formica rufa-group), located at the seismically active Neuwied Basin (Eifel, Germany), have been monitored 24/7 by high-resolution cameras. Early results show that ants have a well-identifiable standard daily routine. Correlation with local seismic events suggests changes in the ants’ behavior hours before the earthquake: the nocturnal rest phase and daily activity are suppressed, and standard daily routine does not resume until the next day. At present, an automated image evaluation routine is being applied to the video streams. Based on this automated approach, a statistical analysis of the ant behavior will be carried out. Abstract Short-term earthquake predictions with an advance warning of several hours or days are currently not possible due to both incomplete understanding of the complex tectonic processes and inadequate observations. Abnormal animal behaviors before earthquakes have been reported previously, but create problems in monitoring and reliability. The situation is different with red wood ants (RWA; Formica rufa-group (Hymenoptera: Formicidae)). They have stationary mounds on tectonically active, gas-bearing fault systems. These faults may be potential earthquake areas. For three years (2009–2012), two red wood ant mounds (Formica rufa-group), located at the seismically active Neuwied Basin (Eifel, Germany), have been monitored 24/7 by high-resolution cameras with both a color and an infrared sensor. Early results show that ants have a well-identifiable standard daily routine. Correlation with local seismic events suggests changes in the ants’ behavior hours before the earthquake: the nocturnal rest phase and daily activity are suppressed, and standard daily routine does not resume until the next day. At present, an automated image evaluation routine is being applied to the more than 45,000 hours of video streams. Based on this automated approach, a statistical analysis of the ants’ behavior will be carried out. In addition, other parameters (climate, geotectonic and biological), which may influence behavior, will be included in the analysis. PMID:26487310

  17. Calcium isotope evidence for dramatic increase of continental weathering during the Toarcian oceanic anoxic event (Early Jurassic)

    NASA Astrophysics Data System (ADS)

    Brazier, Jean-Michel; Suan, Guillaume; Tacail, Théo; Simon, Laurent; Martin, Jeremy E.; Mattioli, Emanuela; Balter, Vincent

    2015-02-01

    The early Toarcian was punctuated by pulses of massive carbon injection that are thought to have triggered, through increased greenhouse conditions, elevated continental discharge and nutrient input, marine anoxia, seawater acidification and species extinctions. Nevertheless, the mode and tempo of changes in continental weathering across this interval remains highly debated, leading to considerable uncertainty about the main causes of these perturbations. In this study we present calcium isotope measurements (?44/40Ca) of well-preserved brachiopods and bulk rock samples from the hemipelagic strata of Pliensbachian-Toarcian age of Peniche in Portugal in order to constrain changes in the calcium cycle and hence changes in continental weathering during the early Toarcian. The data reveal a similar trend as carbon isotope data from the same section and show negative excursions of about 0.5‰ at the Pliensbachian-Toarcian transition (Pl-To) and at the base of the Toarcian Oceanic Anoxic Event (T-OAE) interval. The comparison of ?44/40Ca ratios recorded in brachiopods and bulk rock corrected for variable dolomite contribution indicates that these excursions reflect changes in the global isotopic composition of seawater rather than changes in the dominant mineralogy of calcifying organisms or in hydrological budget of the considered basin. Box modeling results suggest that the Pl-To and T-OAE ?44/40Ca excursions can be explained by a transient 90% decrease of carbonate accumulation due to seawater acidification followed by a 500% increase in continental weathering rates. The sharp increases in continental weathering inferred from the ?44/40Ca ratios seem overall consistent with lower Toarcian sedimentological and biotic records that document rapid crises in carbonate production followed by episodes of increased calcium carbonate burial. Nevertheless, the maximum of carbonate burial recorded by most NW European basinal successions occurs several hundreds of kyrs after that predicted by box modeling results. This mismatch either implies that the European records of carbonate accumulation do not reflect global trends or that the fundamental processes related to the removal of excess alkalinity caused by increased continental weathering are more complex than previously appreciated. Based on the amount of Ca input simulated by box modeling, the injection of tens of thousands of gigatons of carbon with an isotopic composition (?13C) comprised between - 6 ‰ and - 14 ‰ appears as the most likely causes of the ?13C excursions characterizing these two events. These results indicate that environmental and biotic changes of the Pl-To and T-OAE were mainly caused a cascade of environmental changes triggered by the massive carbon emissions from the Karoo-Ferrar volcanism.

  18. Postweaning Exposure to Dietary Zearalenone, a Mycotoxin, Promotes Premature Onset of Puberty and Disrupts Early Pregnancy Events in Female Mice

    PubMed Central

    Ye, Xiaoqin

    2013-01-01

    Zearalenone (ZEA) is a mycotoxin commonly found in contaminated livestock feed and human food with levels in the range of ppb and low ppm. It was hypothesized that ZEA, an endocrine disruptor, could affect puberty and early pregnancy. To test this hypothesis, newly weaned (3 weeks old) C57BL/6J female mice were exposed to 0, 0.002, 4, 10, and 40 ppm ZEA and 0.05 ppm diethylstilbestrol (positive control) in phytoestrogen-free AIN-93G diet. Females exposed to 10 and 40 ppm ZEA diets showed earlier onset of vaginal opening. Those treated with 40 ppm ZEA diet also had earlier first copulation plug and irregular estrous cyclicity. At 8 weeks old, all females were mated with untreated stud males on AIN-93G diet during mating. Treatment resumed upon identification of a vaginal plug on gestation day 0.5 (D0.5). Embryo implantation was assessed on D4.5. Exposure to 40 ppm ZEA diet resulted in reduced percentage of plugged mice with implantation sites, distended uterine appearance, and retained expression of progesterone receptor in D4.5 uterine epithelium. To determine the exposure timing and mechanisms of disrupted embryo implantation, four groups of females were fed with 0 or 40 ppm ZEA diets during premating (weaning to mating) and postmating (D0.5–D4.5), respectively. Premating exposure to 40 ppm ZEA diet reduced fertilization rate, whereas postmating exposure to 40 ppm ZEA diet delayed embryo transport and preimplantation embryo development, which subsequently affected embryo implantation. These data demonstrate that postweaning exposure to dietary ZEA can promote premature onset of puberty and disrupt early pregnancy events. PMID:23291560

  19. High ABCC2 and low ABCG2 gene expression are early events in the colorectal adenoma-carcinoma sequence.

    PubMed

    Andersen, Vibeke; Vogel, Lotte K; Kopp, Tine Iskov; Sæbø, Mona; Nonboe, Annika W; Hamfjord, Julian; Kure, Elin H; Vogel, Ulla

    2015-01-01

    Development of colorectal cancer (CRC) may result from a dysfunctional interplay between diet, gut microbes and the immune system. The ABC transport proteins ABCB1 (P-glycoprotein, Multidrug resistance protein 1, MDR1), ABCC2 (MRP2) and ABCG2 (BCRP) are involved in transport of various compounds across the epithelial barrier. Low mRNA level of ABCB1 has previously been identified as an early event in colorectal carcinogenesis (Andersen et al., PLoS One. 2013 Aug 19;8(8):e72119). ABCC2 and ABCG2 mRNA levels were assessed in intestinal tissue from 122 CRC cases, 106 adenoma cases (12 with severe dysplasia, 94 with mild-moderate dysplasia) and from 18 controls with normal endoscopy. We found significantly higher level of ABCC2 in adenomas with mild to moderate dysplasia and carcinoma tissue compared to the levels in unaffected tissue from the same individual (P = 0.037, P = 0.037, and P<0.0001) and in carcinoma and distant unaffected tissue from CRC cases compared to the level in the healthy individuals (P = 0.0046 and P = 0.036). Furthermore, ABCG2 mRNA levels were significantly lower in adenomas and carcinomas compared to the level in unaffected tissue from the same individuals and compared to tissue from healthy individuals (P<0.0001 for all). The level of ABCB2 in adjacent normal tissue was significantly higher than in tissue from healthy individuals (P = 0.011). In conclusion, this study found that ABCC2 and ABCG2 expression levels were altered already in mild/moderate dysplasia in carcinogenesis suggesting that these ABC transporters are involved in the early steps of carcinogenesis as previously reported for ABCB1. These results suggest that dysfunctional transport across the epithelial barrier may contribute to colorectal carcinogenesis. PMID:25793771

  20. High ABCC2 and Low ABCG2 Gene Expression Are Early Events in the Colorectal Adenoma-Carcinoma Sequence

    PubMed Central

    Andersen, Vibeke; Vogel, Lotte K; Kopp, Tine Iskov; Sæbø, Mona; Nonboe, Annika W.; Hamfjord, Julian; Kure, Elin H.; Vogel, Ulla

    2015-01-01

    Development of colorectal cancer (CRC) may result from a dysfunctional interplay between diet, gut microbes and the immune system. The ABC transport proteins ABCB1 (P-glycoprotein, Multidrug resistance protein 1, MDR1), ABCC2 (MRP2) and ABCG2 (BCRP) are involved in transport of various compounds across the epithelial barrier. Low mRNA level of ABCB1 has previously been identified as an early event in colorectal carcinogenesis (Andersen et al., PLoS One. 2013 Aug 19;8(8):e72119). ABCC2 and ABCG2 mRNA levels were assessed in intestinal tissue from 122 CRC cases, 106 adenoma cases (12 with severe dysplasia, 94 with mild-moderate dysplasia) and from 18 controls with normal endoscopy. We found significantly higher level of ABCC2 in adenomas with mild to moderate dysplasia and carcinoma tissue compared to the levels in unaffected tissue from the same individual (P = 0.037, P = 0.037, and P<0.0001) and in carcinoma and distant unaffected tissue from CRC cases compared to the level in the healthy individuals (P = 0.0046 and P = 0.036). Furthermore, ABCG2 mRNA levels were significantly lower in adenomas and carcinomas compared to the level in unaffected tissue from the same individuals and compared to tissue from healthy individuals (P<0.0001 for all). The level of ABCB2 in adjacent normal tissue was significantly higher than in tissue from healthy individuals (P = 0.011). In conclusion, this study found that ABCC2 and ABCG2 expression levels were altered already in mild/moderate dysplasia in carcinogenesis suggesting that these ABC transporters are involved in the early steps of carcinogenesis as previously reported for ABCB1. These results suggest that dysfunctional transport across the epithelial barrier may contribute to colorectal carcinogenesis. PMID:25793771

  1. Impaired Neurogenesis is an early event in the etiology of Familial Alzheimer’s disease in transgenic mice

    PubMed Central

    Demars, Michael; Hu, Yuan-Shih; Gadadhar, Archana; Lazarov, Orly

    2013-01-01

    Formation of new neurons in the adult brain takes place in the subventricular zone and in the subgranule layer of the dentate gyrus throughout life. Neurogenesis is thought to play a role in hippocampus- and olfaction-dependent learning and memory. However, whether impairments in neurogenesis take place in learning and memory disorders, such as Alzheimer’s disease, is yet to be established. More importantly, it remains to be elucidated whether neurogenic impairments play a role in the course of the disease or are the result of extensive neuropathology. We now report that transgenic mice harboring Familial Alzheimer’s disease-linked mutant APPswe/PS1?E9 exhibit severe impairments in neurogenesis that are evident as early as two months of age. These mice exhibit a significant reduction in the proliferation of neural progenitor cells and their neuronal differentiation. Interestingly, levels of hyperphosphorylated tau, the cytotoxic precursor of the Alzheimer’s disease hallmark neurofibrillary tangles, are particularly high in the neurogenic niches. Isolation of neural progenitor cells in culture reveals that APPswe/PS1?E9-expressing neurospheres exhibit impaired proliferation and tau hyperphosphorylation compared to wild type neurospheres isolated from nontransgenic littermates. This study suggests that impaired neurogenesis is an early critical event in the course of Alzheimer’s disease that may underlie memory impairments, at least in part, and exacerbate neuronal vulnerability in the hippocampal formation and olfaction circuits. Furthermore, impaired neurogenesis is the result of both intrinsic pathology in neural progenitor cells and extrinsic neuropathology in the neurogenic niches. Finally, hyperphosphorylation of the microtubule-associated protein tau, a critical player in cell proliferation, neuronal maturation and axonal transport is a major contributor to impaired neurogenesis in Alzheimer’s disease. PMID:20209626

  2. A late eocene-early Oligocene transgressive event in the Golfo San Jorge basin: Palynological results and stratigraphic implications

    NASA Astrophysics Data System (ADS)

    Paredes, José M.; Foix, Nicolás; Guerstein, G. Raquel; Guler, María V.; Irigoyen, Martín; Moscoso, Pablo; Giordano, Sergio

    2015-11-01

    A new Cenozoic dataset in the subsurface of the South Flank of the Golfo San Jorge Basin (Santa Cruz province) allowed to identify a non-previously recognized transgressive event of late Eocene to early Oligocene age. Below of a marine succession containing a dinoflagellate cyst assemblage that characterizes the C/G palynological zone of the Chenque Formation (early Miocene), a 80-110 m thick marine succession contains a palynological assemblage integrated by Gelatia inflata, Diphyes colligerum and Reticulatosphaera actinocoronata supporting the occurrence of a marine incursion in the basin during the Eocene-Oligocene transition (EOT). The new lithostratigraphic unit - here defined as El Huemul Formation - covers in sharp contact to the Sarmiento Formation, and become thinner from East to West; the unit has been identified in about 1800 well logs covering up to 3500 km2, and its subsurface distribution exceed the boundaries of the study area. The El Huemul Formation consists of a thin lag of glauconitic sandstones with fining-upward log motif, followed by a mudstone-dominated succession that coarsening-upward to sandstones, evidencing a full T-R cycle. Preservation of the El Huemul Formation in the subsurface of the South Flank has been favored by the reactivation of WNW-ESE late Cretaceous normal faults, and by the generation of N-S striking normal faults of Paleocene-Eocene age. Flexural loading associated to igneous intrusions of Paleocene?- middle Eocene age also promoted the increase of subsidence in the South Flank of the basin prior to the transgression.

  3. Abnormal developmental control of replication-timing domains in pediatric acute lymphoblastic leukemia

    PubMed Central

    Ryba, Tyrone; Battaglia, Dana; Chang, Bill H.; Shirley, James W.; Buckley, Quinton; Pope, Benjamin D.; Devidas, Meenakshi; Druker, Brian J.; Gilbert, David M.

    2012-01-01

    Abnormal replication timing has been observed in cancer but no study has comprehensively evaluated this misregulation. We generated genome-wide replication-timing profiles for pediatric leukemias from 17 patients and three cell lines, as well as normal B and T cells. Nonleukemic EBV-transformed lymphoblastoid cell lines displayed highly stable replication-timing profiles that were more similar to normal T cells than to leukemias. Leukemias were more similar to each other than to B and T cells but were considerably more heterogeneous than nonleukemic controls. Some differences were patient specific, while others were found in all leukemic samples, potentially representing early epigenetic events. Differences encompassed large segments of chromosomes and included genes implicated in other types of cancer. Remarkably, differences that distinguished leukemias aligned in register to the boundaries of developmentally regulated replication-timing domains that distinguish normal cell types. Most changes did not coincide with copy-number variation or translocations. However, many of the changes that were associated with translocations in some leukemias were also shared between all leukemic samples independent of the genetic lesion, suggesting that they precede and possibly predispose chromosomes to the translocation. Altogether, our results identify sites of abnormal developmental control of DNA replication in cancer that reveal the significance of replication-timing boundaries to chromosome structure and function and support the replication domain model of replication-timing regulation. They also open new avenues of investigation into the chromosomal basis of cancer and provide a potential novel source of epigenetic cancer biomarkers. PMID:22628462

  4. Early Events in the Life of Apple Roots: Variation in Root Growth Rate is Linked to Mycorrhizal and Nonmycorrhizal Fungal Colonization

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A study was conducted to characterize early events of mycorrhizal and nonmycorrhizal fungal colonization in newly-emerging roots of mature apple (Malus domestica) trees and to determine the relationship to fine root growth rate and development. New roots were traced on root windows to measure growt...

  5. Transcriptomic dose-and-time-course indicators of early key events in a cytotoxicity-mediated mode of action for rodent urinary bladder tumorigenesis

    EPA Science Inventory

    TRANSCRIPTOMIC DOSE- AND TIME-COURSE INDICATORS OF EARLY KEY EVENTS IN A CYTOTOXICITY-MEDIATED MODE OF ACTION FOR RODENT URINARY BLADDER TUMORIGENESISDiuron is a substituted urea compound used globally as an herbicide. Urinary bladder tumors were induced in rats after chronic die...

  6. Microgravity Effects on the Early Events of Biological Nitrogen Fixation in Medicago Truncatula: Results from the SyNRGE Experiment

    NASA Astrophysics Data System (ADS)

    Stutte, Gary W.; Roberts, Michael S.

    2013-02-01

    SyNRGE (Symbiotic Nodulation in a Reduced Gravity Environment) was a sortie mission on STS-135 in the Biological Research in Canisters (BRIC) hardware to study the effect of ?g on a plant-microbe symbiosis resulting in biological nitrogen fixation. Medicago truncatula, a model species for the legume family, was inoculated with its bacterial symbiont, Sinorhizobium meliloti, to observe early biomolecular events associated with infection and nodulation in Petri Dish Fixation Units (PDFU’s). Two sets of experiments were conducted in orbit and in 24-hour delayed ground controls. Experiments were designed to determine if S. meliloti would infect M. truncatula and initiate biomolecular changes associated with nodule formation and if the ?g environment altered the host plant and/or bacteria to induce nodule formation upon return to 1g. Initial analysis results demonstrate that the legumes and bacteria cultivated in ?g have potential to develop a symbiotic interaction, but suggest that ?g alters their ability to form nodules upon return to 1g. (Research supported by NASA ESMD/ Advance Capabilities Division grant NNX10AR09A)

  7. Subsurface North Atlantic warming as a trigger of rapid cooling events: evidences from the Early Pleistocene (MIS 31-19)

    NASA Astrophysics Data System (ADS)

    Hernández-Almeida, I.; Sierro, F.-J.; Cacho, I.; Flores, J.-A.

    2014-10-01

    Subsurface water column dynamics in the subpolar North Atlantic were reconstructed in order to improve the understanding of the cause of abrupt IRD events during cold periods of the Early Pleistocene. We used Mg / Ca-based temperatures of deep-dwelling (Neogloboquadrina pachyderma sinistral) planktonic foraminifera and paired Mg / Ca-?18O measurements to estimate the subsurface temperatures and ?18O of seawater at Site U1314. Carbon isotopes on benthic and planktonic foraminifera from the same site provide information about the ventilation and water column nutrient gradient. Mg / Ca-based temperatures and ?18O of seawater suggest increased temperatures and salinities during ice-rafting, likely due to enhanced northward subsurface transport of subtropical waters during periods of AMOC reduction. Planktonic carbon isotopes support this suggestion, showing coincident increased subsurface ventilation during deposition of ice-rafted detritus (IRD). Warm waters accumulated at subsurface would result in basal warming and break-up of ice-shelves, leading to massive iceberg discharges in the North Atlantic. Release of heat and salt stored at subsurface would help to restart the AMOC. This mechanism is in agreement with modelling and proxy studies that observe a subsurface warming in the North Atlantic in response to AMOC slowdown during the MIS3.

  8. Subsurface North Atlantic warming as a trigger of rapid cooling events: evidence from the early Pleistocene (MIS 31-19)

    NASA Astrophysics Data System (ADS)

    Hernández-Almeida, I.; Sierro, F.-J.; Cacho, I.; Flores, J.-A.

    2015-04-01

    Subsurface water column dynamics in the subpolar North Atlantic were reconstructed in order to improve the understanding of the cause of abrupt ice-rafted detritus (IRD) events during cold periods of the early Pleistocene. We used paired Mg / Ca and ?18O measurements of Neogloboquadrina pachyderma (sinistral - sin.), deep-dwelling planktonic foraminifera, to estimate the subsurface temperatures and seawater ?18O from a sediment core from Gardar Drift, in the subpolar North Atlantic. Carbon isotopes of benthic and planktonic foraminifera from the same site provide information about the ventilation and water column nutrient gradient. Mg / Ca-based temperatures and seawater ?18O suggest increased subsurface temperatures and salinities during ice-rafting, likely due to northward subsurface transport of subtropical waters during periods of weaker Atlantic Meridional Overturning Circulation (AMOC). Planktonic carbon isotopes support this suggestion, showing coincident increased subsurface ventilation during deposition of IRD. Subsurface accumulation of warm waters would have resulted in basal warming and break-up of ice-shelves, leading to massive iceberg discharges in the North Atlantic. The release of heat stored at the subsurface to the atmosphere would have helped to restart the AMOC. This mechanism is in agreement with modelling and proxy studies that observe a subsurface warming in the North Atlantic in response to AMOC slowdown during Marine Isotope Stage (MIS) 3.

  9. Inflammatory Reaction as Determinant of Foreign Body Reaction Is an Early and Susceptible Event after Mesh Implantation

    PubMed Central

    Georgas, Evangelos; Borós, Mihaly; Klosterhalfen, Bernd; Eimer, Christoph; Arndt, Christian; Otto, Stephan; Barski, Dimitri; Ysebaert, Dirk; Ramon, Albert; Otto, Thomas

    2014-01-01

    Purpose. To investigate and relate the ultrashort-term and long-term courses of determinants for foreign body reaction as biocompatibility predictors for meshes in an animal model. Materials and Methods. Three different meshes (TVT, UltraPro, and PVDF) were implanted in sheep. Native and plasma coated meshes were placed bilaterally: (a) interaperitoneally, (b) as fascia onlay, and (c) as muscle onlay (fascia sublay). At 5?min, 20?min, 60?min, and 120?min meshes were explanted and histochemically investigated for inflammatory infiltrate, macrophage infiltration, vessel formation, myofibroblast invasion, and connective tissue accumulation. The results were related to long-term values over 24 months. Results. Macrophage invasion reached highest extents with up to 60% in short-term and decreased within 24 months to about 30%. Inflammatory infiltrate increased within the first 2 hours, the reached levels and the different extents and ranking among the investigated meshes remained stable during long-term follow up. For myofibroblasts, connective tissue, and CD31+ cells, no activity was detected during the first 120?min. Conclusion. The local inflammatory reaction is an early and susceptible event after mesh implantation. It cannot be influenced by prior plasma coating and does not depend on the localisation of implantation. PMID:24783209

  10. Early Results of Three-Year Monitoring of Red Wood Ants' Behavioral Changes and Their Possible Correlation with Earthquake Events.

    PubMed

    Berberich, Gabriele; Berberich, Martin; Grumpe, Arne; Wöhler, Christian; Schreiber, Ulrich

    2013-01-01

    Short-term earthquake predictions with an advance warning of several hours or days are currently not possible due to both incomplete understanding of the complex tectonic processes and inadequate observations. Abnormal animal behaviors before earthquakes have been reported previously, but create problems in monitoring and reliability. The situation is different with red wood ants (RWA; Formica rufa-group (Hymenoptera: Formicidae)). They have stationary mounds on tectonically active, gas-bearing fault systems. These faults may be potential earthquake areas. For three years (2009-2012), two red wood ant mounds (Formica rufa-group), located at the seismically active Neuwied Basin (Eifel, Germany), have been monitored 24/7 by high-resolution cameras with both a color and an infrared sensor. Early results show that ants have a well-identifiable standard daily routine. Correlation with local seismic events suggests changes in the ants' behavior hours before the earthquake: the nocturnal rest phase and daily activity are suppressed, and standard daily routine does not resume until the next day. At present, an automated image evaluation routine is being applied to the more than 45,000 hours of video streams. Based on this automated approach, a statistical analysis of the ants' behavior will be carried out. In addition, other parameters (climate, geotectonic and biological), which may influence behavior, will be included in the analysis. PMID:26487310

  11. The DNA repair endonuclease Mus81 facilitates fast DNA replication in the absence of exogenous damage

    PubMed Central

    Fu, Haiqing; Martin, Melvenia M.; Regairaz, Marie; Huang, Liang; You, Yang; Lin, Chi-Mei; Ryan, Michael; Kim, RyangGuk; Shimura, Tsutomu; Pommier, Yves; Aladjem, Mirit I.

    2015-01-01

    The Mus81 endonuclease resolves recombination intermediates and mediates cellular responses to exogenous replicative stress. Here, we show that Mus81 also regulates the rate of DNA replication during normal growth by promoting replication fork progression while reducing the frequency of replication initiation events. In the absence of Mus81 endonuclease activity, DNA synthesis is slowed and replication initiation events are more frequent. In addition, Mus81 deficient cells fail to recover from exposure to low doses of replication inhibitors and cell viability is dependent on the XPF endonuclease. Despite an increase in replication initiation frequency, cells lacking Mus81 use the same pool of replication origins as Mus81-expressing cells. Therefore, decelerated DNA replication in Mus81 deficient cells does not initiate from cryptic or latent origins not used during normal growth. These results indicate that Mus81 plays a key role in determining the rate of DNA replication without activating a novel group of replication origins. PMID:25879486

  12. Prenatal and Early Life Exposure to Stressful Life Events and Risk of Autism Spectrum Disorders: Population-Based Studies in Sweden and England

    PubMed Central

    Rai, Dheeraj; Golding, Jean; Magnusson, Cecilia; Steer, Colin; Lewis, Glyn; Dalman, Christina

    2012-01-01

    Background and Aim Exposure to stressful life events during pregnancy has been suggested as a potential risk factor for offspring Autism Spectrum Disorders (ASD), but the literature is limited and inconsistent. We tested the hypothesis that maternal exposure to stressful life events would be associated with increased risks of offspring ASD, and that these risks would be highest for exposures during the prenatal period. Methods and Results We used prospectively collected data from two large population based studies in Sweden and England. In the Swedish study of 4429 ASD cases and 43277 controls, our exposure comprised the occurrence of any severe life event before and during pregnancy and the child's early life. In the English study (maximum n?=?11554, ASD n?=?72), we studied the risk of offspring ASD in relation to a combined maternal exposure to multiple (up to 42) common and rare life events, as well as their perceived impact upon the mother during pregnancy and early life. In crude and adjusted regression analyses in both studies, we found no evidence of an association between prenatal life events, or their number and perceived impact and the risk of offspring ASD. Sub-group analysis of ASD with and without intellectual disability in the Swedish study yielded similar results. Conclusion We found no evidence to support the hypotheses that exposure to stressful life events during the prenatal period is associated with an increased risk of offspring ASD. PMID:22719977

  13. H3K4me3 demethylation by the histone demethylase KDM5C/JARID1C promotes DNA replication origin firing

    PubMed Central

    Rondinelli, Beatrice; Schwerer, Hélène; Antonini, Elena; Gaviraghi, Marco; Lupi, Alessio; Frenquelli, Michela; Cittaro, Davide; Segalla, Simona; Lemaitre, Jean-Marc; Tonon, Giovanni

    2015-01-01

    DNA replication is a tightly regulated process that initiates from multiple replication origins and leads to the faithful transmission of the genetic material. For proper DNA replication, the chromatin surrounding origins needs to be remodeled. However, remarkably little is known on which epigenetic changes are required to allow the firing of replication origins. Here, we show that the histone demethylase KDM5C/JARID1C is required for proper DNA replication at early origins. JARID1C dictates the assembly of the pre-initiation complex, driving the binding to chromatin of the pre-initiation proteins CDC45 and PCNA, through the demethylation of the histone mark H3K4me3. Fork activation and histone H4 acetylation, additional early events involved in DNA replication, are not affected by JARID1C downregulation. All together, these data point to a prominent role for JARID1C in a specific phase of DNA replication in mammalian cells, through its demethylase activity on H3K4me3. PMID:25712104

  14. Cumulative inputs of carbon into the Early Toarcian ocean-atmosphere system: from volcanism to an Oceanic Anoxic Event

    NASA Astrophysics Data System (ADS)

    Hermoso, M.; Rickaby, R. E.; Bjerrum, C.; Baudin, F.; Minoletti, F.; Hesselbo, S. P.; Jenkyns, H. C.

    2010-12-01

    The ~ -7‰ negative carbon-isotope excursion (CIE) and the Oceanic Anoxic Event (OAE) that occurred during the Early Toarcian may have been linked, both having effects on the global carbon cycle [1]. The negative CIE represented times of emission of carbon through release of methane from gas hydrates [2] or from Gondwanan organic-rich deposits [3], whereas black shale deposition acted as a carbon sink and hence, as a feedback mechanism for decreasing CO2 levels together with substantial acceleration of continental weathering [4]. However, the precise causal relationship between these two events is still poorly constrained. A high-resolution study in the Paris Basin reveals a phase lag between these two paleoclimatic perturbations [5]. The first step (of the four that compose the descending limb of the CIE) is recorded ~ 5kyr before the onset of anoxia in this basin. In this study, we compared the coupling in the carbon-isotopes between organic (immature phytoplanktonic organic matter) and inorganic (calcareous nannofossil-bearing sediment with an exceptional good preservational state) substrates expressed by ?B and ?p, and the preservation of pelagic calcareous grains in the sediment to assess the evolution of pCO2. In situ record of the organic and inorganic carbon flux to seafloor reveals how these climatic perturbations have driven the local environment. Investigating the competition between emission and sinking of carbon at both long- and short terms allows insights into the dynamics of the global carbon cycle during super-greenhouse periods, and the role of the “biological pump” in a context of very high productivity. During the OAE, both assumed increase in temperature and reduction in surface water salinity are expressed by a ~ -1.5‰ shift in the oxygen-isotopes values in the Paris Basin that persisted after the recovery of the CIE. Additionally, we investigated at very high-resolution the 50-cm-thick interval corresponding to the onset of the CIE, and demonstrated substantial reduction in the content of calcareous nannofossils immediately before the drop in ?13C values. This precursor event is compatible with seawater acidification and may have been a probable consequence of a pulse in the Karoo-Ferrar subaerial volcanism as suggested by a relatively minor (~ -0.5‰) ?13C negative shift. This sequence of events recorded within a period no longer than 50kyr suggests of a causal relationship between volcanism, destabilization of gas hydrates, and the triggering of protracted anoxic conditions. [1] Jenkyns, H.C. (2010). G-cubed 11, Q03004, doi:10.1029/2009GC002788. [2] Hesselbo, S.P., et al. (2000). Nature 406, 392-395. [3] McElwain, J., et al. (2005). Nature 35, 479-482. [4] Cohen, A.S., et al. (2004). Geology 32, 157-160. [5] Hermoso, M., et al. (2009). Paleoceanography 24, PA4208, doi:10.1029/2009PA001764.

  15. Replication Origins and Timing of Temporal Replication in Budding Yeast: How to Solve the Conundrum?

    PubMed Central

    Barberis, Matteo; Spiesser, Thomas W.; Klipp, Edda

    2010-01-01

    Similarly to metazoans, the budding yeast Saccharomyces cereviasiae replicates its genome with a defined timing. In this organism, well-defined, site-specific origins, are efficient and fire in almost every round of DNA replication. However, this strategy is neither conserved in the fission yeast Saccharomyces pombe, nor in Xenopus or Drosophila embryos, nor in higher eukaryotes, in which DNA replication initiates asynchronously throughout S phase at random sites. Temporal and spatial controls can contribute to the timing of replication such as Cdk activity, origin localization, epigenetic status or gene expression. However, a debate is going on to answer the question how individual origins are selected to fire in budding yeast. Two opposing theories were proposed: the “replicon paradigm” or “temporal program” vs. the “stochastic firing”. Recent data support the temporal regulation of origin activation, clustering origins into temporal blocks of early and late replication. Contrarily, strong evidences suggest that stochastic processes acting on origins can generate the observed kinetics of replication without requiring a temporal order. In mammalian cells, a spatiotemporal model that accounts for a partially deterministic and partially stochastic order of DNA replication has been proposed. Is this strategy the solution to reconcile the conundrum of having both organized replication timing and stochastic origin firing also for budding yeast? In this review we discuss this possibility in the light of our recent study on the origin activation, suggesting that there might be a stochastic component in the temporal activation of the replication origins, especially under perturbed conditions. PMID:21037857

  16. Replication foci dynamics: replication patterns are modulated by S-phase checkpoint kinases in fission yeast

    PubMed Central

    Meister, Peter; Taddei, Angela; Ponti, Aaron; Baldacci, Giuseppe; Gasser, Susan M

    2007-01-01

    Although the molecular enzymology of DNA replication is well characterised, how and why it occurs in discrete nuclear foci is unclear. Using fission yeast, we show that replication takes place in a limited number of replication foci, whose distribution changes with progression through S phase. These sites define replication factories which contain on average 14 replication forks. We show for the first time that entire foci are mobile, able both to fuse and re-segregate. These foci form distinguishable patterns during S phase, whose succession is reproducible, defining early-, mid- and late-S phase. In wild-type cells, this same temporal sequence can be detected in the presence of hydroxyurea (HU), despite the reduced rate of replication. In cells lacking the intra-S checkpoint kinase Cds1, replication factories dismantle on HU. Intriguingly, even in the absence of DNA damage, the replication foci in cds1 cells assume a novel distribution that is not present in wild-type cells, arguing that Cds1 kinase activity contributes to the spatio-temporal organisation of replication during normal cell growth. PMID:17304223

  17. Self Replication and Signalling

    E-print Network

    Indranil Chakrabarty; Prashant; B. S. Choudhury

    2007-06-14

    It is known that if one could clone an arbitrary quantum state one could send signal faster than the speed of light. However it remains interesting to see that if one can perfectly self replicate an arbitrary quantum state, does it violate the no signalling principle? Here we see that perfect self replication would also lead to superluminal signalling.

  18. The influence of the thermal environment and other early life events on growth rate of piglets during lactation.

    PubMed

    Pedersen, L J; Schild, S-L Aa; Malmkvist, J

    2015-09-01

    The effects of early life events on average daily weight gain from birth to day 21 (ADG) of suckling pigs kept at different room temperatures (15°C, 20°C and 25°C) from birth to weaning were investigated. Data were collected from litters born by 61 sows in a loose housing system. The ADG for piglets with low birth weight (estimated for birth weights below the 10% percentile) was estimated to be 20 to 30 g higher per day at room temperature 20°C to 25°C compared with 15°C. In contrast, the ADG during the lactation period decreased for larger piglets (estimated for birth weights above the 10% percentile) by 28 g/day at room temperature 25°C compared with 15°C. Thus, high ambient temperatures (20°C to 25°C) are favourable for the growth in smaller piglets during lactation. Neither latency to first suckle nor birth-induced hypoxia, measured as concentration of umbilical cord lactate, affected the growth rate of the piglets. Lowest rectal temperature during the first 24 h after birth had a long-term negative effect on ADG (P<0.05), so that piglets with a lowest rectal temperature of 32.8°C (10% percentile) had an ADG which was on average 19 g lower per day than piglets with a rectal temperature of 37.3°C (90% percentile). Our results showed that hypothermia at birth, low birth weight and high number of suckling piglets lead to reduced ADG during the suckling period. The results suggest that keeping the room temperature at 20°C during lactation to some extent could compensate for the otherwise negative effects of low birth weight on ADG in piglets without decreasing the ADG of high birth weight piglets. However, to avoid hypothermia in the smallest piglets it may be beneficial to increase the room temperature above 20°C during the farrowing period of loose housed sows. PMID:26094618

  19. Strong alkalinization of Chara cell surface in the area of cell wall incision as an early event in mechanoperception.

    PubMed

    Bulychev, Alexander A; Alova, Anna V; Bibikova, Tatiana N

    2013-11-01

    Mechanical wounding of cell walls occurring in plants under the impact of pathogens or herbivores can be mimicked by cell wall incision with a glass micropipette. Measurements of pH at the surface of Chara corallina internodes following microperforation of cell wall revealed a rapid (10-30s) localized alkalinization of the apoplast after a lag period of 10-20s. The pH increase induced by incision could be as large as 3 pH units and relaxed slowly, with a halftime up to 20min. The axial pH profile around the incision zone was bell-shaped and localized to a small area, extending over a distance of about 100?m. The pH response was suppressed by lowering cell turgor upon the replacement of artificial pond water (APW) with APW containing 50mM sorbitol. Stretching of the plasma membrane during its impression into the cell wall defect is likely to activate the Ca(2+) channels, as evidenced from sensitivity of the incision-induced alkalinization to the external calcium concentration and to the addition of Ca(2+)-channel blockers, such as La(3+), Gd(3+), and Zn(2+). The maximal pH values attained at the incision site (~10.0) were close to pH in light-dependent alkaline zones of Chara cells. The involvement of cytoskeleton in the origin of alkaline patch was documented by observations that the incision-induced pH transients were suppressed by the inhibitors of microtubules (oryzalin and taxol) and, to a lesser extent, by the actin inhibitor (cytochalasin B). The results indicate that the localized increase in apoplastic pH is an early event in mechanoperception and depends on light, cytoskeleton, and intracellular calcium. PMID:23850637

  20. A global profile of replicative polymerase usage.

    PubMed

    Daigaku, Yasukazu; Keszthelyi, Andrea; Müller, Carolin A; Miyabe, Izumi; Brooks, Tony; Retkute, Renata; Hubank, Mike; Nieduszynski, Conrad A; Carr, Antony M

    2015-03-01

    Three eukaryotic DNA polymerases are essential for genome replication. Polymerase (Pol) ?-primase initiates each synthesis event and is rapidly replaced by processive DNA polymerases: Pol? replicates the leading strand, whereas Pol? performs lagging-strand synthesis. However, it is not known whether this division of labor is maintained across the whole genome or how uniform it is within single replicons. Using Schizosaccharomyces pombe, we have developed a polymerase usage sequencing (Pu-seq) strategy to map polymerase usage genome wide. Pu-seq provides direct replication-origin location and efficiency data and indirect estimates of replication timing. We confirm that the division of labor is broadly maintained across an entire genome. However, our data suggest a subtle variability in the usage of the two polymerases within individual replicons. We propose that this results from occasional leading-strand initiation by Pol? followed by exchange for Pol?. PMID:25664722

  1. Systematic Determination of Replication Activity Type Highlights Interconnections between Replication,

    E-print Network

    Eldar, Yonina

    Systematic Determination of Replication Activity Type Highlights Interconnections between Replication, Chromatin Structure and Nuclear Localization Shlomit Farkash-Amar1. , Yaara David2. , Andreas Agilent Laboratories Tel-Aviv, Israel Abstract DNA replication is a highly regulated process, with each

  2. Infection of Brachypodium distachyon by formae speciales of Puccinia graminis: early infection events and host-pathogen incompatibility.

    PubMed

    Figueroa, Melania; Alderman, Stephen; Garvin, David F; Pfender, William F

    2013-01-01

    Puccinia graminis causes stem rust, a serious disease of cereals and forage grasses. Important formae speciales of P. graminis and their typical hosts are P. graminis f. sp. tritici (Pg-tr) in wheat and barley, P. graminis f. sp. lolii (Pg-lo) in perennial ryegrass and tall fescue, and P. graminis f. sp. phlei-pratensis (Pg-pp) in timothy grass. Brachypodium distachyon is an emerging genetic model to study fungal disease resistance in cereals and temperate grasses. We characterized the P. graminis-Brachypodium pathosystem to evaluate its potential for investigating incompatibility and non-host resistance to P. graminis. Inoculation of eight Brachypodium inbred lines with Pg-tr, Pg-lo or Pg-pp resulted in sporulating lesions later accompanied by necrosis. Histological analysis of early infection events in one Brachypodium inbred line (Bd1-1) indicated that Pg-lo and Pg-pp were markedly more efficient than Pg-tr at establishing a biotrophic interaction. Formation of appressoria was completed (60-70% of germinated spores) by 12 h post-inoculation (hpi) under dark and wet conditions, and after 4 h of subsequent light exposure fungal penetration structures (penetration peg, substomatal vesicle and primary infection hyphae) had developed. Brachypodium Bd1-1 exhibited pre-haustorial resistance to Pg-tr, i.e. infection usually stopped at appressorial formation. By 68 hpi, only 0.3% and 0.7% of the Pg-tr urediniospores developed haustoria and colonies, respectively. In contrast, development of advanced infection structures by Pg-lo and Pg-pp was significantly more common; however, Brachypodium displayed post-haustorial resistance to these isolates. By 68 hpi the percentage of urediniospores that only develop a haustorium mother cell or haustorium in Pg-lo and Pg-pp reached 8% and 5%, respectively. The formation of colonies reached 14% and 13%, respectively. We conclude that Brachypodium is an apt grass model to study the molecular and genetic components of incompatiblity and non-host resistance to P. graminis. PMID:23441218

  3. Organization of DNA Replication

    PubMed Central

    Chagin, Vadim O.; Stear, Jeffrey H.; Cardoso, M. Cristina

    2010-01-01

    The discovery of the DNA double helix structure half a century ago immediately suggested a mechanism for its duplication by semi-conservative copying of the nucleotide sequence into two DNA daughter strands. Shortly after, a second fundamental step toward the elucidation of the mechanism of DNA replication was taken with the isolation of the first enzyme able to polymerize DNA from a template. In the subsequent years, the basic mechanism of DNA replication and its enzymatic machinery components were elucidated, mostly through genetic approaches and in vitro biochemistry. Most recently, the spatial and temporal organization of the DNA replication process in vivo within the context of chromatin and inside the intact cell are finally beginning to be elucidated. On the one hand, recent advances in genome-wide high throughput techniques are providing a new wave of information on the progression of genome replication at high spatial resolution. On the other hand, novel super-resolution microscopy techniques are just starting to give us the first glimpses of how DNA replication is organized within the context of single intact cells with high spatial resolution. The integration of these data with time lapse microscopy analysis will give us the ability to film and dissect the replication of the genome in situ and in real time. PMID:20452942

  4. Early Jurassic shale chemostratigraphy and UPb ages from the Neuqun Basin (Argentina): Implications for the Toarcian Oceanic Anoxic Event

    E-print Network

    Svensen, Henrik

    Early Jurassic shale chemostratigraphy and U­Pb ages from the Neuquén Basin (Argentina shale section in the Neuquén Basin, Argentina, are presented in order to better constrain the triggering. Chemostratigraphy from a 65 m thick shale-dominated marine section of Late Pliensbachian to Early Toarcian age shows

  5. Selectively replicating adenoviruses for oncolytic therapy.

    PubMed

    Yoon, T K; Shichinohe, T; Laquerre, S; Kasahara, N

    2001-08-01

    The most prevalent problem in cancer therapy is the regrowth and metastasis of malignant cells after standard treatment with surgery, radiation, and/or chemotherapy. Gene therapy approaches have suffered from the inadequate transduction efficiencies of replication-defective vectors that have been used thus far. Replication-competent vectors, particularly adenoviruses that cause cytolysis as part of their natural life cycle, represent an emerging technology that shows considerable promise as a novel treatment option, particularly for locally advanced or recurrent cancer. A number of oncolytic adenoviruses that are designed to replicate selectively in tumor cells by targeting molecular lesions inherent in cancer, or by incorporation of tissue-specific promoters driving the early genes that initiate viral replication, are currently being tested in clinical trials. The results of these clinical trials indicate that, in its current form, oncolytic adenovirus therapy shows the best results and achieves an enhanced tumoricidal effect when used in combination with chemotherapeutic agents such as cisplatin, leucovorin and 5-fluorouracil. Nevertheless, each of the oncolytic adenoviruses in current use exhibits characteristic shortcomings, and there is still considerable room for improvement. Current strategies for improving the selectivity and efficacy of oncolytic adenoviruses include molecular engineering of tumor cell-specific binding tropism, selective modifications of viral early genes and incorporation of cellular promoters to achieve tumor-specific replication, augmentation of anti-tumor activity by incorporation of suicide genes, and manipulation of the immune response. PMID:12188883

  6. The spectral absorption coefficient at 254nm as a real-time early warning proxy for detecting faecal pollution events at alpine karst water resources

    PubMed Central

    Stadler, H.; Klock, E.; Skritek, P.; Mach, R.L.; Zerobin, W.; Farnleitner, A.H.

    2011-01-01

    Because spring water quality from alpine karst aquifers can change very rapidly during event situations, water abstraction management has to be performed in near real-time. Four summer events (2005-2008) at alpine karst springs were investigated in detail in order to evaluate the spectral absorption coefficient at 254nm (SAC254) as a real-time early warning proxy for faecal pollution. For the investigation Low-Earth-Orbit (LEO) Satellite-based data communication between portable hydrometeorological measuring stations and an automated microbiological sampling device was used. The method for event triggered microbial sampling and analyzing was already established and described in a previous paper (Stadler et al., Wat. Sci. Technol. 58(4): 899-909, 2008). Data analysis including on-line event characterisation (i.e. precipitation, discharge, turbidity, SAC254) and comprehensive E. coli determination (n > 800) indicated that SAC254 is a useful early warning proxy. Irrespective of the studied event situations SAC254 always increased 3 to 6 hours earlier than the onset of faecal pollution, featuring different correlation phases. Furthermore, it seems also possible to use SAC254 as a real-time proxy parameter for estimating the extent of faecal pollution after establishing specific spring and event-type calibrations that take into consideration the variability of the occurrence and the transferability of faecal material It should be highlighted that diffuse faecal pollution from wildlife and live stock sources was responsible for spring water contamination at the investigated catchments. In this respect, the SAC254 can also provide useful information to support microbial source tracking efforts where different situations of infiltration have to be investigated. PMID:20962406

  7. The spectral absorption coefficient at 254?nm as a real-time early warning proxy for detecting faecal pollution events at alpine karst water resources.

    PubMed

    Stadler, H; Klock, E; Skritek, P; Mach, R L; Zerobin, W; Farnleitner, A H

    2010-01-01

    Because spring water quality from alpine karst aquifers can change very rapidly during event situations, water abstraction management has to be performed in near real-time. Four summer events (2005-2008) at alpine karst springs were investigated in detail in order to evaluate the spectral absorption coefficient at 254?nm (SAC254) as a real-time early warning proxy for faecal pollution. For the investigation Low-Earth-Orbit (LEO) Satellite-based data communication between portable hydrometeorological measuring stations and an automated microbiological sampling device was used. The method for event triggered microbial sampling and analyzing was already established and described in a previous paper. Data analysis including on-line event characterisation (i.e. precipitation, discharge, turbidity, SAC254) and comprehensive E. coli determination (n>800) indicated that SAC254 is a useful early warning proxy. Irrespective of the studied event situations SAC254 always increased 3 to 6 hours earlier than the onset of faecal pollution, featuring different correlation phases. Furthermore, it seems also possible to use SAC254 as a real-time proxy parameter for estimating the extent of faecal pollution after establishing specific spring and event-type calibrations that take into consideration the variability of the occurrence and the transferability of faecal material It should be highlighted that diffuse faecal pollution from wildlife and live stock sources was responsible for spring water contamination at the investigated catchments. In this respect, the SAC254 can also provide useful information to support microbial source tracking efforts where different situations of infiltration have to be investigated. PMID:20962406

  8. Structural organization of human replication timing domains.

    PubMed

    Boulos, Rasha E; Drillon, Guénola; Argoul, Françoise; Arneodo, Alain; Audit, Benjamin

    2015-10-01

    Recent analysis of genome-wide epigenetic modification data, mean replication timing (MRT) profiles and chromosome conformation data in mammals have provided increasing evidence that flexibility in replication origin usage is regulated locally by the epigenetic landscape and over larger genomic distances by the 3D chromatin architecture. Here, we review the recent results establishing some link between replication domains and chromatin structural domains in pluripotent and various differentiated cell types in human. We reconcile the originally proposed dichotomic picture of early and late constant timing regions that replicate by multiple rather synchronous origins in separated nuclear compartments of open and closed chromatins, with the U-shaped MRT domains bordered by "master" replication origins specified by a localized (?200-300kb) zone of open and transcriptionally active chromatin from which a replication wave likely initiates and propagates toward the domain center via a cascade of origin firing. We discuss the relationships between these MRT domains, topologically associated domains and lamina-associated domains. This review sheds a new light on the epigenetically regulated global chromatin reorganization that underlies the loss of pluripotency and the determination of differentiation properties. PMID:25912651

  9. Recombination enhancement by replication (RER) in Rhizobium etli.

    PubMed

    Valencia-Morales, E; Romero, D

    2000-03-01

    Studies in several organisms show that recombination and replication interact closely. Recombinational repair usually requires associated replication at some stage; moreover, additional replication can induce recombination through either homologous or illegitimate events. In prokaryotes, stimulation of recombination by replication is more dramatic when rolling circle replication is employed. In contrast, theta-type replication induces only a modest increase in recombination frequency. In this article, we show that induction of theta-type replication from a supernumerary origin in the symbiotic plasmid (pSym) of Rhizobium etli leads to a 1000-fold increase in deletion formation on this plasmid. These deletions span 120 kb (the symbiotic region) and have as endpoints the reiterated nitrogenase operons. We have named this phenomenon RER, for recombination enhancement by replication. RER is not affected by the position of the replication origin in the pSym, the direction of advance of the replication fork, or the distance from the origin to the recombining repeats. On the other hand, RER is dependent on an active recA allele, indicating that it is due to homologous recombination. RER displays a strong regionality restricted to the symbiotic region. The similarities and differences of RER with the recombination process observed at the terminus of replication of the Escherichia coli chromosome are discussed. PMID:10757747

  10. Recombination enhancement by replication (RER) in Rhizobium etli.

    PubMed Central

    Valencia-Morales, E; Romero, D

    2000-01-01

    Studies in several organisms show that recombination and replication interact closely. Recombinational repair usually requires associated replication at some stage; moreover, additional replication can induce recombination through either homologous or illegitimate events. In prokaryotes, stimulation of recombination by replication is more dramatic when rolling circle replication is employed. In contrast, theta-type replication induces only a modest increase in recombination frequency. In this article, we show that induction of theta-type replication from a supernumerary origin in the symbiotic plasmid (pSym) of Rhizobium etli leads to a 1000-fold increase in deletion formation on this plasmid. These deletions span 120 kb (the symbiotic region) and have as endpoints the reiterated nitrogenase operons. We have named this phenomenon RER, for recombination enhancement by replication. RER is not affected by the position of the replication origin in the pSym, the direction of advance of the replication fork, or the distance from the origin to the recombining repeats. On the other hand, RER is dependent on an active recA allele, indicating that it is due to homologous recombination. RER displays a strong regionality restricted to the symbiotic region. The similarities and differences of RER with the recombination process observed at the terminus of replication of the Escherichia coli chromosome are discussed. PMID:10757747

  11. BRCA1 promotes unloading of the CMG helicase from a stalled DNA replication fork.

    PubMed

    Long, David T; Joukov, Vladimir; Budzowska, Magda; Walter, Johannes C

    2014-10-01

    The tumor suppressor protein BRCA1 promotes homologous recombination (HR), a high-fidelity mechanism to repair DNA double-strand breaks (DSBs) that arise during normal replication and in response to DNA-damaging agents. Recent genetic experiments indicate that BRCA1 also performs an HR-independent function during the repair of DNA interstrand crosslinks (ICLs). Here we show that BRCA1 is required to unload the CMG helicase complex from chromatin after replication forks collide with an ICL. Eviction of the stalled helicase allows leading strands to be extended toward the ICL, followed by endonucleolytic processing of the crosslink, lesion bypass, and DSB repair. Our results identify BRCA1-dependent helicase unloading as a critical, early event in ICL repair. PMID:25219499

  12. Paleoceanographic changes and population dynamics in two left-coiling events of Pulleniatina during early Pleistocene, ODP 1115B, western equatorial Pacific

    NASA Astrophysics Data System (ADS)

    Chiang, M.; Wei, K.; Chuang, C.; Lo, L.

    2013-12-01

    The alternately left-coiling (LC) and right-coiling (RC) dominance in the populations of planktonic foraminifera Pulleniatina genus defined a series L events during the past 4 Ma. These L events have been used as useful biostratigraphic markers for the Indo-Pacific region, especially the L5 event, which marks the top of Gelasian stage in Early Pleistocene. However, previous studies emphasized on the stratigraphic application of the L events and have little attention on the L events itself. This study focuses on the population dynamics of Pu. during L events and tries to examine the mechanism triggering the L events by studying Core ODP 1115 B (9°11' S, 151°34' E, water depth 1149 m) in Solomon Sea, western equatorial Pacific. Owing to the variance in morphology, we lumped all species of Pu. genus into a 'Pulleniatina complex' rather than subdividing them into different species. Specimens larger than 250 ?m in each sample were sieved into six size-fractions. The Pu. complex as well as their coiling direction were identified under a stereomicroscope. To avoid biased sampling, we examined all Pu. complex specimens larger than 250 ?m. LC and RC relative percentages as well as absolute abundances of Pu. complex in each size-fraction were counted, respectively. In setting LC relative percentage >50% as a threshold, we recognized a distinctive L6 event (~ 2.202 - 2.175 Ma, began between MIS 85 - 84 and ended between MIS 83 - 82), a prominent L5 event (~ 2.147 - 1.875 Ma, began between MIS 82 - 81 and ended between MIS 71 - 70), and could not find a clear L4 event as reported by Saito (1976). The onset of the L5 event was marked by a dramatic reduction of absolute abundance of RC forms that give observers an impression of LC forms dominance. During the L5 event, the LC relative percentages fluctuated by 20 to 40%. The ending of the L5event was characterized by a slow recovery of RC forms in absolute abundance. L6 event was the result of two sudden significant changes in absolute abundance of LC forms that led to pronounced relative percentage changes in coiling direction. For the biostragtigraphic application, these characteristics make the L6 event a better biostratigraphic marker than the L5 event where Pu. is less abundant. The onsets of the L5 and L6 event were corresponding to opposite global climatic changing trends. In addition, linear regression between population parameters and environmental proxies, including those of salinity, ice volume, primary productivity and water temperature from both sea surface and thermocline show week correlations, indicating the causal relationship between the environmental changes and the population dynamics of Pu. is not as strong as expected.

  13. Modeling DNA Replication Intermediates

    SciTech Connect

    Broyde, S.; Roy, D.; Shapiro, R.

    1997-06-01

    While there is now available a great deal of information on double stranded DNA from X-ray crystallography, high resolution NMR and computer modeling, very little is known about structures that are representative of the DNA core of replication intermediates. DNA replication occurs at a single strand/double strand junction and bulged out intermediates near the junction can lead to frameshift mutations. The single stranded domains are particularly challenging. Our interest is focused on strategies for modeling the DNA of these types of replication intermediates. Modeling such structures presents special problems in addressing the multiple minimum problem and in treating the electrostatic component of the force field. We are testing a number of search strategies for locating low energy structures of these types and we are also investigating two different distance dependent dielectric functions in the coulombic term of the force field. We are studying both unmodified DNA and DNA damaged by aromatic amines, carcinogens present in the environment in tobacco smoke, barbecued meats and automobile exhaust. The nature of the structure adopted by the carcinogen modified DNA at the replication fork plays a key role in determining whether the carcinogen will cause a mutation during replication that can initiate the carcinogenic process. In the present work results are presented for unmodified DNA.

  14. Impacts of a water stress followed by an early frost event on beech (Fagus sylvatica L.) susceptibility to Scolytine ambrosia beetles - Research strategy and first results

    NASA Astrophysics Data System (ADS)

    La Spina, Sylvie; de Cannière, Charles; Molenberg, Jean-Marc; Vincke, Caroline; Deman, Déborah; Grégoire, Jean-Claude

    2010-05-01

    Climate change tends to induce more frequent abiotic and biotic extreme events, having large impacts on tree vitality. Weakened trees are then more susceptible to secondary insect outbreaks, as it happened in Belgium in the early 2000s: after an early frost event, secondary Scolytine ambrosia beetles attacks were observed on beech trees. In this study, we test if a combination of stress, i.e. a soil water deficit preceding an early frost, could render trees more attractive to beetles. An experimental study was set in autumn 2008. Two parcels of a beech forest were covered with plastic tents to induce a water stress by rain interception. The parcels were surrounded by 2-meters depth trenches to avoid water supply by streaming. Soil water content and different indicators of tree water use (sap flow, predawn leaf water potential, tree radial growth) were followed. In autumn 2010, artificial frost injuries will be inflicted to trees using dry ice. Trees attractivity for Scolytine insects, and the success of insect colonization will then be studied. The poster will focus on experiment setting and first results (impacts of soil water deficit on trees).

  15. Replication and Distribution of Toxoplasma gondii in the Small Intestine after Oral Infection with Tissue Cysts

    PubMed Central

    Gregg, Beth; Taylor, Betsy C.; John, Beena; Tait-Wojno, Elia D.; Girgis, Natasha M.; Miller, Natalie; Wagage, Sagie; Hunter, Christopher A.

    2013-01-01

    Natural infection by Toxoplasma gondii occurs via oral ingestion of tissue cysts that rupture in the small intestine, releasing zoites that infect locally before disseminating throughout the host. The studies presented here used fluorescent parasites combined with flow cytometry and multiphoton microscopy techniques to understand the events associated with parasite replication in the mucosa. At 3 days postinfection with tissue cysts, parasites were localized in small foci and flow cytometry revealed parasites present in macrophages, neutrophils, and monocytes in the lamina propria. By day 6 postinfection, there were large foci of replicating parasites; however, foci unexpectedly varied in the number of villi involved and were associated with the presence of viable tachyzoites within the intestinal lumen. Consistent with the flow cytometry data, neutrophils and monocytes in the lamina propria were preferentially associated with parasite plaques. In contrast, dendritic cells comprised a small fraction of the infected immune cell population and were localized at the periphery of parasite plaques. Together, these findings reveal the formation of localized sites of parasite replication and inflammation early during infection and suggest that sustained replication of T. gondii in the gut may be a function of pathogen luminal spread. PMID:23460516

  16. Replicated Composite Optics Development

    NASA Technical Reports Server (NTRS)

    Engelhaupt, Darell

    1997-01-01

    Advanced optical systems for applications such as grazing incidence Wolter I x-ray mirror assemblies require extraordinary mirror surfaces in ten-ns of fine surface finish and figure. The impeccable mirror surface is on the inside of the rotational mirror form. One practical method of producing devices with these requirements is to first fabricate an exterior surface for the optical device then replicate that surface to have the inverse component with lightweight characteristics. The replicate optic is not better than the master or mandrel from which it is made. This task is a continuance of previous studies to identify methods and materials for forming these extremely low roughness optical components.

  17. Contingency and statistical laws in replicate microbial closed ecosystems.

    PubMed

    Hekstra, Doeke R; Leibler, Stanislas

    2012-05-25

    Contingency, the persistent influence of past random events, pervades biology. To what extent, then, is each course of ecological or evolutionary dynamics unique, and to what extent are these dynamics subject to a common statistical structure? Addressing this question requires replicate measurements to search for emergent statistical laws. We establish a readily replicated microbial closed ecosystem (CES), sustaining its three species for years. We precisely measure the local population density of each species in many CES replicates, started from the same initial conditions and kept under constant light and temperature. The covariation among replicates of the three species densities acquires a stable structure, which could be decomposed into discrete eigenvectors, or "ecomodes." The largest ecomode dominates population density fluctuations around the replicate-average dynamics. These fluctuations follow simple power laws consistent with a geometric random walk. Thus, variability in ecological dynamics can be studied with CES replicates and described by simple statistical laws. PMID:22632978

  18. The onset of the Early Eocene Climatic Optimum, including the K/X event, at Branch Stream, Clarence Valley, New Zealand

    NASA Astrophysics Data System (ADS)

    Slotnick, B. S.; Dickens, G. R.; Hollis, C. J.; Crampton, J. S.; Strong, P.; Dallanave, E.; Philips, A.

    2014-12-01

    The Early Eocene Climatic Optimum (EECO), lasting from ~53-50 Ma, has been characterized as the warmest sustained interval through the Cenozoic. It was comprised of a broad temperature maximum with elevated atmospheric pCO2, noticeable shifts in carbon cycling, and a variety of faunal and floral changes. This included one, and likely additional, brief (<200 kyr) intervals of extreme warming, the K/X event. At least for the most prominent events, the long-term drop in ?13C and short-term Carbon Isotope Excursions (CIEs) have been coupled to massive fluxes of 13C-depleted carbon into the exogenic system and global climate change. However, much about EECO remains unknown because of a lack of detailed and coupled proxy records; we are currently generating useful records to better characterize lithological and geochemical signatures of EECO. Here, we help rectify this problem by presenting a new lithologic and carbon isotopic record for a ~84-m-thick section of early Eocene upper slope calcareous-rich sediments, now lithified and exposed along Branch Stream, New Zealand. Comparison of new carbon isotopic and lithologic records of this greatly expanded section to nearby Mead Stream identifies multiple negative CIEs in short succession and generally more marl during lowermost EECO (~53.3-51.7 Ma), with the most prominent of these equating to the K/X event. The early Eocene lithologic and ?13C records at Branch and Mead Streams are remarkably similar to each other, with the following distinctions: sequences at Branch Stream are thicker and generally have a wider range of ?13C across CIEs. Both expanded sections are marked by terrigenous dilution, best explained by enhanced seasonal precipitation, elevated greenhouse-gas concentrations, and likely global warming. These data indicate lowermost EECO can be described as a time with a general ?13C low superimposed by a series of short-term climate perturbations.

  19. Early supersymmetry searches in events with missing transverse energy and b-jets with the ATLAS detector

    E-print Network

    The ATLAS collaboration

    2010-01-01

    This note describes a first set of measurements of supersymmetry-sensitive var iables in heavy-flavour enriched final state events with jets and missing transverse energy, from initial \\sqrt{s}=7 TeV proton-proton collisions at the LHC. Events may contain identified leptons (electron, muon) while separate analyses are carried out considering the no-lepton case and the case with additional leptons. The measurements are based on 305 nb^{-1} of data collected with the ATLAS detector. General good agreement is found between data and Standard Model expectations estimated with Monte Carlo simulations.

  20. Correlating carbon and oxygen isotope events in early to middle Miocene shallow marine carbonates in the Mediterranean region using orbitally tuned chemostratigraphy and lithostratigraphy

    NASA Astrophysics Data System (ADS)

    Auer, Gerald; Piller, Werner E.; Reuter, Markus; Harzhauser, Mathias

    2015-04-01

    During the Miocene prominent oxygen isotope events (Mi-events) reflect major changes in glaciation, while carbonate isotope maxima (CM-events) reflect changes in organic carbon burial, particularly during the Monterey carbon isotope excursion. However, despite their importance to the global climate history they have never been recorded in shallow marine carbonate successions. The Decontra section on the Maiella Platform (central Apennines, Italy), however, allows to resolve them for the first time in such a setting during the early to middle Miocene. The present study improves the stratigraphic resolution of parts of the Decontra section via orbital tuning of high-resolution gamma ray (GR) and magnetic susceptibility data to the 405 kyr eccentricity metronome. The tuning allows, within the established biostratigraphic, sequence stratigraphic, and isotope stratigraphic frameworks, a precise correlation of the Decontra section with pelagic records of the Mediterranean region, as well as the global paleoclimatic record and the global sea level curve. Spectral series analyses of GR data further indicate that the 405 kyr orbital cycle is particularly well preserved during the Monterey Event. Since GR is a direct proxy for authigenic uranium precipitation during increased burial of organic carbon in the Decontra section, it follows the same long-term orbital pacing as observed in the carbon isotope records. The 405 kyr GR beat is thus correlated with the carbon isotope maxima observed during the Monterey Event. Finally, the Mi-events can now be recognized in the ?18O record and coincide with plankton-rich, siliceous, or phosphatic horizons in the lithology of the section.

  1. Rumination as a Mechanism Linking Stressful Life Events to Symptoms of Depression and Anxiety: Longitudinal Evidence in Early Adolescents and Adults

    PubMed Central

    Michl, Louisa C.; McLaughlin, Katie A.; Shepherd, Kathrine; Nolen-Hoeksema, Susan

    2014-01-01

    Rumination is a well-established risk factor for the onset of major depression and anxiety symptomatology in both adolescents and adults. Despite the robust associations between rumination and internalizing psychopathology, there is a dearth of research examining factors that might lead to a ruminative response style. In the current study, we examined whether social environmental experiences were associated with rumination. Specifically, we evaluated whether self-reported exposure to stressful life events predicted subsequent increases in rumination. We also investigated whether rumination served as a mechanism underlying the longitudinal association between self-reported stressful life events and internalizing symptoms. Self-reported stressful life events, rumination, and symptoms of depression and anxiety were assessed in 2 separate longitudinal samples. A sample of early adolescents (N = 1,065) was assessed at 3 time points spanning 7 months. A sample of adults (N = 1,132) was assessed at 2 time points spanning 12 months. In both samples, self-reported exposure to stressful life events was associated longitudinally with increased engagement in rumination. In addition, rumination mediated the longitudinal relationship between self-reported stressors and symptoms of anxiety in both samples and the relationship between self-reported life events and symptoms of depression in the adult sample. Identifying the psychological and neurobiological mechanisms that explain a greater propensity for rumination following stressors remains an important goal for future research. This study provides novel evidence for the role of stressful life events in shaping characteristic responses to distress, specifically engagement in rumination, highlighting potentially useful targets for interventions aimed at preventing the onset of depression and anxiety. PMID:23713497

  2. Inhomogeneous DNA replication kinetics is associated with immune system response

    NASA Astrophysics Data System (ADS)

    Bechhoefer, John; Gauthier, Michel G.; Norio, Paolo

    2013-03-01

    In eukaryotic organisms, DNA replication is initiated at ``origins,'' launching ``forks'' that spread bidirectionally to replicate the genome. The distribution and firing rate of these origins and the fork progression velocity form the ``replication program.'' Previous models of DNA replication in eukaryotes have assumed firing rates and replication fork velocities to be homogeneous across the genome. But large variations in origin activity and fork velocity do occur. Here, we generalize our replication model to allow for arbitrary spatial variation of initiation rates and fork velocities in a given region of the genome. We derive and solve rate equations for the forks and replication probability, to obtain the mean-field replication program. After testing the model on simulations, we analyze the changes in replication program that occur during B cell development in the mouse. B cells play a major role in the adaptive immune system by producing the antibodies. We show that the process of cell differentiation is associated with a change in replication program, where the zones of high origin initiation rates located in the immunoglobulin heavy-chain locus shift their position as the locus prepares to undergo the recombination events responsible for generating antibody specificity. This work was funded by HSFP and NSERC-Canada (MGG and JB) and by NIH-NIGMS grant R01GM080606 (PN).

  3. Reduced early visual emotion discrimination as an index of diminished emotion processing in Parkinson's disease? - Evidence from event-related brain potentials.

    PubMed

    Wieser, Matthias J; Klupp, Elisabeth; Weyers, Peter; Pauli, Paul; Weise, David; Zeller, Daniel; Classen, Joseph; Mühlberger, Andreas

    2012-10-01

    Although Parkinson's disease (PD) is defined by its motor symptoms, it is now well recognized that cognitive and affective domains, such as recognition of emotion from facial expressions, may also be impaired. To examine brain mechanisms involved in processing of emotion recognition from facial expressions, we obtained affective ratings and visual event-related potentials (ERPs) in response to facial expressions from 18 PD patients under dopamine-replacement therapy, and 17 healthy age- and sex-matched controls. In control subjects, the early posterior negativity (EPN) of the ERP, which is thought to reflect early perceptual emotion discrimination, was larger in response to emotional compared to neutral facial expressions. In contrast, this emotional modulation of the EPN was absent in PD patients indicating impaired early emotion discrimination. Behaviorally, PD patients showed no impairments in emotion recognition as measured by affective ratings. These findings suggest that facial emotion processing may be disrupted at an early stage of visual neural processing in PD. Absence of behavioral impairment may point to compensatory strategies of emotion recognition in medicated PD patients. Further research should clarify these dissociations between behavioral and neurophysiological levels of emotion processing in PD. PMID:21764048

  4. Liquefaction features at an archaeological site: Investigations of past earthquake events at the Early Christian Basilica, Ancient Lechaion Harbour, Corinth, Greece

    NASA Astrophysics Data System (ADS)

    Minos-Minopoulos, Despina; Pavlopoulos, Kosmas; Apostolopoulos, George; Lekkas, Efthymis; Dominey-Howes, Dale

    2015-09-01

    A synthesis of investigations carried out at the archaeological site of the Early Christian Basilica, located in the ancient harbour of Lechaion, Corinth, Greece in order to study the origin and triggering mechanism of deformation structures observed on the temple floor, is presented. These surface structures are indicative of earthquake induced ground liquefaction and their relationship with the subsurface soil stratigraphy and structure is examined. Investigations of stratigraphic data from archaeological excavations conducted from 1956 to 1965 provide indications of artificial fill deposits overlying a sandy-gravelly substratum. Geophysical survey of EM, GPR and ERT provided further information regarding the substratum properties/stratigraphy of the site indicating subsurface fissures and lateral spreading trends that are in agreement with the surface deformation structures. Lithostratigraphic data obtained from four vibracores drilled in the southern aisle of the temple, suggest estuarine deposits of coarse sand to fine gravel with grain size properties indicative of layers with high liquefaction potential. The results of the study, suggest at least three seismic events that induced ground liquefaction at the site. The first event pre-dates the construction of the Basilica, when Lechaion harbour was in operation. The second event post-dates the construction of the Basilica potentially corresponding to the regionally damaging A.D. 524 earthquake, followed by the third event, that commensurate with the A.D. 551 earthquake and the destruction of the temple.

  5. High resolution chronology of late Cretaceous-early Tertiary events determined from 21,000 yr orbital-climatic cycles in marine sediments

    NASA Technical Reports Server (NTRS)

    Herbert, Timothy D.; Dhondt, Steven

    1988-01-01

    A number of South Atlantic sites cored by the Deep Sea Drilling Project (DSDP) recovered late Cretaceous and early Tertiary sediments with alternating light-dark, high-low carbonate content. The sedimentary oscillations were turned into time series by digitizing color photographs of core segments at a resolution of about 5 points/cm. Spectral analysis of these records indicates prominent periodicity at 25 to 35 cm in the Cretaceous intervals, and about 15 cm in the early Tertiary sediments. The absolute period of the cycles that is determined from paleomagnetic calibration at two sites is 20,000 to 25,000 yr, and almost certainly corresponds to the period of the earth's precessional cycle. These sequences therefore contain an internal chronometer to measure events across the K/T extinction boundary at this scale of resolution. The orbital metronome was used to address several related questions: the position of the K/T boundary within magnetic chron 29R, the fluxes of biogenic and detrital material to the deep sea immediately before and after the K/T event, the duration of the Sr anomaly, and the level of background climatic variability in the latest Cretaceous time. The carbonate/color cycles that were analyzed contain primary records of ocean carbonate productivity and chemistry, as evidenced by bioturbational mixing of adjacent beds and the weak lithification of the rhythmic sequences. It was concluded that sedimentary sequences that contain orbital cyclicity are capable of providing resolution of dramatic events in earth history with much greater precision than obtainable through radiometric methods. The data show no evidence for a gradual climatic deterioration prior to the K/T extinction event, and argue for a geologically rapid revolution at this horizon.

  6. Helicase Loading at Chromosomal Origins of Replication

    E-print Network

    Bell, Stephen P.

    Loading of the replicative DNA helicase at origins of replication is of central importance in DNA replication. As the first of the replication fork proteins assemble at chromosomal origins of replication, the loaded helicase ...

  7. Majority Vote and Decision Template Based Ensemble Classifiers Trained on Event Related Potentials for Early Diagnosis of Alzheimer's Disease

    E-print Network

    Polikar, Robi

    for Early Diagnosis of Alzheimer's Disease Nicholas Stepenosky1 , Deborah Green2 , John Kounios2@rowan.edu ABSTRACT With the rapid increase in the population of elderly individuals affected by Alzheimer's disease templates. 1. INTRODUCTION Alzheimer's disease (AD) is the most common type of de- mentia, a degenerative

  8. The Madotz Urgonian platform (Aralar, northern Spain): Paleoecological changes in response to Early Aptian global environmental events

    E-print Network

    Gilli, Adrian

    The Madotz Urgonian platform (Aralar, northern Spain): Paleoecological changes in response to Early. The paleoecological change coinciding with the base of OAE1a occurred at a time of sea level rise and it coincided with a demise of heavily calcified nannoconids in the Tethys and Pacific Oceans. The paleoecological change

  9. Self-Replication of Mesa Patterns in Reaction-Diffusion T. KOLOKOLNIKOV , M.J. WARD

    E-print Network

    Ward, Michael Jeffrey

    Preprint 1 Self-Replication of Mesa Patterns in Reaction-Diffusion Systems T. KOLOKOLNIKOV , M of a mesa self-replication event that ultimately leads to the creation of additional mesas. The initiation of Nishiura and Ueyema [Physica D, 130, No. 1, (1999), pp. 73­104], believed to be responsible for self-replication

  10. Modulation of HCV Replication After Combination Antiretroviral Therapy in HCV/HIV Coinfected Patients

    PubMed Central

    Sherman, Kenneth E.; Guedj, Jeremie; Shata, Mohamed Tarek; Blackard, Jason T.; Rouster, Susan D.; Castro, Mario; Feinberg, Judith; Sterling, Richard K.; Goodman, Zachary; Aronow, Bruce J.; Perelson, Alan S.

    2015-01-01

    The hepatitis C virus (HCV) is an important contributor to morbidity and mortality in patients coinfected with human immunodeficiency virus (HIV). Coinfection results in increased HCV replication and more rapid rates of liver disease progression. The effect of HIV combination antiretroviral therapy (cART) on HCV replication has not been studied in depth. To address this issue, we enrolled a small cohort of HCV/HIV coinfected patients into a cART initiation trial, and used dynamic modeling combined with evaluation of immune responses and microarray profiles to determine how effective treatment of HIV affects HCV. Treatment with cART resulted in HCV flare and alanine aminotransferase (ALT) increase (2× or more increase from baseline) in a subset of treated patients. Subjects with evidence of hepatic injury (increased ALT) were more likely to have HCV-specific immune responses directed against HCV epitopes. Over time, HCV viral loads declined. Reproducible and biologically important gene expression changes occurred in patients who underwent successful cART, particularly with respect to downregulation of genes with known antiviral roles. Our findings suggest that the effective suppression of HIV by cART initiates a cascade of early and late events in treated patients with HCV. Early events involving downregulation of interferon-stimulated genes may lead to transiently increased viral replication and hepatic injury. At later time points, HCV viral load declines to levels comparable to those seen in the setting of HCV monoinfection. These findings support early antiretroviral therapy in those with HCV/HIV coinfection. PMID:25101888

  11. Tel1ATM dictates the replication timing of short yeast telomeres.

    PubMed

    Cooley, Carol; Davé, Anoushka; Garg, Mansi; Bianchi, Alessandro

    2014-10-01

    Telomerase action is temporally linked to DNA replication. Although yeast telomeres are normally late replicating, telomere shortening leads to early firing of subtelomeric DNA replication origins. We show that double-strand breaks flanked by short telomeric arrays cause origin firing early in S phase at late-replicating loci and that this effect on origin firing time is dependent on the Tel1(ATM) checkpoint kinase. The effect of Tel1(ATM) on telomere replication timing extends to endogenous telomeres and is stronger than that elicited by Rif1 loss. These results establish that Tel1(ATM) specifies not only the extent but also the timing of telomerase recruitment. PMID:25122631

  12. Early Solar System Alkali Fractionation Events Recorded by K-Ca Isotopes in the Yamato-74442 LL-Chondritic Breccia

    NASA Technical Reports Server (NTRS)

    Tatsunori, T.; Misawa, K.; Okano, O.; Shih, C.-Y.; Nyquist, L. E.; Simon, J. I.; Tappa, M. J.; Yoneda, S.

    2015-01-01

    Radiogenic ingrowth of Ca-40 due to decay of K-40 occurred early in the solar system history causing the Ca-40 abundance to vary within different early-former reservoirs. Marshall and DePaolo ] demonstrated that the K-40/Ca-40 decay system could be a useful radiogenic tracer for studies of terrestrial rocks. Shih et al. [3,4] determined 40K/40Ca ages of lunar granitic rock fragments and discussed the chemical characteristics of their source materials. Recently, Yokoyama et al. [5] showed the application of the K-40/Ca-40 chronometer for high K/Ca materials in ordinary chondrites (OCs). High-precision calcium isotopic data are needed to constrain mixing processes among early solar system materials and the time of planetesimal formation. To better constrain the solar system calcium isotopic compositions among astromaterials, we have determined the calcium isotopic compositions of OCs and an angrite. We further estimated a source K/Ca ratio for alkali-rich fragments in a chondritic breccia using the estimated solar system initial Ca-40/Ca-44.

  13. Epitope-specific crosslinking of CD45 down-regulates membrane-associated tyrosine phosphatase activity and triggers early signalling events in human activated T cells

    PubMed Central

    Spertini, François; Perret-Menoud, Veronique; Barbier, Nathalie; Chatila, Talal; Barbey, Catherine; Corthesy, Blaise

    2004-01-01

    CD45 engagement by monoclonal antibodies on human activated T cells triggers tumour necrosis factor-? (TNF-?) gene transcription in an epitope-specific manner. To dissect the early signalling events leading to TNF-? gene expression, we established that CD45 crosslinking resulted in tyrosine phosphorylation of p56lck, ZAP-70, CD3-?, LAT and Vav. This was accompanied by down-regulation of membrane-associated protein tyrosine phosphatase activity in the absence of demonstration of enhanced p56lck, p72syk and ZAP-70 kinase activity, which remained constitutive. These early events eventually triggered an intracellular Ca2+ rise and phosphoinositide turnover. We conclude that down-regulation of membrane-associated tyrosine phosphatase activity by CD45 extracytoplasmic domain multimerization led, in an epitope-specific fashion, to unopposed tyrosine kinase activity and to the activation of the T-cell receptor/CD3 complex signalling cascade, resulting in TNF-? gene expression. This model strongly suggests that CD45 extracytoplasmic tail multimerization may contribute to the modulation T-cell functions. PMID:15554922

  14. Studies on the Coordination of Ribosomal Protein Assembly Events Involved in Processing and Stabilization of Yeast Early Large Ribosomal Subunit Precursors

    PubMed Central

    Sauert, Martina; Martín-Marcos, Pilar; Tamame, Mercedes; Tschochner, Herbert; Griesenbeck, Joachim; Milkereit, Philipp

    2015-01-01

    Cellular production of ribosomes involves the formation of highly defined interactions between ribosomal proteins (r-proteins) and ribosomal RNAs (rRNAs). Moreover in eukaryotic cells, efficient ribosome maturation requires the transient association of a large number of ribosome biogenesis factors (RBFs) with newly forming ribosomal subunits. Here, we investigated how r-protein assembly events in the large ribosomal subunit (LSU) rRNA domain II are coordinated with each other and with the association of RBFs in early LSU precursors of the yeast Saccharomyces cerevisiae. Specific effects on the pre-ribosomal association of RBFs could be observed in yeast mutants blocked in LSU rRNA domain II assembly. Moreover, formation of a cluster of r-proteins was identified as a downstream event in LSU rRNA domain II assembly. We analyzed in more detail the functional relevance of eukaryote specific bridges established by this r-protein cluster between LSU rRNA domain II and VI and discuss how they can support the stabilization and efficient processing of yeast early LSU precursor RNAs. PMID:26642313

  15. Prevalence and Predictors of Early Cardiovascular Events after Kidney Transplantation: Evaluation of Pre-Transplant Cardiovascular Work-Up

    PubMed Central

    Delville, Marianne; Sabbah, Laurent; Girard, Delphine; Elie, Caroline; Manceau, Sandra; Piketty, Marie; Martinez, Frank; Méjean, Arnaud; Legendre, Christophe; Sberro-Soussan, Rebecca

    2015-01-01

    Introduction Cardiovascular disease is the leading cause of mortality after renal transplantation. The purpose of this study was to analyze cardiovascular risk factors at transplantation, occurrence of cardiovascular events in the first year after transplantation and evaluate pre-transplant work-up. Material and Method In total, 244 renal transplant recipients older than 50 years were included. The results of pre-transplant work-up, including clinical evaluation, electrocardiogram, echocardiography, myocardial perfusion testing and coronary angiography were analyzed. Results Patients had multiple risk factors at inclusion on renal transplantation waiting list as high blood pressure (94.7%), dyslipidemia (81.1%), smoking (45.3%), diabetes (23.6%), past history of cardiovascular disease (21.3%) and obesity (12.7%). Following transplantation, 15.5% (n = 38) of patients experienced a cardiovascular event, including 2.8% (n = 7) acute coronary syndrome, 5.8% (n = 14) isolated increase in troponin level and 5.3% (n = 13) new onset atrial fibrillation. The pre-transplant parameters associated with a cardiovascular event were a past medical history of cardiovascular disease (HR = 2.06 [1.06–4.03], p = 0.03), echocardiographic left ventricular hypertrophy (HR = 2.04 [1.04–3.98], p = 0.037) and abnormal myocardial perfusion testing (HR = 2.25 [1.09 –5.96], p = 0.03). Pre-transplantation evaluation allowed the diagnosis of unknown coronary artery lesions in 8.9% of patients. PMID:26107641

  16. A New Replicator: A theoretical framework for analysing replication

    PubMed Central

    2010-01-01

    Background Replicators are the crucial entities in evolution. The notion of a replicator, however, is far less exact than the weight of its importance. Without identifying and classifying multiplying entities exactly, their dynamics cannot be determined appropriately. Therefore, it is importance to decide the nature and characteristics of any multiplying entity, in a detailed and formal way. Results Replication is basically an autocatalytic process which enables us to rest on the notions of formal chemistry. This statement has major implications. Simple autocatalytic cycle intermediates are considered as non-informational replicators. A consequence of which is that any autocatalytically multiplying entity is a replicator, be it simple or overly complex (even nests). A stricter definition refers to entities which can inherit acquired changes (informational replicators). Simple autocatalytic molecules (and nests) are excluded from this group. However, in turn, any entity possessing copiable information is to be named a replicator, even multicellular organisms. In order to deal with the situation, an abstract, formal framework is presented, which allows the proper identification of various types of replicators. This sheds light on the old problem of the units and levels of selection and evolution. A hierarchical classification for the partition of the replicator-continuum is provided where specific replicators are nested within more general ones. The classification should be able to be successfully applied to known replicators and also to future candidates. Conclusion This paper redefines the concept of the replicator from a bottom-up theoretical approach. The formal definition and the abstract models presented can distinguish between among all possible replicator types, based on their quantity of variable and heritable information. This allows for the exact identification of various replicator types and their underlying dynamics. The most important claim is that replication, in general, is basically autocatalysis, with a specific defined environment and selective force. A replicator is not valid unless its working environment, and the selective force to which it is subject, is specified. PMID:20219099

  17. Hepatitis D Virus Replication.

    PubMed

    Taylor, John M

    2015-01-01

    This work reviews specific related aspects of hepatitis delta virus (HDV) reproduction, including virion structure, the RNA genome, the mode of genome replication, the delta antigens, and the assembly of HDV using the envelope proteins of its helper virus, hepatitis B virus (HBV). These topics are considered with perspectives ranging from a history of discovery through to still-unsolved problems. HDV evolution, virus entry, and associated pathogenic potential and treatment of infections are considered in other articles in this collection. PMID:26525452

  18. The Early Miocene "Bisciaro volcaniclastic event" (northern Apennines, Italy): a key study for the geodynamic evolution of the central-western Mediterranean

    NASA Astrophysics Data System (ADS)

    Guerrera, Francesco; Martín-Martín, Manuel; Raffaelli, Giuliana; Tramontana, Mario

    2015-06-01

    The Early Miocene Bisciaro Fm., a marly limestone succession cropping out widely in the Umbria-Romagna-Marche Apennines, is characterized by a high amount of volcaniclastic content, characterizing this unit as a peculiar event of the Adria Plate margin. Because of this volcaniclastic event, also recognizable in different sectors of the central-western Mediterranean chains, this formation is proposed as a "marker" for the geodynamic evolution of the area. In the Bisciaro Fm., the volcaniclastic supply starts with the "Raffaello" bed (Earliest Aquitanian) that marks the base of the formation and ends in the lower portion of the Schlier Fm. (Late Burdigalian-Langhian p.p.). Forty-one studied successions allowed the recognition of three main petrofacies: (1) Pyroclastic Deposits (volcanic materials more than 90 %) including the sub-petrofacies 1A, Vitroclastic/crystallo- vitroclastic tuffs; 1B, Bentonitic deposits; and 1C, Ocraceous and blackish layers; (2) Resedimented Syn-Eruptive Volcanogenic Deposits (volcanic material 30-90 %) including the sub-petrofacies 2A, High- density volcanogenic turbidites; 2B, Low- density volcanogenic turbidites; 2C, Crystal- rich volcanogenic deposits; and 2D, Glauconitic- rich volcaniclastites; (3) Mixing of Volcaniclastic Sediments with Marine Deposits (volcanic material 5-30 %, mixed with marine sediments: marls, calcareous marls, and marly limestones). Coeval volcaniclastic deposits recognizable in different tectonic units of the Apennines, Maghrebian, and Betic Chains show petrofacies and chemical-geochemical features related to a similar calc-alkaline magmatism. The characterization of this event led to the hypothesis of a co-genetic relationship between volcanic activity centres (primary volcanic systems) and depositional basins (depositional processes) in the Early Miocene palaeogeographic and palaeotectonic evolution of the central-western Mediterranean region. The results support the proposal of a geodynamic model of this area that considers previously proposed interpretations.

  19. Ancient DNA from South-East Europe Reveals Different Events during Early and Middle Neolithic Influencing the European Genetic Heritage

    PubMed Central

    Hervella, Montserrat; Rotea, Mihai; Izagirre, Neskuts; Constantinescu, Mihai; Alonso, Santos; Ioana, Mihai; Laz?r, C?t?lin; Ridiche, Florin; Soficaru, Andrei Dorian; Netea, Mihai G.; de-la-Rua, Concepcion

    2015-01-01

    The importance of the process of Neolithization for the genetic make-up of European populations has been hotly debated, with shifting hypotheses from a demic diffusion (DD) to a cultural diffusion (CD) model. In this regard, ancient DNA data from the Balkan Peninsula, which is an important source of information to assess the process of Neolithization in Europe, is however missing. In the present study we show genetic information on ancient populations of the South-East of Europe. We assessed mtDNA from ten sites from the current territory of Romania, spanning a time-period from the Early Neolithic to the Late Bronze Age. mtDNA data from Early Neolithic farmers of the Star?evo Cri? culture in Romania (Cârcea, Gura Baciului and Negrile?ti sites), confirm their genetic relationship with those of the LBK culture (Linienbandkeramik Kultur) in Central Europe, and they show little genetic continuity with modern European populations. On the other hand, populations of the Middle-Late Neolithic (Boian, Zau and Gumelni?a cultures), supposedly a second wave of Neolithic migration from Anatolia, had a much stronger effect on the genetic heritage of the European populations. In contrast, we find a smaller contribution of Late Bronze Age migrations to the genetic composition of Europeans. Based on these findings, we propose that permeation of mtDNA lineages from a second wave of Middle-Late Neolithic migration from North-West Anatolia into the Balkan Peninsula and Central Europe represent an important contribution to the genetic shift between Early and Late Neolithic populations in Europe, and consequently to the genetic make-up of modern European populations. PMID:26053041

  20. Histone acetylation controls the inactive X chromosome replication dynamics

    PubMed Central

    Casas-Delucchi, Corella S.; Brero, Alessandro; Rahn, Hans-Peter; Solovei, Irina; Wutz, Anton; Cremer, Thomas; Leonhardt, Heinrich; Cardoso, M. Cristina

    2011-01-01

    In mammals, dosage compensation between male and female cells is achieved by inactivating one female X chromosome (Xi). Late replication of Xi was proposed to be involved in the maintenance of its silenced state. Here, we show a highly synchronous replication of the Xi within 1 to 2?h during early-mid S-phase by following DNA replication in living mammalian cells with green fluorescent protein-tagged replication proteins. The Xi was replicated before or concomitant with perinuclear or perinucleolar facultative heterochromatin and before constitutive heterochromatin. Ectopic expression of the X-inactive-specific transcript (Xist) gene from an autosome imposed the same synchronous replication pattern. We used mutations and chemical inhibition affecting different epigenetic marks as well as inducible Xist expression and we demonstrate that histone hypoacetylation has a key role in controlling Xi replication. The epigenetically controlled, highly coordinated replication of the Xi is reminiscent of embryonic genome replication in flies and frogs before genome activation and might be a common feature of transcriptionally silent chromatin. PMID:21364561

  1. Checkpoint Activation of an Unconventional DNA Replication Program in Tetrahymena

    PubMed Central

    Sandoval, Pamela Y.; Lee, Po-Hsuen; Meng, Xiangzhou; Kapler, Geoffrey M.

    2015-01-01

    The intra-S phase checkpoint kinase of metazoa and yeast, ATR/MEC1, protects chromosomes from DNA damage and replication stress by phosphorylating subunits of the replicative helicase, MCM2-7. Here we describe an unprecedented ATR-dependent pathway in Tetrahymena thermophila in which the essential pre-replicative complex proteins, Orc1p, Orc2p and Mcm6p are degraded in hydroxyurea-treated S phase cells. Chromosomes undergo global changes during HU-arrest, including phosphorylation of histone H2A.X, deacetylation of histone H3, and an apparent diminution in DNA content that can be blocked by the deacetylase inhibitor sodium butyrate. Most remarkably, the cell cycle rapidly resumes upon hydroxyurea removal, and the entire genome is replicated prior to replenishment of ORC and MCMs. While stalled replication forks are elongated under these conditions, DNA fiber imaging revealed that most replicating molecules are produced by new initiation events. Furthermore, the sole origin in the ribosomal DNA minichromosome is inactive and replication appears to initiate near the rRNA promoter. The collective data raise the possibility that replication initiation occurs by an ORC-independent mechanism during the recovery from HU-induced replication stress. PMID:26218270

  2. Checkpoint Activation of an Unconventional DNA Replication Program in Tetrahymena.

    PubMed

    Sandoval, Pamela Y; Lee, Po-Hsuen; Meng, Xiangzhou; Kapler, Geoffrey M

    2015-07-01

    The intra-S phase checkpoint kinase of metazoa and yeast, ATR/MEC1, protects chromosomes from DNA damage and replication stress by phosphorylating subunits of the replicative helicase, MCM2-7. Here we describe an unprecedented ATR-dependent pathway in Tetrahymena thermophila in which the essential pre-replicative complex proteins, Orc1p, Orc2p and Mcm6p are degraded in hydroxyurea-treated S phase cells. Chromosomes undergo global changes during HU-arrest, including phosphorylation of histone H2A.X, deacetylation of histone H3, and an apparent diminution in DNA content that can be blocked by the deacetylase inhibitor sodium butyrate. Most remarkably, the cell cycle rapidly resumes upon hydroxyurea removal, and the entire genome is replicated prior to replenishment of ORC and MCMs. While stalled replication forks are elongated under these conditions, DNA fiber imaging revealed that most replicating molecules are produced by new initiation events. Furthermore, the sole origin in the ribosomal DNA minichromosome is inactive and replication appears to initiate near the rRNA promoter. The collective data raise the possibility that replication initiation occurs by an ORC-independent mechanism during the recovery from HU-induced replication stress. PMID:26218270

  3. Complementary Replication Peter F. Stadler

    E-print Network

    Stadler, Peter F.

    Complementary Replication By Peter F. Stadler Institut f¨ur Theoretische Chemie der Universit@DGOGWDG1 or A8443GAD@AWIUNI11 #12; Stadler: Complementary Replication Abstract Differential equations for the kinetics of complementary replicating macromolecules in a flow reactor are derived. It is shown

  4. RNASEK Is a V-ATPase-Associated Factor Required for Endocytosis and the Replication of Rhinovirus, Influenza A Virus, and Dengue Virus.

    PubMed

    Perreira, Jill M; Aker, Aaron M; Savidis, George; Chin, Christopher R; McDougall, William M; Portmann, Jocelyn M; Meraner, Paul; Smith, Miles C; Rahman, Motiur; Baker, Richard E; Gauthier, Annick; Franti, Michael; Brass, Abraham L

    2015-08-01

    Human rhinovirus (HRV) causes upper respiratory infections and asthma exacerbations. We screened multiple orthologous RNAi reagents and identified host proteins that modulate HRV replication. Here, we show that RNASEK, a transmembrane protein, was needed for the replication of HRV, influenza A virus, and dengue virus. RNASEK localizes to the cell surface and endosomal pathway and closely associates with the vacuolar ATPase (V-ATPase) proton pump. RNASEK is required for endocytosis, and its depletion produces enlarged clathrin-coated pits (CCPs) at the cell surface. These enlarged CCPs contain endocytic cargo and are bound by the scissioning GTPase, DNM2. Loss of RNASEK alters the localization of multiple V-ATPase subunits and lowers the levels of the ATP6AP1 subunit. Together, our results show that RNASEK closely associates with the V-ATPase and is required for its function; its loss prevents the early events of endocytosis and the replication of multiple pathogenic viruses. PMID:26212330

  5. Simple systems that exhibit self-directed replication

    NASA Technical Reports Server (NTRS)

    Reggia, James A.; Armentrout, Steven L.; Chou, Hui-Hsien; Peng, Yun

    1993-01-01

    Biological experience and intuition suggest that self-replication is an inherently complex phenomenon, and early cellular automata models support that conception. More recently, simpler computational models of self-directed replication called sheathed loops have been developed. It is shown here that 'unsheathing' these structures and altering certain assumptions about the symmetry of their components leads to a family of nontrivial self-replicating structures some substantially smaller and simpler than those previously reported. The dependence of replication time and transition function complexity on initial structure size, cell state symmetry, and neighborhood are examined. These results support the view that self-replication is not an inherently complex phenomenon but rather an emergent property arising from local interactions in systems that can be much simpler than is generally believed.

  6. Choreography of the Mycobacterium Replication Machinery during the Cell Cycle

    PubMed Central

    Trojanowski, Damian; Ginda, Katarzyna; Pióro, Monika; Ho?ówka, Joanna; Skut, Partycja; Jakimowicz, Dagmara

    2015-01-01

    ABSTRACT It has recently been demonstrated that bacterial chromosomes are highly organized, with specific positioning of the replication initiation region. Moreover, the positioning of the replication machinery (replisome) has been shown to be variable and dependent on species-specific cell cycle features. Here, we analyzed replisome positions in Mycobacterium smegmatis, a slow-growing bacterium that exhibits characteristic asymmetric polar cell extension. Time-lapse fluorescence microscopy analyses revealed that the replisome is slightly off-center in mycobacterial cells, a feature that is likely correlated with the asymmetric growth of Mycobacterium cell poles. Estimates of the timing of chromosome replication in relation to the cell cycle, as well as cell division and chromosome segregation events, revealed that chromosomal origin-of-replication (oriC) regions segregate soon after the start of replication. Moreover, our data demonstrate that organization of the chromosome by ParB determines the replisome choreography. PMID:25691599

  7. The changing dielectric properties of CHO cells can be used to determine early apoptotic events in a bioprocess.

    PubMed

    Braasch, Katrin; Nikolic-Jaric, Marija; Cabel, Tim; Salimi, Elham; Bridges, Greg E; Thomson, Doug J; Butler, Michael

    2013-11-01

    To ensure maximum productivity of recombinant proteins it is desirable to prolong cell viability during a mammalian cell bioprocess, and therefore important to carefully monitor cell density and viability. In this study, five different and independent methods of monitoring were applied to Chinese hamster ovary (CHO) cells grown in a batch culture in a controlled bioreactor to determine cell density and/or cell viability. They included: a particle counter, trypan blue exclusion (Cedex), an in situ bulk capacitance probe, an off-line fluorescent flow cytometer, and a prototype dielectrophoretic (DEP) cytometer. These various techniques gave similar values during the exponential growth phase. However, beyond the exponential growth phase the viability measurements diverged. Fluorescent flow cytometry with a range of fluorescent markers was used to investigate this divergence and to establish the progress of cell apoptosis: the cell density estimates by the intermediate stage apoptosis assay agreed with those obtained by the bulk capacitance probe and the early stage apoptosis assay viability measurements correlated well with the DEP cytometer. The trypan blue assay showed higher estimates of viable cell density and viability compared to the capacitance probe or the DEP cytometer. The DEP cytometer measures the dielectric properties of individual cells and identified at least two populations of cells, each with a distinct polarizability. As verified by comparison with the Nexin assay, one population was associated with viable (non-apoptotic) cells and the other with apoptotic cells. From the end of the exponential through the stationary and decline stages there was a gradual shift of cell count from the viable into the apoptotic population. However, the two populations maintained their individual dielectric properties throughout this shift. This leads to the conclusion that changes in bulk dielectric properties of cultures might be better modeled as shifts in cells between different dielectric sub-populations, rather than assuming a homogeneous dielectric population. This shows that bulk dielectric probes are sensitive to the early apoptotic changes in cells. DEP cytometry offers a novel and unique technology for analyzing and characterizing mammalian cells based on their dielectric properties, and suggests a potential application of the device as a low-cost, label-free, electronic monitor of physiological changes in cells. PMID:23818314

  8. Patch dynamics and the timing of colonization-abandonment events by male Kirtland's Warblers in an early succession habitat

    USGS Publications Warehouse

    Donner, D.M.; Ribic, C.A.; Probst, J.R.

    2010-01-01

    Habitat colonization and abandonment affects the distribution of a species in space and time, ultimately influencing the duration of time habitat is used and the total area of habitat occupied in any given year. Both aspects have important implications to long-term conservation planning. The importance of patch isolation and area to colonization-extinction events is well studied, but little information exists on how changing regional landscape structure and population dynamics influences the variability in the timing of patch colonization and abandonment events. We used 26 years of Kirtland's Warbler (Dendroica kirtlandii) population data taken during a habitat restoration program (1979-2004) across its historical breeding range to examine the influence of patch attributes and temporal large-scale processes, specifically the rate of habitat turnover and fraction of occupied patches, on the year-to-year timing of patch colonization and abandonment since patch origin. We found the timing of patch colonization and abandonment was influenced by patch and large-scale regional factors. In this system, larger patches were typically colonized earlier (i.e., at a younger age) and abandoned later than smaller patches. Isolated patches (i.e., patches farther from another occupied patch) were generally colonized later and abandoned earlier. Patch habitat type affected colonization and abandonment; colonization occurred at similar patch ages between plantation and wildfire areas (9 and 8.5 years, respectively), but plantations were abandoned at earlier ages (13.9 years) than wildfire areas (16.4 years) resulting in shorter use. As the fraction of occupied patches increased, patches were colonized and abandoned at earlier ages. Patches were abandoned at older ages when the influx of new habitat patches was at low and high rates. Our results provide empirical support for the temporal influence of patch dynamics (i.e., patch destruction, creation, and succession) on local colonization and extinction processes that help explain large-scale patterns of habitat occupancy. Results highlight the need for practitioners to consider the timing of habitat restoration as well as total amount and spatial arrangement of habitat to sustain populations.

  9. Remote Correlation of Paleoceanographic Events in the Northern Parts of Bering and Barents Seas during the Termination I and Early Holocene

    NASA Astrophysics Data System (ADS)

    Ivanova, E. V.; Ovsepyan, E.; Murdmaa, I.; de Vernal, A.; Risebrobakken, B.; Seitkalieva, E.; Radionova, E.; Alekhina, G.

    2014-12-01

    The Barents and Bering seas are closely linked to the High Arctic and to the THC by marine gateways as well as by land-sea and ocean-atmosphere interactions. Our multi-proxy time series demonstrate that these remote seas exhibited dramatic changes during the deglaciation through a succession of global and regional paleoceanographic events including the beginning of Termination I (BT1), Heinrich-1 or Oldest Dryas (OD), Bølling-Allerød (B/A), Younger Dryas (YD) and early Holocene (EH). In the NW Barents Sea, the increased subsurface-to-bottom Atlantic water inflow via the Kvitøya-Erik Eriksen trough (cores S 2519 and S 2528) is inferred at the late OD, late B/A and late YD/EH transition. These events are generally coupled with the strengthened AMOC. A remarkable sea surface warming and sea ice retreat are documented at ~ 13 ka BP. Surface warming and strong Atlantic water inflow were followed by intense iceberg calving in the Erik Eriksen Trough as indicated by the high IRD content of Core S-2519. The rock fragments are unsorted and mainly angular suggesting their ice-rafted (likely iceberg-rafted) origin. Svalbard glaciers apparently derived the material dominated by black schistous mudstones, hard limestones with coral remains, fine-grained sandstones from nearby islands, and icebergs spread it in the Kvitøya-Erik Eriksen Trough during the early deglaciation. The ice rafted coarse terrigenous material supply during the BT1 is also suggested for the NW Bering Sea. In the NW Pacific, NW Bering Sea and Sea of Okhotsk, surface bioproductivity peaked at B/A and EH mainly due to the global warming, enhanced nutrient supply by surface currents from the flooded northeastern shelf, intensified vertical mixing and water exchange through the opened straits. Oxygen-depleted bottom water at intermediate depths characterized several locations including the NW Bering Sea (Core SO201-2-85KL).

  10. Hypercholesterolemia induces short-term spatial memory impairments in mice: up-regulation of acetylcholinesterase activity as an early and causal event?

    PubMed

    Moreira, Eduardo Luiz Gasnhar; de Oliveira, Jade; Engel, Daiane Fátima; Walz, Roger; de Bem, Andreza Fabro; Farina, Marcelo; Prediger, Rui Daniel S

    2014-04-01

    Epidemiological studies have indicated hypercholesterolemia in midlife as a risk factor for dementia in later life, bringing cholesterol to the forefront of Alzheimer's disease research. Herein, we modeled mild hypercholesterolemia in mice to evaluate biochemical and behavioral alterations linked to hypercholesterolemia. Swiss mice were fed a high fat/cholesterol diet (20 % fat and 1.25 % cholesterol) for an 8-week period (from 12 to 18 weeks old) and were tested on the object location, forced swimming and elevated plus-maze tasks. We also investigated hypercholesterolemia-induced changes on acetylcholinesterase (AChE) activity, oxidative damage, amyloid precursor protein (APP) processing and blood brain barrier (BBB) integrity within the prefrontal cortex and hippocampus. It was found that increased AChE activity within the prefrontal cortex and hippocampus is an early event associated with hypercholesterolemia-induced short-term memory impairments. We observed no signs of antioxidant imbalance and/or oxidative damage or changes in cortical and hippocampal densities of beta-site amyloid precursor protein-cleaving enzyme 1 and aquaporin-4, biomarkers of APP processing and BBB integrity, respectively. In addition, we treated SH-SY5Y human neuroblastoma cells with low-density lipoprotein (LDL) cholesterol in an attempt to manipulate cell cholesterol content. Notably, LDL cholesterol increased in a dose-dependent manner the activity of AChE in SH-SY5Y cells. The present findings provide new evidence that increased AChE activity within the prefrontal cortex and hippocampus is an early event associated with hypercholesterolemia-induced cognitive impairments. PMID:24166183

  11. W Phase Inversion and Tsunami Inundation Modeling for Tsunami Early Warning: Case Study for the 2011 Tohoku Event

    NASA Astrophysics Data System (ADS)

    Gusman, Aditya Riadi; Tanioka, Yuichiro

    2014-07-01

    Centroid moment tensor solutions for the 2011 Tohoku earthquake are determined by W phase inversions using 5 and 10 min data recorded by the Full Range Seismograph Network of Japan (F-net). By a scaling relation of moment magnitude to rupture area and an assumption of rigidity of 4 × 1010 N m-2, simple rectangular earthquake fault models are estimated from the solutions. Tsunami inundations in the Sendai Plain, Minamisanriku, Rikuzentakata, and Taro are simulated using the estimated fault models. Then the simulated tsunami inundation area and heights are compared with the observations. Even the simulated tsunami heights and inundations from the W phase solution that used only 5 min data are considerably similar to the observations. The results are improved when using 10 min of W phase data. These show that the W phase solutions are reliable to be used for tsunami inundation modeling. Furthermore, the technique that combines W phase inversion and tsunami inundation modeling can produce results that have sufficient accuracy for tsunami early warning purposes.

  12. CCR4 Controls the Suppressive Effects of Regulatory T Cells on Early and Late Events during Severe Sepsis

    PubMed Central

    Molinaro, Raphael; Pecli, Cyntia; Guilherme, Rafael F.; Alves-Filho, José Carlos; Cunha, Fernando Q.; Canetti, Claudio; Kunkel, Steven L.; Bozza, Marcelo T.; Benjamim, Claudia F.

    2015-01-01

    Sepsis is a deadly disease characterized by an overwhelming release of inflammatory mediators and the activation of different types of cells. This altered state of cell activation, termed leukocyte reprogramming, contributes to patient outcome. However, the understanding of the process underlying sepsis and the role of regulatory T cells (Tregs) in sepsis remains to be elucidated. In this study, we investigated the role of CCR4, the CCL17/CCL22 chemokine receptor, in the innate and acquired immune responses during severe sepsis and the role of Tregs in effecting the outcome. In contrast with wild-type (WT) mice subjected to cecal ligation and puncture (CLP) sepsis, CCR4-deficient (CCR4-/-) septic mice presented an increased survival rate, significant neutrophil migration toward the infection site, a low bacterial count in the peritoneum, and reduced lung inflammation and serum cytokine levels. Thus, a better early host response may favor an adequate long-term response. Consequently, the CCR4-/- septic mice were not susceptible to secondary fungal infection, in contrast with the WT septic mice. Furthermore, Tregs cells from the CCR4-/- septic mice showed reduced suppressive effects on neutrophil migration (both in vivo and in vitro), lymphocyte proliferation and ROS production from activated neutrophils, in contrast with what was observed for Tregs from the WT septic mice. These data show that CCR4 is involved in immunosuppression after severe sepsis and suggest that CCR4+ Tregs negatively modulate the short and long-term immune responses. PMID:26197455

  13. Early event-related brain potentials and hemispheric asymmetries reveal mind-wandering while reading and predict comprehension.

    PubMed

    Broadway, James M; Franklin, Michael S; Schooler, Jonathan W

    2015-04-01

    The electroencephalogram (EEG) of mind-wandering (MW) was examined in event-related potentials (ERPs) and pre-stimulus alpha (8-12 Hz), over lateral-posterior sites of left and right brain hemispheres, while individuals read text passages. After controlling for individual differences in general intelligence (g), P1-asymmetry was greater (right-minus- left) and N1 amplitudes were more negative, when individuals were not MW (i.e., they were reading attentively). Approximately 82% of variance in reading comprehension was accounted for by the predictors: g, pre-stimulus alpha, left- and right-hemisphere P1, and left-hemisphere N1 (when individuals were not MW). Together, individual differences in MW-sensitive ERPs uniquely accounted for approximately 38% of the variance in reading comprehension, over and above prediction by g and pre-stimulus alpha. The within-person effect of MW on P1-asymmetry was estimated to account for an additional 4.6% of criterion variance. Implications for EEG/ERP research into attention, language processing, hemispheric asymmetries, and individual differences are discussed. PMID:25738641

  14. Transantarctic disjunctions in Schistochilaceae (Marchantiophyta) explained by early extinction events, post-Gondwanan radiations and palaeoclimatic changes.

    PubMed

    Sun, Yu; He, Xiaolan; Glenny, David

    2014-07-01

    The liverworts are the first diverging land plant group with origins in the Ordovician. The family Schistochilaceae exhibits diverse morphology and widely disjunct geographic ranges within the Southern Hemisphere. The family has been presented as a classic example of Gondwanan biogeographic distribution, with extant species ranges resulting from vicariance events. In this study, we present results that elucidate the origin and diversification of Schistochilaceae. We conducted a comprehensive time-calibrated, molecular-based phylogenetic analysis and different approaches for ancestral range inference of the family. Schistochilaceae is inferred to have originated in the Late Cretaceous, in an ancestral area including southern South America, West Antarctica and New Zealand. Despite a family origin at c. 100Ma, most of the diversification of Schistochilaceae occurred in New Zealand after the 80Ma opening of the Tasman Sea that isolated New Zealand from the rest of Gondwana. Most dispersals were transoceanic. The northward migration of the Schistochilaceae is probably linked with the spread of temperate vascular plant forest ecosystems that have Late Cretaceous southern origins and have maintained suitable environments for the family throughout the Cenozoic. The distribution and biogeographic history of the family is very similar to that of Nothofagaceae. PMID:24680916

  15. Reliable Communication Infrastructure for Adaptive Data Replication

    E-print Network

    Pedone, Fernando

    Reliable Communication Infrastructure for Adaptive Data Replication Mouna Allani1 , Beno Abstract. In this paper, we propose a data replication algorithm adap- tive to unreliable environments. The data replication algorithm, named Adaptive Data Replication (ADR), has already an adaptiveness mecha

  16. Demonstration of a Novel Synchrophasor-based Situational Awareness System: Wide Area Power System Visualization, On-line Event Replay and Early Warning of Grid Problems

    SciTech Connect

    Rosso, A.

    2012-12-31

    Since the large North Eastern power system blackout on August 14, 2003, U.S. electric utilities have spent lot of effort on preventing power system cascading outages. Two of the main causes of the August 14, 2003 blackout were inadequate situational awareness and inadequate operator training In addition to the enhancements of the infrastructure of the interconnected power systems, more research and development of advanced power system applications are required for improving the wide-area security monitoring, operation and planning in order to prevent large- scale cascading outages of interconnected power systems. It is critically important for improving the wide-area situation awareness of the operators or operational engineers and regional reliability coordinators of large interconnected systems. With the installation of large number of phasor measurement units (PMU) and the related communication infrastructure, it will be possible to improve the operators’ situation awareness and to quickly identify the sequence of events during a large system disturbance for the post-event analysis using the real-time or historical synchrophasor data. The purpose of this project was to develop and demonstrate a novel synchrophasor-based comprehensive situational awareness system for control centers of power transmission systems. The developed system named WASA (Wide Area Situation Awareness) is intended to improve situational awareness at control centers of the power system operators and regional reliability coordinators. It consists of following main software modules: • Wide-area visualizations of real-time frequency, voltage, and phase angle measurements and their contour displays for security monitoring. • Online detection and location of a major event (location, time, size, and type, such as generator or line outage). • Near-real-time event replay (in seconds) after a major event occurs. • Early warning of potential wide-area stability problems. The system has been deployed and demonstrated at the Tennessee Valley Authority (TVA) and ISO New England system using real-time synchrophasor data from openPDC. Apart from the software product, the outcome of this project consists of a set of technical reports and papers describing the mathematical foundations and computational approaches of different tools and modules, implementation issues and considerations, lessons learned, and the results of lidation processes.

  17. Replication timing is regulated by the number of MCMs loaded at origins.

    PubMed

    Das, Shankar P; Borrman, Tyler; Liu, Victor W T; Yang, Scott C-H; Bechhoefer, John; Rhind, Nicholas

    2015-12-01

    Replication timing is a crucial aspect of genome regulation that is strongly correlated with chromatin structure, gene expression, DNA repair, and genome evolution. Replication timing is determined by the timing of replication origin firing, which involves activation of MCM helicase complexes loaded at replication origins. Nonetheless, how the timing of such origin firing is regulated remains mysterious. Here, we show that the number of MCMs loaded at origins regulates replication timing. We show for the first time in vivo that multiple MCMs are loaded at origins. Because early origins have more MCMs loaded, they are, on average, more likely to fire early in S phase. Our results provide a mechanistic explanation for the observed heterogeneity in origin firing and help to explain how defined replication timing profiles emerge from stochastic origin firing. These results establish a framework in which further mechanistic studies on replication timing, such as the strong effect of heterochromatin, can be pursued. PMID:26359232

  18. Patterns of human occupation during the early Holocene in the Central Ebro Basin (NE Spain) in response to the 8.2 ka climatic event

    NASA Astrophysics Data System (ADS)

    González-Sampériz, P.; Utrilla, P.; Mazo, C.; Valero-Garcés, B.; Sopena, MC.; Morellón, M.; Sebastián, M.; Moreno, A.; Martínez-Bea, M.

    2009-03-01

    The Central Ebro River Basin (NE Spain) is the most northern area of truly semi-arid Mediterranean climate in Europe and prehistoric human occupation there has been strongly influenced by this extreme environmental condition. Modern climate conditions single out this region due to the harsh environment, characterised by the highest absolute summer temperatures of the Ebro River Basin. The Bajo Aragón region (SE Ebro River Basin) was intensively populated during the Early Holocene (9400-8200 cal yr BP) but the settlements were abandoned abruptly at around 8200 cal yr BP. We propose that this "archaeological silence" was caused by the regional impact of the global abrupt 8.2 ka cold event. Available regional paleoclimate archives demonstrate the existence of an aridity crisis then that interrupted the humid Early Holocene. That environmental crisis would have forced hunter-gatherer groups from the Bajo Aragón to migrate to regions with more favourable conditions (i.e. more humid mountainous areas) and only return in the Neolithic. Coherently, archaeological sites persist during this crisis in the nearby Iberian Range (Maestrazgo) and the North Ebro River area (Pre-Pyrenean mountains and along the northwestern Ebro Basin).

  19. Replication Stress in Mammalian Cells and Its Consequences for Mitosis

    PubMed Central

    Gelot, Camille; Magdalou, Indiana; Lopez, Bernard S.

    2015-01-01

    The faithful transmission of genetic information to daughter cells is central to maintaining genomic stability and relies on the accurate and complete duplication of genetic material during each cell cycle. However, the genome is routinely exposed to endogenous and exogenous stresses that can impede the progression of replication. Such replication stress can be an early cause of cancer or initiate senescence. Replication stress, which primarily occurs during S phase, results in consequences during mitosis, jeopardizing chromosome segregation and, in turn, genomic stability. The traces of replication stress can be detected in the daughter cells during G1 phase. Alterations in mitosis occur in two types: 1) local alterations that correspond to breaks, rearrangements, intertwined DNA molecules or non-separated sister chromatids that are confined to the region of the replication dysfunction; 2) genome-wide chromosome segregation resulting from centrosome amplification (although centrosomes do not contain DNA), which amplifies the local replication stress to the entire genome. Here, we discuss the endogenous causes of replication perturbations, the mechanisms of replication fork restart and the consequences for mitosis, chromosome segregation and genomic stability. PMID:26010955

  20. Folate levels modulate oncogene-induced replication stress and tumorigenicity

    PubMed Central

    Lamm, Noa; Maoz, Karin; Bester, Assaf C; Im, Michael M; Shewach, Donna S; Karni, Rotem; Kerem, Batsheva

    2015-01-01

    Chromosomal instability in early cancer stages is caused by replication stress. One mechanism by which oncogene expression induces replication stress is to drive cell proliferation with insufficient nucleotide levels. Cancer development is driven by alterations in both genetic and environmental factors. Here, we investigated whether replication stress can be modulated by both genetic and non-genetic factors and whether the extent of replication stress affects the probability of neoplastic transformation. To do so, we studied the effect of folate, a micronutrient that is essential for nucleotide biosynthesis, on oncogene-induced tumorigenicity. We show that folate deficiency by itself leads to replication stress in a concentration-dependent manner. Folate deficiency significantly enhances oncogene-induced replication stress, leading to increased DNA damage and tumorigenicity in vitro. Importantly, oncogene-expressing cells, when grown under folate deficiency, exhibit a significantly increased frequency of tumor development in mice. These findings suggest that replication stress is a quantitative trait affected by both genetic and non-genetic factors and that the extent of replication stress plays an important role in cancer development. PMID:26197802

  1. Persistently stalled replication forks inhibit nucleotide excision repair in trans by sequestering Replication protein A

    PubMed Central

    Tsaalbi-Shtylik, Anastasia; Moser, Jill; Mullenders, Leon H. F.; Jansen, Jacob G.; de Wind, Niels

    2014-01-01

    Rev3, the catalytic subunit of DNA polymerase ?, is essential for translesion synthesis of cytotoxic DNA photolesions, whereas the Rev1 protein plays a noncatalytic role in translesion synthesis. Here, we reveal that mammalian Rev3?/? and Rev1?/? cell lines additionally display a nucleotide excision repair (NER) defect, specifically during S phase. This defect is correlated with the normal recruitment but protracted persistence at DNA damage sites of factors involved in an early stage of NER, while repair synthesis is affected. Remarkably, the NER defect becomes apparent only at 2 h post-irradiation indicating that Rev3 affects repair synthesis only indirectly, rather than performing an enzymatic role in NER. We provide evidence that the NER defect is caused by scarceness of Replication protein A (Rpa) available to NER, resulting from its sequestration at stalled replication forks. Also the induction of replicative stress using hydroxyurea precludes the accumulation of Rpa at photolesion sites, both in Rev3?/? and in wild-type cells. These data support a model in which the limited Rpa pool coordinates replicative stress and NER, resulting in increased cytotoxicity of ultraviolet light when replicative stress exceeds a threshold. PMID:24464993

  2. Event Name: _________________________________ Event Date: ___________________

    E-print Network

    Oviedo, Néstor J.

    Event Name: _________________________________ Event Date: ___________________ 1 Social Justice Programs ­ Event Co-Sponsorship Form The Social Justice Programs: 1. A completed "Club and Organization Advising Form/Event Form" must

  3. Cell-cycle regulated transcription associates with DNA replication timing in yeast and human

    E-print Network

    Hunter B. Fraser

    2013-08-08

    Eukaryotic DNA replication follows a specific temporal program, with some genomic regions consistently replicating earlier than others, yet what determines this program is largely unknown. Highly transcribed regions have been observed to replicate in early S-phase in all plant and animal species studied to date, but this relationship is thought to be absent from both budding yeast and fission yeast. No association between cell-cycle regulated transcription and replication timing has been reported for any species. Here I show that in budding yeast, fission yeast, and human, the genes most highly transcribed during S-phase replicate early, whereas those repressed in S-phase replicate late. Transcription during other cell-cycle phases shows either the opposite correlation with replication timing, or no relation. The relationship is strongest near late-firing origins of replication, which is not consistent with a previously proposed model -- that replication timing may affect transcription -- and instead suggests a potential mechanism involving the recruitment of limiting replication initiation factors during S-phase. These results suggest that S-phase transcription may be an important determinant of DNA replication timing across eukaryotes, which may explain the well-established association between transcription and replication timing.

  4. Re-replication of a Centromere Induces Chromosomal Instability and Aneuploidy

    PubMed Central

    Hanlon, Stacey L.; Li, Joachim J.

    2015-01-01

    The faithful inheritance of chromosomes during cell division requires their precise replication and segregation. Numerous mechanisms ensure that each of these fundamental cell cycle events is performed with a high degree of fidelity. The fidelity of chromosomal replication is maintained in part by re-replication controls that ensure there are no more than two copies of every genomic segment to distribute to the two daughter cells. This control is enforced by inhibiting replication initiation proteins from reinitiating replication origins within a single cell cycle. Here we show in Saccharomyces cerevisiae that re-replication control is important for the fidelity of chromosome segregation. In particular, we demonstrate that transient re-replication of centromeric DNA due to disruption of re-replication control greatly induces aneuploidy of the re-replicated chromosome. Some of this aneuploidy arises from missegregation of both sister chromatids to one daughter cell. Aneuploidy can also arise from the generation of an extra sister chromatid via homologous recombination, suggesting that centromeric re-replication can trigger breakage and repair events that expand chromosome number without causing chromosomal rearrangements. Thus, we have identified a potential new non-mitotic source of aneuploidy that can arise from a defect in re-replication control. Given the emerging connections between the deregulation of replication initiation proteins and oncogenesis, this finding may be relevant to the aneuploidy that is prevalent in cancer. PMID:25901968

  5. Autonomous replication of plasmids bearing monkey DNA origin-enriched sequences

    SciTech Connect

    Frappier, L.; Zannis-Hadjopoulos, M.

    1987-10-01

    Twelve clones of origin-enriched sequences (ORS) isolated from early replicating monkey (CV-1) DNA were examined for transient episomal replication in transfected CV-1, COS-7, and HeLa cells. Plasmid DNA was isolated at time intervals after transfection and screened by the Dpn I resistance assay or by the bromodeoxyuridine substitution assay to differentiate between input and replicated DNA. The authors have identified four monkey ORS (ORS3, -8, -9, and -12) that can support plasmid replication in mammalian cells. This replication is carried out in a controlled and semiconservative manner characteristic of mammalian replicons. ORS replication was most efficient in HeLa cells. Electron microscopy showed ORS8 and ORS12 plasmids of the correct size with replication bubbles. Using a unique restriction site in ORS12, we have mapped the replication bubble within the monkey DNA sequence.

  6. Analysis of replication error (RER+) phenotypes in cervical carcinoma.

    PubMed

    Larson, A A; Kern, S; Sommers, R L; Yokota, J; Cavenee, W K; Hampton, G M

    1996-03-15

    Infection of epithelial cells with human papillomavirus is an important early event in the development of cervical dysplasia. However, progression to overt malignancy appears dependent upon further genetic and/or epigenetic events. We have recently developed methodologies for the simultaneous analysis of loss of heterozygosity (LOH) at multiple PCR-based microsatellite loci using semiautomated fluorescent DNA sequencing technology to determine the locations of tumor suppressor genes which are inactivated during tumor progression. While examining 30 microsatellite loci for LOH on chromosomes 3p, 4, and 11q, we detected novel tumor-specific alleles indicative of microsatellite instability (MI). The methodology allowed rapid and accurate comparison of over 3000 genotypes from 89 primary tumors and 10 cervical carcinoma-derived cell lines and showed that five tumors (5.6%) and one human papillomavirus-negative cell line, C33A, had genetic features consistent with a replication error (RER+) phenotype as defined by MI at two or more loci. In each of the RER+ tumors, LOH was also observed at one or more loci on each of the three chromosomes examined. These findings suggest that defects in DNA repair-associated genes are rarely acquired and do not supersede allelic loss during cervical carcinogenesis. In addition, the semiautomated multiplex approach has proven unequivocal in the detection and interpretation of MI and should greatly accelerate the rapidity and accuracy of analysis of such defects in tumors. Moreover, the number of loci that can be relatively easily examined in this way will also allow a detailed statistical consideration of the importance of such events. PMID:8640835

  7. Tight Chk1 Levels Control Replication Cluster Activation in Xenopus

    PubMed Central

    Wiggins, Jennifer M.; Barbosa, Pedro; Libeau, Pierre; Priam, Pierre; Narassimprakash, Hemalatha; Grodzenski, Xenia; Marheineke, Kathrin

    2015-01-01

    DNA replication in higher eukaryotes initiates at thousands of origins according to a spatio-temporal program. The ATR/Chk1 dependent replication checkpoint inhibits the activation of later firing origins. In the Xenopus in vitro system initiations are not sequence dependent and 2-5 origins are grouped in clusters that fire at different times despite a very short S phase. We have shown that the temporal program is stochastic at the level of single origins and replication clusters. It is unclear how the replication checkpoint inhibits late origins but permits origin activation in early clusters. Here, we analyze the role of Chk1 in the replication program in sperm nuclei replicating in Xenopus egg extracts by a combination of experimental and modelling approaches. After Chk1 inhibition or immunodepletion, we observed an increase of the replication extent and fork density in the presence or absence of external stress. However, overexpression of Chk1 in the absence of external replication stress inhibited DNA replication by decreasing fork densities due to lower Cdk2 kinase activity. Thus, Chk1 levels need to be tightly controlled in order to properly regulate the replication program even during normal S phase. DNA combing experiments showed that Chk1 inhibits origins outside, but not inside, already active clusters. Numerical simulations of initiation frequencies in the absence and presence of Chk1 activity are consistent with a global inhibition of origins by Chk1 at the level of clusters but need to be combined with a local repression of Chk1 action close to activated origins to fit our data. PMID:26046346

  8. Acceleration of large active earthflows triggered by massive snow accumulation events: evidences from monitoring the Corvara landslide in early 2014 (Dolomites, Italy)

    NASA Astrophysics Data System (ADS)

    Corsini, Alessandro; Mulas, Marco; Marcato, Gianluca; Chinellato, Giulia; Mair, Volkmar

    2015-04-01

    In the Dolomites of Italy, snowfall during winter 2013/2014 was exceptionally abundant. Major snowfall events occurred from late December 2013 to mid-March 2014. Snow accumulation in Badia Valley peaked in early February: from 2 to 4 meters with a positive gradient respect to altimetry and accordingly to wind accumulation zones. Below 2000 m asl, due to the mild temperatures recorded before the onset of snowfall, the relatively dry snow cover was mostly deposited on top of unfrozen soils. The Corvara landslide is a large active earthflow located close to Corvara in Badia, at an elevation from 2000 to 1600 m. It's displacement rate before, during and after the exceptional snowfall period was monitored at high temporal frequency. Surface displacement was measured bi-weekly by differential GPS in several benchmarks in the source, track and accumulation zone. Deep displacement was monitored semi-continuously by two in-place inclinometers at 48 m depth in the accumulation zone, across the main deep-seated sliding surface. Results show an acceleration of movements, both at surface and at depth, soon after the massive snow accumulation event of 31st January to 2nd February 2014, which suddenly increased snow thickness from 1 to more than 2 metres. Short time lags between the onset of the acceleration of movements in the source, the track and the accumulation zones were also recorded. The landslide then maintained a relatively constant velocity during the high snow cover period extended to earlyApril and underwent a progressive deceleration during the snowmelt period that lasted until mid-June. The fact that the acceleration of the Corvara earthflow was triggered by a massive and rapid snow accumulation event, provides a quite different perspective from the generally adopted one that considers the destabilizing effect of snow only in relation to the increase of groundwater level during rapid snowmelt. A full explanation of the processes associated to the dynamics observed in Corvara is undoubtedly still an open issue. However, it can be tentatively speculated that in the some sectors of the source and track zone, where sliding surfaces are relatively shallow -around 15 m deep -, the weight of the copiously fallen snow induced a distributed undrained loading in the already fully saturated and confined landslide mass. Or, alternatively, that snow accumulation over the unfrozen soil induced groundwater levels above the ground. To explain how acceleration of movements occurred as deep as 48 m in the accumulation zone, it might be argued that the mass and/or the pore pressure transfer from the track to the accumulation zone - evidenced by the time lag of velocity peaks- can have played a role in indirectly transferring to the accumulation zone the acceleration induced by massive snowfall in the track zone. To provide more robust answers, further monitoring data collection and analysis is needed. Thus, while waiting for other massive snowfall events, three continuous GPS receivers and a water pressure transducer in the soil have been added to the monitoring network during 2014.

  9. Changes in the Phosphoproteome and Metabolome Link Early Signaling Events to Rearrangement of Photosynthesis and Central Metabolism in Salinity and Oxidative Stress Response in Arabidopsis.

    PubMed

    Chen, Yanmei; Hoehenwarter, Wolfgang

    2015-12-01

    Salinity and oxidative stress are major factors affecting and limiting the productivity of agricultural crops. The molecular and biochemical processes governing the plant response to abiotic stress have often been researched in a reductionist manner. Here, we report a systemic approach combining metabolic labeling and phosphoproteomics to capture early signaling events with quantitative metabolome analysis and enzyme activity assays to determine the effects of salt and oxidative stress on plant physiology. K(+) and Na(+) transporters showed coordinated changes in their phosphorylation pattern, indicating the importance of dynamic ion homeostasis for adaptation to salt stress. Unique phosphorylation sites were found for Arabidopsis (Arabidopsis thaliana) SNF1 kinase homolog10 and 11, indicating their central roles in the stress-regulated responses. Seven Sucrose Non-fermenting1-Related Protein Kinase2 kinases showed varying levels of phosphorylation at multiple serine/threonine residues in their kinase domain upon stress, showing temporally distinct modulation of the various isoforms. Salinity and oxidative stress also lead to changes in protein phosphorylation of proteins central to photosynthesis, in particular the kinase State Transition Protein7 required for state transition and light-harvesting II complex proteins. Furthermore, stress-induced changes of the phosphorylation of enzymes of central metabolism were observed. The phosphorylation patterns of these proteins were concurrent with changes in enzyme activity. This was reflected by altered levels of metabolites, such as the sugars sucrose and fructose, glycolysis intermediates, and amino acids. Together, our study provides evidence for a link between early signaling in the salt and oxidative stress response that regulates the state transition of photosynthesis and the rearrangement of primary metabolism. PMID:26471895

  10. Early Holocene change in atmospheric circulation in the Northern great plains: An upstream view of the 8.2 ka cold event

    USGS Publications Warehouse

    Dean, W.E.; Forester, R.M.; Bradbury, J.P.

    2002-01-01

    Elk Lake, in northwestern Minnesota, contains numerous proxy records of climatic and environmental change contained in varved sediments with annual resolution for the last 10,000 years. These proxies show that about 8200 calendar years ago (8.2 cal. ka; 7300 radiocarbon years) Elk Lake went from a well-stratified lake that was wind-protected in a boreal forest to a well-mixed lake in open prairie savanna receiving northwesterly wind-blown dust, probably from the dry floor of Lake Agassiz. This change in climate marks the initiation of the widely recognized mid-Holocene "altithermal" in central North America. The coincidence of this change with the so-called 8.2 cal. ka cold event, recognized in ice-core and other records from the circum-North Atlantic, and thought by some to be caused by catastrophic discharge of freshwater from proglacial lakes Agassiz and Ojibway, suggests that the two "events" might be related. Our interpretation of the Elk Lake proxy records, and of other records from less accurately dated sites, suggests that change in climate over North America was the result of a fundamental change in atmospheric circulation in response to marked changes in the relative proportions of land, water, and, especially, glacial ice in North America during the early Holocene. This change in circulation probably post-dates the final drainage of proglacial lakes along the southern margin of the Laurentide ice sheet, and may have produced a minor perturbation in climate over Greenland that resulted in a brief cold pulse detected in ice cores. ?? 2002 Elsevier Science Ltd. All rights reserved.

  11. Prebiotic chemistry: Replicating towards complexity

    NASA Astrophysics Data System (ADS)

    Chen, Irene A.

    2015-03-01

    Replication of long nucleic acid sequences was required for the evolution of biological complexity during the origin of life; however, short sequences are normally better replicators than long ones. A common physical environment now provides a simple mechanism to reverse this trend and enables long sequences to flourish.

  12. Charter School Replication. Policy Guide

    ERIC Educational Resources Information Center

    Rhim, Lauren Morando

    2009-01-01

    "Replication" is the practice of a single charter school board or management organization opening several more schools that are each based on the same school model. The most rapid strategy to increase the number of new high-quality charter schools available to children is to encourage the replication of existing quality schools. This policy guide…

  13. Archaeology of Eukaryotic DNA Replication

    PubMed Central

    Makarova, Kira S.; Koonin, Eugene V.

    2013-01-01

    Recent advances in the characterization of the archaeal DNA replication system together with comparative genomic analysis have led to the identification of several previously uncharacterized archaeal proteins involved in replication and currently reveal a nearly complete correspondence between the components of the archaeal and eukaryotic replication machineries. It can be inferred that the archaeal ancestor of eukaryotes and even the last common ancestor of all extant archaea possessed replication machineries that were comparable in complexity to the eukaryotic replication system. The eukaryotic replication system encompasses multiple paralogs of ancestral components such that heteromeric complexes in eukaryotes replace archaeal homomeric complexes, apparently along with subfunctionalization of the eukaryotic complex subunits. In the archaea, parallel, lineage-specific duplications of many genes encoding replication machinery components are detectable as well; most of these archaeal paralogs remain to be functionally characterized. The archaeal replication system shows remarkable plasticity whereby even some essential components such as DNA polymerase and single-stranded DNA-binding protein are displaced by unrelated proteins with analogous activities in some lineages. PMID:23881942

  14. Dynamic organization of DNA replication in mammalian cell nuclei: spatially and temporally defined replication of chromosome-specific alpha-satellite DNA sequences

    PubMed Central

    1992-01-01

    Five distinct patterns of DNA replication have been identified during S- phase in asynchronous and synchronous cultures of mammalian cells by conventional fluorescence microscopy, confocal laser scanning microscopy, and immunoelectron microscopy. During early S-phase, replicating DNA (as identified by 5-bromodeoxyuridine incorporation) appears to be distributed at sites throughout the nucleoplasm, excluding the nucleolus. In CHO cells, this pattern of replication peaks at 30 min into S-phase and is consistent with the localization of euchromatin. As S-phase continues, replication of euchromatin decreases and the peripheral regions of heterochromatin begin to replicate. This pattern of replication peaks at 2 h into S-phase. At 5 h, perinucleolar chromatin as well as peripheral areas of heterochromatin peak in replication. 7 h into S-phase interconnecting patches of electron-dense chromatin replicate. At the end of S-phase (9 h), replication occurs at a few large regions of electron-dense chromatin. Similar or identical patterns have been identified in a variety of mammalian cell types. The replication of specific chromosomal regions within the context of the BrdU-labeling patterns has been examined on an hourly basis in synchronized HeLa cells. Double labeling of DNA replication sites and chromosome-specific alpha-satellite DNA sequences indicates that the alpha-satellite DNA replicates during mid S-phase (characterized by the third pattern of replication) in a variety of human cell types. Our data demonstrates that specific DNA sequences replicate at spatially and temporally defined points during the cell cycle and supports a spatially dynamic model of DNA replication. PMID:1740468

  15. Replicative stress, stem cells and aging.

    PubMed

    Ruzankina, Yaroslava; Asare, Amma; Brown, Eric J

    2008-01-01

    DNA synthesis is a remarkably vulnerable phase in the cell cycle. In addition to introduction of errors during semi-conservative replication, the inherently labile structure of the replication fork, as well as numerous pitfalls encountered in the course of fork progression, make the normally stable double stranded molecule susceptible to collapse and recombination. As described in this issue, maintenance of genome integrity in the face of such events is essential to prevent the premature onset of age-related diseases. At the organismal level, the roles for such maintenance are numerous; however, the preservation of stem and progenitor cell pools may be particularly important as indicated by several genetically engineered mouse models. Stresses on stem and progenitor cell pools, in the form of telomere shortening (Terc(-/-)) or other genome maintenance failures (ATR(mKO), Ku86(-/-), LIG4(Y288C), XPD(R722W/R722W), etc.), have been shown to degrade tissue renewal capacity and accelerate the appearance of age-related phenotypes. In the case of telomere shortening, exhaustion of replicative potential appears to be at least partially dependent on the cell cycle regulatory component of the DNA damage response. Therefore, both the genome maintenance mechanisms that counter DNA damage and the cell cycle checkpoint responses to damage strongly influence the onset of age-related diseases and do so, at least in part, by affecting long-term stem and progenitor cell potential. PMID:18462780

  16. News & Events Event Calendar

    E-print Network

    Papalambros, Panos

    News & Events Event Calendar ARC Annual Conference Research Seminars Press Room Event Archives ARC dummies are used routinely to evaluate the safety of vehicles and the performance of restraint systems

  17. Modifications of the chemical structure of phenolics differentially affect physiological activities in pulvinar cells of Mimosa pudica L. I. Multimode effect on early membrane events.

    PubMed

    Rocher, Françoise; Dédaldéchamp, Fabienne; Saeedi, Saed; Fleurat-Lessard, Pierrette; Chollet, Jean-Francois; Roblin, Gabriel

    2014-11-01

    A study of the structure-activity relationship carried out on several benzoic acid-related phenolics indicates that this type of compounds hinders the osmocontractile reaction of pulvinar cells in the range of 0-100%. Tentatively, we tried to find a way that could explain this differential action. With this aim, the relationship between the inhibitory effect and important molecular physico-chemical parameters (namely lipophilicity and degree of dissociation) was drawn. In addition, the effect of a variety of these compounds was investigated on their capacity to modify the electrical transmembrane potential and induce modifications in proton fluxes. Finally, using plasma membrane vesicles purified from pulvinar tissues, we examined the effects of some selected compounds on the proton pump activity and catalytic activity of the plasma membrane H(+)-ATPase. Taken together, the results indicate that a modification of the molecular structure of phenolics may induce important variation in the activity of the compound on these early membrane events. Among the tested phenolics, salicylic acid (SA) and acetylsalicylic acid (ASA, aspirin) are of particuler note, as they showed atypical effects on the physiological processes studied. PMID:25306527

  18. Epigenetic changes at the insulin-like growth factor II/H19 locus in developing kidney is an early event in Wilms tumorigenesis.

    PubMed

    Okamoto, K; Morison, I M; Taniguchi, T; Reeve, A E

    1997-05-13

    Relaxation of imprinting at the insulin-like growth factor II (IFG-II)/H19 locus is a major mechanism involved in the onset of sporadic Wilms tumor and several other embryonal tumors. The high prevalence of histologically abnormal foci in kidney adjacent to Wilms tumors suggests that tumor-predisposing genetic/epigenetic lesion might also be found at high frequency in Wilms tumor-bearing kidneys. Focusing on Wilms tumors with relaxation of IFG-II imprinting, we determined the frequency of epigenetic change at the IFG-II/H19 locus in adjacent kidney. In all kidneys adjacent to these Wilms tumors, we detected substantial mosaicism for a population of cells with relaxation of IFG-II imprinting and biallelic H19 methylation, regardless of whether the patient had a tumor-predisposing syndrome or not. The high proportion of epigenetically modified cells among "normal" tissue indicates that the epigenetic error occurred very early in development, before the onset of Wilms tumor. Not only does this suggest that the major Wilms tumor-predisposing event occurs within the first few days of development, but it also suggests that sporadic Wilms tumor may represent one end of a spectrum of overgrowth disorders characterized by mosaic epigenetic change at the IFG-II/H19 locus. PMID:9144243

  19. Regulation of desmocollin gene expression in the epidermis: CCAAT/enhancer-binding proteins modulate early and late events in keratinocyte differentiation.

    PubMed Central

    Smith, Conrad; Zhu, Kuichun; Merritt, Anita; Picton, Rhian; Youngs, Denise; Garrod, David; Chidgey, Martyn

    2004-01-01

    Desmocollins (Dscs) are desmosomal cadherins that exhibit differentiation-specific patterns of expression in the epidermis. Dsc3 expression is strongest in basal cell layers, whereas Dsc1 is largely confined to upper, terminally differentiating strata. To understand better the processes by which Dsc expression is regulated in the epidermis, we have isolated Dsc3 and Dsc1 5'-flanking DNAs and analysed their activity in primary keratinocytes. In the present study, we found that transcription factors of the CCAAT/enhancer-binding protein family play a role in the regulation of expression of both Dscs and, in so doing, implicate this class of transcription factors in both early and late events in keratinocyte differentiation. We show that Dscs are differentially regulated by C/EBP (CCAAT/enhancer-binding protein) family members, with Dsc3 expression being activated by C/EBPbeta but not C/EBPalpha, and the reverse being the case for Dsc1. Expression of both Dscs is activated by another family member, C/EBPdelta. These results show for the first time how desmosomal cadherin gene expression is regulated and provide a mechanism for the control of other differentiation-specific genes in the epidermis. PMID:15030314

  20. Early bioenergetic evolution

    PubMed Central

    Sousa, Filipa L.; Thiergart, Thorsten; Landan, Giddy; Nelson-Sathi, Shijulal; Pereira, Inês A. C.; Allen, John F.; Lane, Nick; Martin, William F.

    2013-01-01

    Life is the harnessing of chemical energy in such a way that the energy-harnessing device makes a copy of itself. This paper outlines an energetically feasible path from a particular inorganic setting for the origin of life to the first free-living cells. The sources of energy available to early organic synthesis, early evolving systems and early cells stand in the foreground, as do the possible mechanisms of their conversion into harnessable chemical energy for synthetic reactions. With regard to the possible temporal sequence of events, we focus on: (i) alkaline hydrothermal vents as the far-from-equilibrium setting, (ii) the Wood–Ljungdahl (acetyl-CoA) pathway as the route that could have underpinned carbon assimilation for these processes, (iii) biochemical divergence, within the naturally formed inorganic compartments at a hydrothermal mound, of geochemically confined replicating entities with a complexity below that of free-living prokaryotes, and (iv) acetogenesis and methanogenesis as the ancestral forms of carbon and energy metabolism in the first free-living ancestors of the eubacteria and archaebacteria, respectively. In terms of the main evolutionary transitions in early bioenergetic evolution, we focus on: (i) thioester-dependent substrate-level phosphorylations, (ii) harnessing of naturally existing proton gradients at the vent–ocean interface via the ATP synthase, (iii) harnessing of Na+ gradients generated by H+/Na+ antiporters, (iv) flavin-based bifurcation-dependent gradient generation, and finally (v) quinone-based (and Q-cycle-dependent) proton gradient generation. Of those five transitions, the first four are posited to have taken place at the vent. Ultimately, all of these bioenergetic processes depend, even today, upon CO2 reduction with low-potential ferredoxin (Fd), generated either chemosynthetically or photosynthetically, suggesting a reaction of the type ‘reduced iron ? reduced carbon’ at the beginning of bioenergetic evolution. PMID:23754820

  1. NACSA Charter School Replication Guide: The Spectrum of Replication Options. Authorizing Matters. Replication Brief 1

    ERIC Educational Resources Information Center

    O'Neill, Paul

    2010-01-01

    One of the most important and high-profile issues in public education reform today is the replication of successful public charter school programs. With more than 5,000 failing public schools in the United States, there is a tremendous need for strong alternatives for parents and students. Replicating successful charter school models is an…

  2. The Fork in the Road: Histone Partitioning During DNA Replication

    PubMed Central

    Annunziato, Anthony T.

    2015-01-01

    In the following discussion the distribution of histones at the replication fork is examined, with specific attention paid to the question of H3/H4 tetramer "splitting." After a presentation of early experiments surrounding this topic, more recent contributions are detailed. The implications of these findings with respect to the transmission of histone modifications and epigenetic models are also addressed. PMID:26110314

  3. Eliminating Synchronization Bottlenecks Using Adaptive Replication

    E-print Network

    Rinard, Martin

    Eliminating Synchronization Bottlenecks Using Adaptive Replication MARTIN C. RINARD Massachusetts technique, adaptive replication, for automatically eliminating syn- chronization bottlenecks synchronization bottlenecks by replicating objects. Each thread can then update its own local replica without

  4. GORDA: An Open Architecture for Database Replication

    E-print Network

    Rodrigues, Luís E.T.

    GORDA: An Open Architecture for Database Replication Extended Report Alfrnio Correia Jr. University of Lisboa Abstract Recently, third party solutions for database replication have been enjoying an increasing without the overhead of synchronous replication; clustering for scalability and availability

  5. Regulating DNA Replication in Eukarya

    PubMed Central

    Siddiqui, Khalid; On, Kin Fan; Diffley, John F.X.

    2013-01-01

    DNA replication is tightly controlled in eukaryotic cells to ensure that an exact copy of the genetic material is inherited by both daughter cells. Oscillating waves of cyclin-dependent kinase (CDK) and anaphase-promoting complex/cyclosome (APC/C) activities provide a binary switch that permits the replication of each chromosome exactly once per cell cycle. Work from several organisms has revealed a conserved strategy whereby inactive replication complexes are assembled onto DNA during periods of low CDK and high APC activity but are competent to execute genome duplication only when these activities are reversed. Periods of high CDK and low APC/C serve an essential function by blocking reassembly of replication complexes, thereby preventing rereplication. Higher eukaryotes have evolved additional CDK-independent mechanisms for preventing rereplication. PMID:23838438

  6. The chromatin remodeling complex NoRC controls replication timing of rRNA genes.

    PubMed

    Li, Junwei; Santoro, Raffaella; Koberna, Karel; Grummt, Ingrid

    2005-01-12

    The ATP-dependent chromatin remodeling complex NoRC silences a fraction of mammalian ribosomal RNA genes (rDNA) by establishing heterochromatic structures at the rDNA promoter. Here we show that NoRC also plays a role in replication timing of rDNA. rDNA is replicated in a biphasic manner, active genes ( approximately 60%) replicating early and silent ones ( approximately 40%) replicating late in S-phase. The chromatin structure that marks active and silent rDNA repeats is propagated during cell division. To examine the function of NoRC in epigenetic inheritance and replication timing, we have monitored the chromatin structure, transcriptional activity and replication timing of rDNA in a cell line that moderately overexpresses NoRC. NoRC is exclusively associated with late-replicating rDNA arrays. Overexpression of NoRC silences rDNA transcription, reduces the size and number of nucleoli, impairs cell proliferation and resets replication timing from early to late. The results demonstrate that NoRC is an important determinant of replication timing and epigenetic marks are heritably maintained through DNA replication. PMID:15577942

  7. The effect of Ku on telomere replication time is mediated by telomere length but is independent of histone tail acetylation

    PubMed Central

    Lian, Hui-Yong; Robertson, E. Douglas; Hiraga, Shin-ichiro; Alvino, Gina M.; Collingwood, David; McCune, Heather J.; Sridhar, Akila; Brewer, Bonita J.; Raghuraman, M. K.; Donaldson, Anne D.

    2011-01-01

    DNA replication in Saccharomyces cerevisiae proceeds according to a temporal program. We have investigated the role of the telomere-binding Ku complex in specifying late replication of telomere-proximal sequences. Genome-wide analysis shows that regions extending up to 80 kb from telomeres replicate abnormally early in a yku70 mutant. We find that Ku does not appear to regulate replication time by binding replication origins directly, nor is its effect on telomere replication timing mediated by histone tail acetylation. We show that Ku instead regulates replication timing through its effect on telomere length, because deletion of the telomerase regulator Pif1 largely reverses the short telomere defect of a yku70 mutant and simultaneously rescues its replication timing defect. Consistent with this conclusion, deleting the genome integrity component Elg1 partially rescued both length and replication timing of yku70 telomeres. Telomere length–mediated control of replication timing requires the TG1–3 repeat-counting component Rif1, because a rif1 mutant replicates telomeric regions early, despite having extended TG1–3 tracts. Overall, our results suggest that the effect of Ku on telomere replication timing results from its impact on TG1–3 repeat length and support a model in which Rif1 measures telomere repeat length to ensure that telomere replication timing is correctly programmed. PMID:21441303

  8. The effect of Ku on telomere replication time is mediated by telomere length but is independent of histone tail acetylation.

    PubMed

    Lian, Hui-Yong; Robertson, E Douglas; Hiraga, Shin-ichiro; Alvino, Gina M; Collingwood, David; McCune, Heather J; Sridhar, Akila; Brewer, Bonita J; Raghuraman, M K; Donaldson, Anne D

    2011-05-15

    DNA replication in Saccharomyces cerevisiae proceeds according to a temporal program. We have investigated the role of the telomere-binding Ku complex in specifying late replication of telomere-proximal sequences. Genome-wide analysis shows that regions extending up to 80 kb from telomeres replicate abnormally early in a yku70 mutant. We find that Ku does not appear to regulate replication time by binding replication origins directly, nor is its effect on telomere replication timing mediated by histone tail acetylation. We show that Ku instead regulates replication timing through its effect on telomere length, because deletion of the telomerase regulator Pif1 largely reverses the short telomere defect of a yku70 mutant and simultaneously rescues its replication timing defect. Consistent with this conclusion, deleting the genome integrity component Elg1 partially rescued both length and replication timing of yku70 telomeres. Telomere length-mediated control of replication timing requires the TG(1-3) repeat-counting component Rif1, because a rif1 mutant replicates telomeric regions early, despite having extended TG(1-3) tracts. Overall, our results suggest that the effect of Ku on telomere replication timing results from its impact on TG(1-3) repeat length and support a model in which Rif1 measures telomere repeat length to ensure that telomere replication timing is correctly programmed. PMID:21441303

  9. Ultrastructural Characterization and Three-Dimensional Architecture of Replication Sites in Dengue Virus-Infected Mosquito Cells

    PubMed Central

    Junjhon, Jiraphan; Pennington, Janice G.; Edwards, Thomas J.; Perera, Rushika; Lanman, Jason

    2014-01-01

    ABSTRACT During dengue virus infection of host cells, intracellular membranes are rearranged into distinct subcellular structures such as double-membrane vesicles, convoluted membranes, and tubular structures. Recent electron tomographic studies have provided a detailed three-dimensional architecture of the double-membrane vesicles, representing the sites of dengue virus replication, but temporal and spatial evidence linking membrane morphogenesis with viral RNA synthesis is lacking. Integrating techniques in electron tomography and molecular virology, we defined an early period in virus-infected mosquito cells during which the formation of a virus-modified membrane structure, the double-membrane vesicle, is proportional to the rate of viral RNA synthesis. Convoluted membranes were absent in dengue virus-infected C6/36 cells. Electron tomographic reconstructions elucidated a high-resolution view of the replication complexes inside vesicles and allowed us to identify distinct pathways of particle formation. Hence, our findings extend the structural details of dengue virus replication within mosquito cells and highlight their differences from mammalian cells. IMPORTANCE Dengue virus induces several distinct intracellular membrane structures within the endoplasmic reticulum of mammalian cells. These structures, including double-membrane vesicles and convoluted membranes, are linked, respectively, with viral replication and viral protein processing. However, dengue virus cycles between two disparate animal groups with differing physiologies: mammals and mosquitoes. Using techniques in electron microscopy, we examined the differences between intracellular structures induced by dengue virus in mosquito cells. Additionally, we utilized techniques in molecular virology to temporally link events in virus replication to the formation of these dengue virus-induced membrane structures. PMID:24522909

  10. DNA replication, transcription and translation operate with astounding speed and fidelity in bacterial cells1

    E-print Network

    DNA replication, transcription and translation operate with astounding speed and fidelity of the molecules in the reaction vessel. For processive events, such as DNA repli- cation, transcription a number of recent examples in which in vitro single-molecule Bacterial replication, transcription

  11. The Iannaccone-Lutz Model of School Board Change: A Replication in New Mexico

    ERIC Educational Resources Information Center

    Le Doux, Eugene P.; Burlingame, Martin

    1973-01-01

    Scholarly growth in the study of politics of education rests in part on replication of theories to explicate recurring political events. Describes a study that sought to replicate and extend scholarly work done in California concerning the predictions of school board election results. (Author)

  12. The Biology of Replicative Senescence

    SciTech Connect

    Campisi, J.

    1996-12-04

    Most cells cannot divide indefinitely due to a processtermed cellular or replicative senescence. Replicative senescence appearsto be a fundamental feature of somatic cells, with the exception of mosttumour cells and possibly certain stem cells. How do cells sense thenumber of divisions they have completed? Although it has not yet beencritically tested, the telomere shortening hypothesis is currentlyperhaps the best explanation for a cell division 'counting' mechanism.Why do cells irreversibly cease proliferation after completing a finitenumber of divisions? It is now known that replicative senescence altersthe expression of a few crucial growth-regulatory genes. It is not knownhow these changes in growth-regulatory gene expression are related totelomere shortening in higher eukaryotes. However, lower eukaryotes haveprovided several plausible mechanisms. Finally, what are thephysiological consequences of replicative senescence? Several lines ofevidence suggest that, at least in human cells, replicative senescence isa powerful tumour suppressive mechanism. There is also indirect evidencethat replicative senescence contributes to ageing. Taken together,current findings suggest that, at least in mammals, replicativesenescence may have evolved to curtail tumorigenesis, but may also havethe unselected effect of contributing to age-related pathologies,including cancer.

  13. Loss of ARID1A expression is an early molecular event in tumor progression from ovarian endometriotic cyst to clear cell and endometrioid carcinoma

    PubMed Central

    Ayhan, Ayse; Mao, Tsui-Lien; Seckin, Tamer; Wu, Chen-Hsuan; Guan, Bin; Ogawa, Hiroshi; Futagami, Masayuki; Mizukami, Hiroki; Yokoyama, Yoshihito; Kurman, Robert J.; Shih, Ie-Ming

    2012-01-01

    OBJECTIVES ARID1A is a recently identified tumor suppressor participating in chromatin remodeling. Somatic inactivating mutations of ARID1A and loss of its expression occur most frequently in ovarian clear cell and endometrioid carcinomas and uterine endometrioid carcinomas. Since endometriosis is thought to be a precursor of most ovarian clear cell and endometrioid carcinomas, we undertook an analysis of ARID1A expression of these tumors arising within an endometriotic cyst (endometrioma). MATERIALS/METHODS Our immunohistochemical study set consisted of 47 endometriotic cysts containing clear cell carcinoma in 24 cases, well-differentiated ovarian endometrioid carcinoma in 20 and mixed clear cell and endometrioid carcinoma in 3. RESULTS ARID1A loss was observed in 31 (66%) of 47 carcinomas and therefore these cases were informative for determining the temporal sequence of loss of ARID1A expression in tumor progression. In 16 of the 47 cases, ARID1A immunoreactivity was retained in both the endometriotic cyst and the carcinoma and thus these cases were not informative. All of the 31 informative cases showed loss of ARID1A immunoreactivity in the carcinoma and in the endometriotic cyst epithelium in direct continuity with the carcinoma but not in the cyst epithelium that was not adjacent to the tumor. CONCLUSIONS The findings in this study provide cogent evidence that loss of ARID1A function as shown by loss of expression, presumably due to mutations, is an early molecular event, occurring before malignant transformation, in the development of the majority of ovarian clear cell and endometrioid carcinomas arising in endometriomas. PMID:22976498

  14. Involuntary switching of attention mediates differences in event-related responses to complex tones between early and late Spanish-English bilinguals.

    PubMed

    Ortiz-Mantilla, Silvia; Choudhury, Naseem; Alvarez, Barbara; Benasich, April A

    2010-11-29

    Most research with bilinguals has used speech stimuli to demonstrate differences in auditory processing abilities. Two main factors have been identified as modulators of such differences: proficiency and age of acquisition of the second language (L2). However, whether the bilingual brain differs from the monolingual in the efficient processing of non-verbal auditory events (known to be critical to the acoustic analysis of the speech stream) remains unclear. In this EEG/ERP study, using the mismatch negativity (MMN), P3a, and late negativity (LN), we examined differences in discrimination, involuntary switching of attention and reorienting of attention between monolinguals and bilinguals as they processed complex tones. Further, we examined the role that age of acquisition plays in modulating such responses. A group of English monolinguals and a group of proficient Spanish-English bilinguals were presented with a multiple-deviant oddball paradigm with four deviant conditions (duration, frequency, silent gap, and frequency modulation). Late bilinguals, who learned English after age 10, exhibited larger MMN and P3a responses than early bilinguals, across all deviant conditions. Significant associations were found between amplitude of the responses and both age of L2 acquisition and years of L2 experience. Individuals who acquired English at later ages and had fewer years of L2 experience had larger MMN, P3a, and LN responses than those who learned it earlier. These findings demonstrate that age of L2 acquisition is an important modulator of auditory responses in bilinguals even when processing non-speech signals. Involuntary attention switching is suggested as the main factor driving these differences. PMID:20849832

  15. Replication stress activates DNA repair synthesis in mitosis.

    PubMed

    Minocherhomji, Sheroy; Ying, Songmin; Bjerregaard, Victoria A; Bursomanno, Sara; Aleliunaite, Aiste; Wu, Wei; Mankouri, Hocine W; Shen, Huahao; Liu, Ying; Hickson, Ian D

    2015-12-10

    Oncogene-induced DNA replication stress has been implicated as a driver of tumorigenesis. Many chromosomal rearrangements characteristic of human cancers originate from specific regions of the genome called common fragile sites (CFSs). CFSs are difficult-to-replicate loci that manifest as gaps or breaks on metaphase chromosomes (termed CFS 'expression'), particularly when cells have been exposed to replicative stress. The MUS81-EME1 structure-specific endonuclease promotes the appearance of chromosome gaps or breaks at CFSs following replicative stress. Here we show that entry of cells into mitotic prophase triggers the recruitment of MUS81 to CFSs. The nuclease activity of MUS81 then promotes POLD3-dependent DNA synthesis at CFSs, which serves to minimize chromosome mis-segregation and non-disjunction. We propose that the attempted condensation of incompletely duplicated loci in early mitosis serves as the trigger for completion of DNA replication at CFS loci in human cells. Given that this POLD3-dependent mitotic DNA synthesis is enhanced in aneuploid cancer cells that exhibit intrinsically high levels of chromosomal instability (CIN(+)) and replicative stress, we suggest that targeting this pathway could represent a new therapeutic approach. PMID:26633632

  16. Simultaneous regulation of cell size and chromosome replication in bacteria

    E-print Network

    Po-Yi Ho; Ariel Amir

    2015-07-24

    Bacteria are able to maintain a narrow distribution of cell sizes by regulating the timing of cell divisions. In rich nutrient conditions, cells divide much faster than their chromosomes replicate. This implies that cells maintain multiple rounds of chromosome replication per cell division by regulating the timing of chromosome replications. Here, we show that both cell size and chromosome replication may be simultaneously regulated by the long-standing initiator accumulation strategy. The strategy proposes that initiators are produced in proportion to the volume increase and is accumulated at each origin of replication, and chromosome replication is initiated when a critical amount per origin has accumulated. We show that this model maps to the incremental model of size control, which was previously shown to reproduce experimentally observed correlations between various events in the cell cycle and explains the exponential dependence of cell size on the growth rate of the cell. Furthermore, we show that this model also leads to the efficient regulation of the timing of initiation and the number of origins consistent with existing experimental results.

  17. Role of ATM in the Formation of the Replication Compartment during Lytic Replication of Epstein-Barr Virus in Nasopharyngeal Epithelial Cells

    PubMed Central

    Hau, Pok Man; Deng, Wen; Jia, Lin; Yang, Jie; Tsurumi, Tatsuya; Chiang, Alan Kwok Shing; Huen, Michael Shing-Yan

    2014-01-01

    ABSTRACT Epstein-Barr virus (EBV), a type of oncogenic herpesvirus, is associated with human malignancies. Previous studies have shown that lytic reactivation of EBV in latently infected cells induces an ATM-dependent DNA damage response (DDR). The involvement of ATM activation has been implicated in inducing viral lytic gene transcription to promote lytic reactivation. Its contribution to the formation of a replication compartment during lytic reactivation of EBV remains poorly defined. In this study, the role of ATM in viral DNA replication was investigated in EBV-infected nasopharyngeal epithelial cells. We observed that induction of lytic infection of EBV triggers ATM activation and localization of DDR proteins at the viral replication compartments. Suppression of ATM activity using a small interfering RNA (siRNA) approach or a specific chemical inhibitor profoundly suppressed replication of EBV DNA and production of infectious virions in EBV-infected cells induced to undergo lytic reactivation. We further showed that phosphorylation of Sp1 at the serine-101 residue is essential in promoting the accretion of EBV replication proteins at the replication compartment, which is crucial for replication of viral DNA. Knockdown of Sp1 expression by siRNA effectively suppressed the replication of viral DNA and localization of EBV replication proteins to the replication compartments. Our study supports an important role of ATM activation in lytic reactivation of EBV in epithelial cells, and phosphorylation of Sp1 is an essential process downstream of ATM activation involved in the formation of viral replication compartments. Our study revealed an essential role of the ATM-dependent DDR pathway in lytic reactivation of EBV, suggesting a potential antiviral replication strategy using specific DDR inhibitors. IMPORTANCE Epstein-Barr virus (EBV) is closely associated with human malignancies, including undifferentiated nasopharyngeal carcinoma (NPC), which has a high prevalence in southern China. EBV can establish either latent or lytic infection depending on the cellular context of infected host cells. Recent studies have highlighted the importance of the DNA damage response (DDR), a surveillance mechanism that evolves to maintain genome integrity, in regulating lytic EBV replication. However, the underlying molecular events are largely undefined. ATM is consistently activated in EBV-infected epithelial cells when they are induced to undergo lytic reactivation. Suppression of ATM inhibits replication of viral DNA. Furthermore, we observed that phosphorylation of Sp1 at the serine-101 residue, a downstream event of ATM activation, plays an essential role in the formation of viral replication compartments for replication of virus DNA. Our study provides new insights into the mechanism through which EBV utilizes the host cell machinery to promote replication of viral DNA upon lytic reactivation. PMID:25355892

  18. Responding to the event deluge

    NASA Astrophysics Data System (ADS)

    Williams, Roy D.; Barthelmy, Scott D.; Denny, Robert B.; Graham, Matthew J.; Swinbank, John

    2012-09-01

    We present the VOEventNet infrastructure for large-scale rapid follow-up of astronomical events, including selection, annotation, machine intelligence, and coordination of observations. The VOEvent standard is central to this vision, with distributed and replicated services rather than centralized facilities. We also describe some of the event brokers, services, and software that are connected to the network. These technologies will become more important in the coming years, with new event streams from Gaia, LOFAR, LIGO, LSST, and many others.

  19. Optimistic Algorithms for Partial Database Replication

    E-print Network

    Pedone, Fernando

    Optimistic Algorithms for Partial Database Replication Nicolas Schiper1, Rodrigo Schmidt2 the problem of partial database repli- cation. Numerous previous works have investigated database replication, however, most of them focus on full replication. We are here interested in genuine partial replication

  20. Shell Separation for Mirror Replication

    NASA Technical Reports Server (NTRS)

    1999-01-01

    NASA's Space Optics Manufacturing Center has been working to expand our view of the universe via sophisticated new telescopes. The Optics Center's goal is to develop low-cost, advanced space optics technologies for the NASA program in the 21st century - including the long-term goal of imaging Earth-like planets in distant solar systems. To reduce the cost of mirror fabrication, Marshall Space Flight Center (MSFC) has developed replication techniques, the machinery, and materials to replicate electro-formed nickel mirrors. Optics replication uses reusable forms, called mandrels, to make telescope mirrors ready for final finishing. MSFC optical physicist Bill Jones monitors a device used to chill a mandrel, causing it to shrink and separate from the telescope mirror without deforming the mirror's precisely curved surface.

  1. Effect of Microgravity on Early Events of Biological Nitrogen Fixation in Medicago Truncatula: Initial Results from the SyNRGE Experiment

    NASA Technical Reports Server (NTRS)

    Stutte, Gary W.; Roberts, Michael S.

    2011-01-01

    SyNRGE (Symbiotic Nodulation in a Reduced Gravity Environment) was a sortie mission on STS-135 in the Biological Research in Canisters (BRIC) hardware to study the effect of microgravity on a plant-microbe symbiosis resulting in biological nitrogen fixation. Medicago truncatula, a model species of the legume family, was inoculated with its bacterial symbiont, Sinorhizobium meliloti, to observe early events associated with infection and nodulation in Petri Dish Fixation Units (PDFUs). Two sets of experiments were conducted in orbit and in 24-hour delayed ground controls. Experiment one was designed to determine if S. meliloti infect M. truncatula and initiate physiological changes associated with nodule formation. Roots of five-day-old M. truncatula cultivar Jemalong A17 (Enodll::gus) were inoculated 24 hr before launch with either S. meliloti strain 1021 or strain ABS7 and integrated into BRIC-PDFU hardware placed in a 4 C Cold Bag for launch on Atlantis. Inoculated plants and uninoculated controls were maintained in the dark at ambient temperature in the middeck of STS-135 for 11 days before fixation in RNAlater(tM) by crew activation of the PDFU. Experiment two was designed to determine if microgravity altered the process of bacterial infection and host plant nodule formation. Seeds of two M. truncatula cultivar Jemalong A17 lines, the Enodll::gus used in experiment 1, and SUNN, a super-nodulating mutant of A17, were germinated on orbit for 11 days in the middeck cabin and returned to Earth alive inside of BRIC-PDFU's at 4 C. S. meliloti strains 1021 and ABS7 were cultivated separately in broth culture on orbit and also returned to Earth alive. After landing, flight- and groundgrown plants and bacteria were transferred from BRIC-PDFU's into Nunc(tm) 4-well plates for reciprocity crosses. Rates of plant growth and nodule development on Buffered Nodulation Medium (lacking nitrogen) were measured for 14 days. Preliminary analysis' of Experiment 1 confirms that legumes and bacteria cultivated in space 'initiate the symbiotic interaction leading to nitrogen fixation and that bacteria retain the ability to form nodules on M. truncatula roots. Initial assessment of experiment 2 shows 100% seed germination and excellent bacterial growth in microgravity.

  2. Restricted replication of simian immunodeficiency virus strain 239 in macrophages is determined by env but is not due to restricted entry.

    PubMed Central

    Mori, K; Ringler, D J; Desrosiers, R C

    1993-01-01

    Virus derived from the infectious, pathogenic, molecular clone of simian immunodeficiency virus (SIV) called SIVmac239 replicates poorly in primary rhesus monkey alveolar macrophage cultures. Variants with three to nine amino acid changes in the envelope replicate 100 to 1,000 times more efficiently in these macrophage cultures than parental SIVmac239. Early events, including virus entry into cells, were analyzed by measuring the amounts of newly synthesized viral DNA 14 to 16 h after infection of macrophages by using a quantitative polymerase chain reaction method. SIVmac239 ws found to enter macrophages with an efficiency similar to that of the macrophage-tropic derivatives. The assay indeed measured newly synthesized viral DNA since detection was inhibited by the reverse transcriptase inhibitors azidothymidine and foscarnet and by heat inactivation of the virus stock prior to infection. Furthermore, entry of SIVmac239 and macrophage-tropic variant into macrophages was inhibited by monoclonal antibody against CD4. Analysis of the time course of viral DNA accumulation showed that although initial entry of SIVmac239 into cells occurred normally, subsequent logarithmic increases in the amounts of viral DNA associated with spread of virus through the macrophage cultures was blocked. Increasing the amount of SIVmac239 incubated with macrophages increased the amount of virus entering the cell, but this could not overcome the block to replication. Thus, restricted replication of SIVmac239 in macrophages is determined by the envelope, but surprisingly it is not due to restricted virus entry. Images PMID:7682627

  3. A Replication of Failure, Not a Failure to Replicate

    ERIC Educational Resources Information Center

    Holden, Gary; Barker, Kathleen; Kuppens, Sofie; Rosenberg, Gary; LeBreton, Jonathan

    2015-01-01

    Purpose: The increasing role of systematic reviews in knowledge production demands greater rigor in the literature search process. The performance of the Social Work Abstracts (SWA) database has been examined multiple times over the past three decades. The current study is a replication within this line of research. Method: Issue-level coverage…

  4. Exploiting replication in distributed systems

    NASA Technical Reports Server (NTRS)

    Birman, Kenneth P.; Joseph, T. A.

    1989-01-01

    Techniques are examined for replicating data and execution in directly distributed systems: systems in which multiple processes interact directly with one another while continuously respecting constraints on their joint behavior. Directly distributed systems are often required to solve difficult problems, ranging from management of replicated data to dynamic reconfiguration in response to failures. It is shown that these problems reduce to more primitive, order-based consistency problems, which can be solved using primitives such as the reliable broadcast protocols. Moreover, given a system that implements reliable broadcast primitives, a flexible set of high-level tools can be provided for building a wide variety of directly distributed application programs.

  5. The Mcm Complex: Unwinding the Mechanism of a Replicative Helicase

    PubMed Central

    Bochman, Matthew L.; Schwacha, Anthony

    2009-01-01

    Summary: The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication. Consistent with its central role in this process, much prior work has illustrated that Mcm2-7 loading and activation are landmark events in the regulation of DNA replication. Unlike any other hexameric helicase, Mcm2-7 is composed of six unique and essential subunits. Although the unusual oligomeric nature of this complex has long hampered biochemical investigations, recent advances with both the eukaryotic as well as the simpler archaeal Mcm complexes provide mechanistic insight into their function. In contrast to better-studied homohexameric helicases, evidence suggests that the six Mcm2-7 complex ATPase active sites are functionally distinct and are likely specialized to accommodate the regulatory constraints of the eukaryotic process. PMID:19946136

  6. Role for RNA:DNA hybrids in origin-independent replication priming in a eukaryotic system.

    PubMed

    Stuckey, Ruth; García-Rodríguez, Néstor; Aguilera, Andrés; Wellinger, Ralf Erik

    2015-05-01

    DNA replication initiates at defined replication origins along eukaryotic chromosomes, ensuring complete genome duplication within a single S-phase. A key feature of replication origins is their ability to control the onset of DNA synthesis mediated by DNA polymerase-? and its intrinsic RNA primase activity. Here, we describe a novel origin-independent replication process that is mediated by transcription. RNA polymerase I transcription constraints lead to persistent RNA:DNA hybrids (R-loops) that prime replication in the ribosomal DNA locus. Our results suggest that eukaryotic genomes have developed tools to prevent R-loop-mediated replication events that potentially contribute to copy number variation, particularly relevant to carcinogenesis. PMID:25902524

  7. Role for RNA:DNA hybrids in origin-independent replication priming in a eukaryotic system

    PubMed Central

    Stuckey, Ruth; García-Rodríguez, Néstor; Aguilera, Andrés; Wellinger, Ralf Erik

    2015-01-01

    DNA replication initiates at defined replication origins along eukaryotic chromosomes, ensuring complete genome duplication within a single S-phase. A key feature of replication origins is their ability to control the onset of DNA synthesis mediated by DNA polymerase-? and its intrinsic RNA primase activity. Here, we describe a novel origin-independent replication process that is mediated by transcription. RNA polymerase I transcription constraints lead to persistent RNA:DNA hybrids (R-loops) that prime replication in the ribosomal DNA locus. Our results suggest that eukaryotic genomes have developed tools to prevent R-loop–mediated replication events that potentially contribute to copy number variation, particularly relevant to carcinogenesis. PMID:25902524

  8. The requirement of yeast replication origins for pre-replication complex proteins is modulated by

    E-print Network

    Blow, J. Julian

    The requirement of yeast replication origins for pre-replication complex proteins is modulated Replication Research Group, Wellcome Trust Biocentre, University of Dundee, Dow Street, Dundee DD1 5EH-chromosome maintenance proteins Mcm2­7 are essential for DNA replication. They are loaded onto replication origins during

  9. Choosing a suitable method for the identification of replication origins in microbial genomes

    PubMed Central

    Song, Chengcheng; Zhang, Shaocun; Huang, He

    2015-01-01

    As the replication of genomic DNA is arguably the most important task performed by a cell and given that it is controlled at the initiation stage, the events that occur at the replication origin play a central role in the cell cycle. Making sense of DNA replication origins is important for improving our capacity to study cellular processes and functions in the regulation of gene expression, genome integrity in much finer detail. Thus, clearly comprehending the positions and sequences of replication origins which are fundamental to chromosome organization and duplication is the first priority of all. In view of such important roles of replication origins, tremendous work has been aimed at identifying and testing the specificity of replication origins. A number of computational tools based on various skew types have been developed to predict replication origins. Using various in silico approaches such as Ori-Finder, and databases such as DoriC, researchers have predicted the locations of replication origins sites for thousands of bacterial chromosomes and archaeal genomes. Based on the predicted results, we should choose an effective method for identifying and confirming the interactions at origins of replication. Here we describe the main existing experimental methods that aimed to determine the replication origin regions and list some of the many the practical applications of these methods. PMID:26483774

  10. Chameleon Chasing II: A Replication.

    ERIC Educational Resources Information Center

    Newsom, Doug A.; And Others

    1993-01-01

    Replicates a 1972 survey of students, educators, and Public Relations Society of America members regarding who the public relations counselor really serves. Finds that, in 1992, most respondents thought primary responsibility was to the client, then to the client's relevant publics, then to self, then to society, and finally to media. Compares…

  11. Replication and Reporting: A Commentary.

    ERIC Educational Resources Information Center

    Polio, Charlene; Gass, Susan

    1997-01-01

    Addresses the need for replication studies in the field of second-language acquisition and discusses the problems surrounding standards of reporting research. Notes a lack of uniform standards in reporting second-language learners' proficiency levels and proposes ways to achieve more thorough reporting of research that will allow others to engage…

  12. Replication and G2 checkpoints: their response to caffeine.

    PubMed

    Pelayo, H R; Lastres, P; De la Torre, C

    2001-02-01

    Under long hydroxyurea treatments, evidence was obtained for the sequential activation of four checkpoints located between the onset of S phase and mitosis in Allium cepa L. root meristems. Biparametric flow cytometry (Br-DNA/total DNA) showed that cells initially accumulated at early S phase but, after a delay, they resumed replication and paused again at mid S phase. Cells not only overrode this second replication block but also any G2 checkpoint they encountered. Thus, a late mitotic wave was produced in the presence of hydroxyurea. The wave was formed by cells that had apparently completed their replication (normal mitoses), while others displayed anaphases/telophases with less than the expected DNA content and with chromosomal breaks (aberrant mitoses). The presence of aberrant mitoses is direct evidence for the undue override of the two G2 checkpoints responsible for surveillance of completion of DNA synthesis and repair, respectively. Caffeine selectively abrogated the G2 block produced by the checkpoint that controls post-replication DNA repair, as it advanced the entry of cells into an aberrant mitosis. However, caffeine proved not to be the universal checkpoint-evading agent as postulated. Caffeine did not modify the spontaneous override of the replication checkpoints. Moreover, it seems to enforce the checkpoint that controls the completion of DNA synthesis, as the appearance of the late wave of normal mitoses produced in the presence of hydroxyurea was prevented by the use of caffeine. PMID:11289610

  13. Functional interactions of DNA topoisomerases with a human replication origin

    PubMed Central

    Abdurashidova, Gulnara; Radulescu, Sorina; Sandoval, Oscar; Zahariev, Sotir; Danailov, Miltcho B; Demidovich, Alexander; Santamaria, Laura; Biamonti, Giuseppe; Riva, Silvano; Falaschi, Arturo

    2007-01-01

    The human DNA replication origin, located in the lamin B2 gene, interacts with the DNA topoisomerases I and II in a cell cycle-modulated manner. The topoisomerases interact in vivo and in vitro with precise bonds ahead of the start sites of bidirectional replication, within the pre-replicative complex region; topoisomerase I is bound in M, early G1 and G1/S border and topoisomerase II in M and the middle of G1. The Orc2 protein competes for the same sites of the origin bound by either topoisomerase in different moments of the cell cycle; furthermore, it interacts on the DNA with topoisomerase II during the assembly of the pre-replicative complex and with DNA-bound topoisomerase I at the G1/S border. Inhibition of topoisomerase I activity abolishes origin firing. Thus, the two topoisomerases are closely associated with the replicative complexes, and DNA topology plays an essential functional role in origin activation. PMID:17290216

  14. Crinivirus replication and host interactions

    PubMed Central

    Kiss, Zsofia A.; Medina, Vicente; Falk, Bryce W.

    2013-01-01

    Criniviruses comprise one of the genera within the family Closteroviridae. Members in this family are restricted to the phloem and rely on whitefly vectors of the genera Bemisia and/or Trialeurodes for plant-to-plant transmission. All criniviruses have bipartite, positive-sense single-stranded RNA genomes, although there is an unconfirmed report of one having a tripartite genome. Lettuce infectious yellows virus (LIYV) is the type species of the genus, the best studied so far of the criniviruses and the first for which a reverse genetics system was developed. LIYV RNA 1 encodes for proteins predicted to be involved in replication, and alone is competent for replication in protoplasts. Replication results in accumulation of cytoplasmic vesiculated membranous structures which are characteristic of most studied members of the Closteroviridae. These membranous structures, often referred to as Beet yellows virus (BYV)-type vesicles, are likely sites of RNA replication. LIYV RNA 2 is replicated in trans when co-infecting cells with RNA 1, but is temporally delayed relative to RNA 1. Efficient RNA 2 replication also is dependent on the RNA 1-encoded RNA-binding protein, P34. No LIYV RNA 2-encoded proteins have been shown to affect RNA replication, but at least four, CP (major coat protein), CPm (minor coat protein), Hsp70h, and P59 are virion structural components and CPm is a determinant of whitefly transmissibility. Roles of other LIYV RNA 2-encoded proteins are largely as yet unknown, but P26 is a non-virion protein that accumulates in cells as characteristic plasmalemma deposits which in plants are localized within phloem parenchyma and companion cells over plasmodesmata connections to sieve elements. The two remaining crinivirus-conserved RNA 2-encoded proteins are P5 and P9. P5 is 39 amino acid protein and is encoded at the 5? end of RNA 2 as ORF 1 and is part of the hallmark closterovirus gene array. The orthologous gene in BYV has been shown to play a role in cell-to-cell movement and indicated to be localized to the endoplasmic reticulum as a Type III integral membrane protein. The other small protein, P9, is encoded by ORF 4 overlaps with ORF 3 that encodes the structural protein, P59. P9 seems to be unique to viruses in the genus Crinivirus, as no similar protein has been detected in viruses of the other two genera of the Closteroviridae. PMID:23730299

  15. Crinivirus replication and host interactions.

    PubMed

    Kiss, Zsofia A; Medina, Vicente; Falk, Bryce W

    2013-01-01

    Criniviruses comprise one of the genera within the family Closteroviridae. Members in this family are restricted to the phloem and rely on whitefly vectors of the genera Bemisia and/or Trialeurodes for plant-to-plant transmission. All criniviruses have bipartite, positive-sense single-stranded RNA genomes, although there is an unconfirmed report of one having a tripartite genome. Lettuce infectious yellows virus (LIYV) is the type species of the genus, the best studied so far of the criniviruses and the first for which a reverse genetics system was developed. LIYV RNA 1 encodes for proteins predicted to be involved in replication, and alone is competent for replication in protoplasts. Replication results in accumulation of cytoplasmic vesiculated membranous structures which are characteristic of most studied members of the Closteroviridae. These membranous structures, often referred to as Beet yellows virus (BYV)-type vesicles, are likely sites of RNA replication. LIYV RNA 2 is replicated in trans when co-infecting cells with RNA 1, but is temporally delayed relative to RNA 1. Efficient RNA 2 replication also is dependent on the RNA 1-encoded RNA-binding protein, P34. No LIYV RNA 2-encoded proteins have been shown to affect RNA replication, but at least four, CP (major coat protein), CPm (minor coat protein), Hsp70h, and P59 are virion structural components and CPm is a determinant of whitefly transmissibility. Roles of other LIYV RNA 2-encoded proteins are largely as yet unknown, but P26 is a non-virion protein that accumulates in cells as characteristic plasmalemma deposits which in plants are localized within phloem parenchyma and companion cells over plasmodesmata connections to sieve elements. The two remaining crinivirus-conserved RNA 2-encoded proteins are P5 and P9. P5 is 39 amino acid protein and is encoded at the 5' end of RNA 2 as ORF 1 and is part of the hallmark closterovirus gene array. The orthologous gene in BYV has been shown to play a role in cell-to-cell movement and indicated to be localized to the endoplasmic reticulum as a Type III integral membrane protein. The other small protein, P9, is encoded by ORF 4 overlaps with ORF 3 that encodes the structural protein, P59. P9 seems to be unique to viruses in the genus Crinivirus, as no similar protein has been detected in viruses of the other two genera of the Closteroviridae. PMID:23730299

  16. Timing of Early Proterozoic collisional and extensional events in the granulite-gneiss-charnockite-granite complex, Lake Baikal, USSR: A U-Pb, Rb-Sr, and Sm-Nd isotopic study

    SciTech Connect

    Aftalion, M. ); Bibikova, E.V. ); Bowes, D.R. ); Hopwood, A.M. ); Perchuk, L.L. )

    1991-11-01

    In the Sharyzhalgay Complex of the Lake Baikal region in eastern Siberia Early Proterozoic collisional and extensional events were separated by ca. 100 m.yr. The earlier collisional event, associated with the development of granulites and gneisses as the result of high-grade dynamothermal metamorphism, took place close to 1965 {plus minus} 4 Ma. A {sup 207}Pb/{sup 204}Pb vs. {sup 206}Pb/{sup 204}Pb isochron for zircon from five size fractions and a six point Rb-Sr whole-rock errorchron give generally corresponding ages of 1956 {plus minus} 8 and 1963 {plus minus} 163 Ma, respectively. The later extensional event, associated with charnockitization due to the uprise of fluids and heat in a regime corresponding to the middle to upper crustal levels of a Basin and Range-type province, was initiated in the 1880-1860 Ma period. The event was continued with magmatic emplacement of granitic masses into the deep levels of caldera-like structures, possibly during the upper time range of lower concordia intercept ages of 1817 +30/{minus}32 and 1797 +40/{minus}44 Ma for two distinctly different zircon populations in a pyroxene-bearing granodiorite interpreted as an evolved (and contaminated) product of the mantle-derived magma that was the source of CO{sub 2} involved in the charnockitization. Upper intercept ages of 2784 +48/{minus}45 and 2775 +61/{minus}55 Ma indicate late Archean crust at depth as the source region of the incorporated zircon. T{sub DM} ages from Sm-Nd isotopic data show that the protolith of the lithologically layered supracrustal assemblage, subsequently polyphase deformed and polymetamorphosed in Early Proterozoic times, was also formed in Early Proterozoic (not Archean) times.

  17. A Host Susceptibility Gene, DR1, Facilitates Influenza A Virus Replication by Suppressing Host Innate Immunity and Enhancing Viral RNA Replication

    PubMed Central

    Hsu, Shih-Feng; Su, Wen-Chi; Jeng, King-Song

    2015-01-01

    ABSTRACT Influenza A virus (IAV) depends on cellular factors to complete its replication cycle; thus, investigation of the factors utilized by IAV may facilitate antiviral drug development. To this end, a cellular transcriptional repressor, DR1, was identified from a genome-wide RNA interference (RNAi) screen. Knockdown (KD) of DR1 resulted in reductions of viral RNA and protein production, demonstrating that DR1 acts as a positive host factor in IAV replication. Genome-wide transcriptomic analysis showed that there was a strong induction of interferon-stimulated gene (ISG) expression after prolonged DR1 KD. We found that beta interferon (IFN-?) was induced by DR1 KD, thereby activating the JAK-STAT pathway to turn on ISG expression, which led to a strong inhibition of IAV replication. This result suggests that DR1 in normal cells suppresses IFN induction, probably to prevent undesired cytokine production, but that this suppression may create a milieu that favors IAV replication once cells are infected. Furthermore, biochemical assays of viral RNA replication showed that DR1 KD suppressed viral RNA replication. We also showed that DR1 associated with all three subunits of the viral RNA-dependent RNA polymerase (RdRp) complex, indicating that DR1 may interact with individual components of the viral RdRp complex to enhance viral RNA replication. Thus, DR1 may be considered a novel host susceptibility gene for IAV replication via a dual mechanism, not only suppressing the host defense to indirectly favor IAV replication but also directly facilitating viral RNA replication. IMPORTANCE Investigations of virus-host interactions involved in influenza A virus (IAV) replication are important for understanding viral pathogenesis and host defenses, which may manipulate influenza virus infection or prevent the emergence of drug resistance caused by a high error rate during viral RNA replication. For this purpose, a cellular transcriptional repressor, DR1, was identified from a genome-wide RNAi screen as a positive regulator in IAV replication. In the current studies, we showed that DR1 suppressed the gene expression of a large set of host innate immunity genes, which indirectly facilitated IAV replication in the event of IAV infection. Besides this scenario, DR1 also directly enhanced the viral RdRp activity, likely through associating with individual components of the viral RdRp complex. Thus, DR1 represents a novel host susceptibility gene for IAV replication via multiple functions, not only suppressing the host defense but also enhancing viral RNA replication. DR1 may be a potential target for drug development against influenza virus infection. PMID:25589657

  18. Event Information Event Name

    E-print Network

    Royer, Dana

    ? Sponsor Holds: Date Tickets Go on Sale: Ticket Printing Info (as it appears on tickets: ______________________________________________________________ All tech needs must be confirmed with Mark Gawlak and Barbara Ally 3 weeks in advance of event

  19. In vitro replication of poliovirus

    SciTech Connect

    Lubinski, J.M.

    1986-01-01

    Poliovirus is a member of the Picornaviridae whose genome is a single stranded RNA molecule of positive polarity surrounded by a proteinaceous capsid. Replication of poliovirus occurs via negative strand intermediates in infected cells using a virally encoded RNA-dependent RNA polymerase and host cell proteins. The authors have exploited the fact that complete cDNA copies of the viral genome when transfected onto susceptible cells generate virus. Utilizing the bacteriophage SP6 DNA dependent RNA polymerase system to synthesize negative strands in vitro and using these in an in vitro reaction the authors have generated full length infectious plus strands. Mutagenesis of the 5' and 3' ends of the negative and positive strands demonstrated that replication could occur either de novo or be extensions of the templates from their 3' ends or from nicks occurring during replication. The appearance of dimeric RNA molecules generated in these reactions was not dependent upon the same protein required for de novo initiation. Full length dimeric RNA molecules using a 5' /sup 32/P end-labelled oligo uridylic acid primer and positive strand template were demonstrated in vitro containing only the 35,000 Mr host protein and the viral RNA-dependent RNA polymerase. A model for generating positive strands without protein priming by cleavage of dimeric RNA molecules was proposed.

  20. Nuclear matrix support of DNA replication.

    PubMed

    Anachkova, Boyka; Djeliova, V; Russev, G

    2005-12-01

    In higher eukaryotic cells, DNA is tandemly arranged into 10(4) replicons that are replicated once per cell cycle during the S phase. To achieve this, DNA is organized into loops attached to the nuclear matrix. Each loop represents one individual replicon with the origin of replication localized within the loop and the ends of the replicon attached to the nuclear matrix at the bases of the loop. During late G1 phase, the replication origins are associated with the nuclear matrix and dissociated after initiation of replication in S phase. Clusters of several replicons are operated together by replication factories, assembled at the nuclear matrix. During replication, DNA of each replicon is spooled through these factories, and after completion of DNA synthesis of any cluster of replicons, the respective replication factories are dismantled and assembled at the next cluster to be replicated. Upon completion of replication of any replicon cluster, the resulting entangled loops of the newly synthesized DNA are resolved by topoisomerases present in the nuclear matrix at the sites of attachment of the loops. Thus, the nuclear matrix plays a dual role in the process of DNA replication: on one hand, it represents structural support for the replication machinery and on the other, provides key protein factors for initiation, elongation, and termination of the replication of eukaryotic DNA. PMID:16167334

  1. Semiconservative replication in the quasispecies model

    NASA Astrophysics Data System (ADS)

    Tannenbaum, Emmanuel; Deeds, Eric J.; Shakhnovich, Eugene I.

    2004-06-01

    This paper extends Eigen’s quasispecies equations to account for the semiconservative nature of DNA replication. We solve the equations in the limit of infinite sequence length for the simplest case of a static, sharply peaked fitness landscape. We show that the error catastrophe occurs when ? , the product of sequence length and per base pair mismatch probability, exceeds 2 ln [2/ ( 1+1/k ) ] , where k>1 is the first-order growth rate constant of the viable “master” sequence (with all other sequences having a first-order growth rate constant of 1 ). This is in contrast to the result of ln k for conservative replication. In particular, as k?? , the error catastrophe is never reached for conservative replication, while for semiconservative replication the critical ? approaches 2 ln 2 . Semiconservative replication is therefore considerably less robust than conservative replication to the effect of replication errors. We also show that the mean equilibrium fitness of a semiconservatively replicating system is given by k ( 2 e-?/2 -1 ) below the error catastrophe, in contrast to the standard result of k e-? for conservative replication (derived by Kimura and Maruyama in 1966). From this result it is readily shown that semiconservative replication is necessary to account for the observation that, at sufficiently high mutagen concentrations, faster replicating cells will die more quickly than more slowly replicating cells. Thus, in contrast to Eigen’s original model, the semiconservative quasispecies equations are able to provide a mathematical basis for explaining the efficacy of mutagens as chemotherapeutic agents.

  2. Pupil Replication Frank Spaan Alan Greenaway

    E-print Network

    Greenaway, Alan

    Pupil Replication Frank Spaan Alan Greenaway Erwan Prot Vincent Mourai #12;16 May 2005 www.phy.hw.ac.uk/~phyhic 2 PREDRIS · Pupil Replication for Extreme Dynamic Range Imaging Spectroscopy · Start: 1 April 2005 · Two years, funded by PPARC · Publication: Pupil Replication for Exo- Planet Imaging; ApJL, 10 January

  3. Replication of MASS segmentators Andrei Tokovinin

    E-print Network

    Tokovinin, Andrei A.

    Replication of MASS segmentators Andrei Tokovinin Version 1. Dec. 26, 2004 1 The need of replication The Pupil Segmentation Unit, or segmentators, of MASS-DIMM instruments represent a system of small production costs, simplify the alignment and assure uniform high quality. Additional advantage of replication

  4. Fig. 1. Data replication example in MANET

    E-print Network

    Haas, Zygmunt J.

    Fig. 1. Data replication example in MANET Quantitative Analysis of Partition Statistics and their Impact on Data Replication in MANETs Ke Shi Zygmunt J. Haas School of Computer Sci. and Tech. School@mail.hust.edu.cn haas@ece.cornell.edu Abstract Data replication is, indeed, a widely used redundancy scheme

  5. Genetic Variation in Human DNA Replication Timing

    E-print Network

    Zhang, Jianzhi

    Article Genetic Variation in Human DNA Replication Timing Amnon Koren,1,2 Robert E. Handsaker,1://dx.doi.org/10.1016/j.cell.2014.10.025 SUMMARY Genomic DNA replicates in a choreographed tempo- ral order from proliferating cells, read depth along chromosomes reflected DNA replication activity in those

  6. Pupil Replication for exo-planet imaging

    E-print Network

    Greenaway, Alan

    Pupil Replication for exo-planet imaging Frank Spaan Alan Greenaway #12;14-15 December 2005 Durham replication helps 0 5 10 15 20 -12 -10 -8 -6 -4 -2 0 Off Axis Distance LogIntensity(normalised) diffraction · Start with normal telescope · Include replication optics and second imaging lens. · Axial wavefront

  7. Viral replication and genetics Nabil A. NIMER

    E-print Network

    Viral replication and genetics Nabil A. NIMER Dept . Biotechnology & Genetic Engineering Faculty, and sometimes without even a single enzyme to start the process of replication. This is why it must rely so heavily on the host cell for the materials it needs for reproduction and why the replication of viruses

  8. Replication Origin Specification Gets a Push.

    PubMed

    Plosky, Brian S

    2015-12-01

    During the gap between G1 and S phases when replication origins are licensed and fired, it is possible that DNA translocases could disrupt pre-replicative complexes (pre-RCs). In this issue of Molecular Cell, Gros et al. (2015) find that pre-RCs can be pushed along DNA and retain the ability to support replication. PMID:26638172

  9. Protein aggregates are associated with replicative aging without compromising protein quality control.

    PubMed

    Saarikangas, Juha; Barral, Yves

    2015-01-01

    Differentiation of cellular lineages is facilitated by asymmetric segregation of fate determinants between dividing cells. In budding yeast, various aging factors segregate to the aging (mother)-lineage, with poorly understood consequences. In this study, we show that yeast mother cells form a protein aggregate during early replicative aging that is maintained as a single, asymmetrically inherited deposit over the remaining lifespan. Surprisingly, deposit formation was not associated with stress or general decline in proteostasis. Rather, the deposit-containing cells displayed enhanced degradation of cytosolic proteasome substrates and unimpaired clearance of stress-induced protein aggregates. Deposit formation was dependent on Hsp42, which collected non-random client proteins of the Hsp104/Hsp70-refolding machinery, including the prion Sup35. Importantly, loss of Hsp42 resulted in symmetric inheritance of its constituents and prolonged the lifespan of the mother cell. Together, these data suggest that protein aggregation is an early aging-associated differentiation event in yeast, having a two-faceted role in organismal fitness. PMID:26544680

  10. Development of a Systems Computational Model to Investigate Early Biological Events in Hepatic Activation of Constitutive Androstane Receptor (CAR) by Phenobarbital

    EPA Science Inventory

    Activation of the nuclear receptor CAR (constitutive active/androstane receptor) is implicated in the control several key biological events such as metabolic pathways. Here, we combined data from literature with information obtained from in vitro assays in the US EPA ToxCast dat...

  11. The Chemistry of Early Self-Replicating Systems

    NASA Technical Reports Server (NTRS)

    Bada, Jeffrey L. (Principal Investigator)

    2003-01-01

    The NASA Specialized Center of Research and Training in Exobiology (NSCORT/Exobiology) is a program within the UCSD California Space Institute (Dr. Wolfgang Berger, Director) currently funded by a second 5 year Federal Demonstration Project Grant from NASA. Its specific aims are: 1. The support and training of Postdoctoral, Graduate, and Undergraduate Fellows in Exobiology. 2. The support of research by the Principal Investigators and Fellows in the field of Exobiology. 3. Outreach programs emphasizing the dissemination and exchange of information concerning Exobiology within the scientific community, primary, secondary and college students, and the general public. 4. Host of the 1999 meeting of the International Society for the Study of the Origin of Life (ISSOL) held at the University of California, San Diego in La Jolla, California, from Sunday, July 11 through Friday, July 16,1999.

  12. The Chemistry of Early Self-Replicating Systems

    NASA Technical Reports Server (NTRS)

    Bada, Jeffrey L.

    1996-01-01

    The NASA Specialized Center of Research and Training (NSCORT) in Exobiology is a consortium of scientists at the University of California at San Diego (UCSD), The Salk Institute for Biological Studies (Salk) and The Scripps Research Institute (TSRI). All three institutions are located in close geographical proximity in La Jolla, California. The NSCORT/Exobiology is administered through the Scripps Institution of Oceanography. Since its inception in January 1992, the NSCORT in Exobiology has made major contributions with respect to the question of how life began on Earth. The Principal Investigators (PIs) and their associated Fellows have published numerous articles in peer reviewed journals on topics relevant to Exobiology. They have presented papers and sponsored symposia at several meetings of national and international scientific societies. A total of 30 undergraduate, 12 graduate and 15 postdoctoral Fellows have been supported by the NSCORT. The Fellows have met on their own at least once a month to discuss Exobiology topics and research progress. The NSCORT has arranged seminars and evening discussion meetings, and offered an undergraduate class on "Biochemical Evolution" as well as graduate courses dealing with topics in Exobiology. A visiting scientist program has allowed 11 scientists from the U.S. and 4 foreign countries to conduct cooperative research with the various PIs. An active outreach program has been initiated, which includes an Exobiology high school level teaching module and curriculum guide, and an elementary school level booklet about basic atomic structure and formation of the universe, Sun and Earth. A World Wide Web Homepage (http://www-chem.ucsd.edu/-nscort/ NSCORT.html) has been developed, which describes the NSCORT activities, research programs and Fellowship opportunities. The various activities of the NSCORT in Exobiology have received wide-spread coverage in both the scientific and public media. The major function of the NSCORT is the training of young scientists in the field of Exo- biology. Thus, the bulk of the $1,000,000 annual budget is used to support the research and training of undergraduate, graduate and post-doctoral Fellows who are selected on a competitive basis. About five Fellows at each level are supported each year. Our goal is to train scientists whose major research interest is Exobiology, but whose mastery in the classical fields of chemistry, biology and earth science is so strong that they outstanding candidates for either graduate school or academic tenure-track positions in departments at leading national and international Universities. Applicants for these Fellowships are solicited by advertisements in journals such as Science and Nature and in organizational newsletters such as the one published by the International Society for the Study of the Origin of Life (ISSOL), by contacting academic and NASA colleagues working in Exobiology or related fields and by recruiting students who have already been admitted into the various academic programs with which the PIs are affiliated.

  13. The Chemistry of Early Self-replicating Systems

    NASA Technical Reports Server (NTRS)

    Bada, Jeffrey L.

    2005-01-01

    The NASA Specialized Center of Research and Training in Exobiology (NSCORT/Exobiology) is a program within the University of California, San Diego, California Space Institute (Dr. Wolfgang Berger, Director). It has been funded by two 5-year Federal Demonstration Project Grants from NASA; and currently (February 1, 2003-December 31,2004) received supplemental funding to support our research completion of the NAG5-4546 Final Report for past 5 years, seminars, public lectures, and support for program administrative office. The program's specific aims have been: 1. The support and training of Postdoctoral, Graduate, and Undergraduate Fellows in Exobiology. 2. The support of research by the Principal Investigators and Fellows in the field of Exobiology. 3. Outreach programs emphasizing the dissemination and exchange of information concerning Exobiology within the scientific community, primary, secondary and college students, and the general public. 4. Public Lectures, Discussion S e m h q Seminars and Fellows Journals Club. 5. Host of the 2003 Public Lectures "Celebrating 50 Years of Prebiotic Chemistry" held at the University of California, San Diego in La Jolla, California on June 10,2003. 6. Host of the 1999 meeting of the International Society for the Study of the Origin of Life (ISSOL) held at the University of California, San Diego in La Jolla, California, from Sunday, July 11 through Friday, July 16,1999.

  14. Dihydropyridines Inhibit Translation and Early Replication of Hepatitis C Virus 

    E-print Network

    Klemashevich, Cory

    2013-05-09

    additional DHP compounds. We also show that DHP compounds inhibit IRES dependent translation in full-length HCV. This inhibition of two separate steps of the viral life cycle may be a unique feature of DHPs making them superior DAAs. Among these DHPs...

  15. Modeling genome-wide replication kinetics reveals a mechanism for regulation of replication timing

    E-print Network

    Bechhoefer, John

    Modeling genome-wide replication kinetics reveals a mechanism for regulation of replication timing are powerful tools to probe genome-wide replication kinetics. The rich data sets that result contain more model that incorporates probabilistic initiation of origins and passive replication. Using the model, we

  16. Replication occurs at discrete foci spaced throughout nuclei replicating in A. D. MILLS1

    E-print Network

    Blow, J. Julian

    Replication occurs at discrete foci spaced throughout nuclei replicating in vitro A. D. MILLS1 , J Xenopus sperm nuclei were induced to replicate synchronously in a low-speed supernatant (LSS) of Xenopus eggs by preincu- bation in a high-speed supernatant (HSS). DNA replication was observed

  17. A cis-replication element functions in both orientations to enhance replication of Turnip crinkle virus

    E-print Network

    Simon, Anne

    A cis-replication element functions in both orientations to enhance replication of Turnip crinkle Abstract Turnip crinkle virus (TCV) (family Tombusviridae, genus Carmovirus) is a positive-sense RNA virus-dependent RNA polymerase; RNA virus replication; RNA enhancer; Turnip crinkle virus; cis-acting replication

  18. Optimal Placement of Origins for DNA Replication

    E-print Network

    Jens Karschau; J. Julian Blow; Alessandro P. S. de Moura

    2012-02-02

    DNA replication is an essential process in biology and its timing must be robust so that cells can divide properly. Random fluctuations in the formation of replication starting points, called origins, and the subsequent activation of proteins lead to variations in the replication time. We analyse these stochastic properties of DNA and derive the positions of origins corresponding to the minimum replication time. We show that under some conditions the minimization of replication time leads to the grouping of origins, and relate this to experimental data in a number of species showing origin grouping.

  19. Causes and Consequences of Replication Stress

    PubMed Central

    Zeman, Michelle K.; Cimprich, Karlene A.

    2015-01-01

    Replication stress is a complex phenomenon which has serious implications for genome stability, cell survival, and human disease. Generation of aberrant replication fork structures containing single-stranded DNA activates the replication stress response, primarily mediated by the kinase ATM- and Rad3-related (ATR). ATR and its downstream effectors stabilize and help to restart stalled replication forks, avoiding the generation of DNA damage and genome instability. Understanding these pathways may be key to diagnosis and treatment of human diseases caused by defective responses to replication stress. PMID:24366029

  20. Replication Stress: A Lifetime of Epigenetic Change

    PubMed Central

    Khurana, Simran; Oberdoerffer, Philipp

    2015-01-01

    DNA replication is essential for cell division. Challenges to the progression of DNA polymerase can result in replication stress, promoting the stalling and ultimately collapse of replication forks. The latter involves the formation of DNA double-strand breaks (DSBs) and has been linked to both genome instability and irreversible cell cycle arrest (senescence). Recent technological advances have elucidated many of the factors that contribute to the sensing and repair of stalled or broken replication forks. In addition to bona fide repair factors, these efforts highlight a range of chromatin-associated changes at and near sites of replication stress, suggesting defects in epigenome maintenance as a potential outcome of aberrant DNA replication. Here, we will summarize recent insight into replication stress-induced chromatin-reorganization and will speculate on possible adverse effects for gene expression, nuclear integrity and, ultimately, cell function. PMID:26378584

  1. Enhanced Deletion Formation by Aberrant DNA Replication in Escherichia Coli

    PubMed Central

    Saveson, C. J.; Lovett, S. T.

    1997-01-01

    Repeated genes and sequences are prone to genetic rearrangements including deletions. We have investigated deletion formation in Escherichia coli strains mutant for various replication functions. Deletion was selected between 787 base pair tandem repeats carried either on a ColE1-derived plasmid or on the E. coli chromosome. Only mutations in functions associated with DNA Polymerase III elevated deletion rates in our assays. Especially large increases were observed in strains mutant in dnaQ, the ? editing subunit of Pol III, and dnaB, the replication fork helicase. Mutations in several other functions also altered deletion formation: the ? polymerase (dnaE), the ? clamp loader complex (holC, dnaX), and the ? clamp (dnaN) subunits of Pol III and the primosomal proteins, dnaC and priA. Aberrant replication stimulated deletions through several pathways. Whereas the elevation in dnaB strains was mostly recA- and lexA-dependent, that in dnaQ strains was mostly recA- and lexA-independent. Deletion product analysis suggested that slipped mispairing, producing monomeric replicon products, may be preferentially increased in a dnaQ mutant and sister-strand exchange, producing dimeric replicon products, may be elevated in dnaE mutants. We conclude that aberrant Polymerase III replication can stimulate deletion events through several mechanisms of deletion and via both recA-dependent and independent pathways. PMID:9177997

  2. The Role of Temporal Abundance Structure and Habitat Preferences in the Survival of Conodonts during the Mid-Early Silurian Ireviken Mass Extinction Event

    PubMed Central

    Spiridonov, Andrej; Brazauskas, Antanas; Radzevi?ius, Sigitas

    2015-01-01

    The Ireviken event was one of the most intense extinction episodes that occurred during the mid-Paleozoic era. It had a strong global effect on a range of clades, with conodonts, graptolites and chitinozoans affected most. Using geophysical proxies and conodont species parameters of their temporal abundance structure we investigate how they affected the selectivity of conodont species survival during this calamity. After performing bivariate logistic analyses on 34 species of conodonts, we find three variables that were statistically significantly associated with their odds of survival. These namely include spectral exponents that describe degrees of autocorrelation in a time series, the skewness of species abundance distribution, and average environmental preferences, which are mostly determined by ancient water depths at sampling sites. Model selection of multivariate logistic models found the best model includes species local abundance skewness and substrate preference. A similar pattern is revealed through the regression tree analysis. The apparent extinction selectivity points to a possible causes of environmental deterioration during the Ireviken event. The significant positive relationship between extinction risk and preferential existence in deeper environments suggests the open ocean causal mechanisms of biotic stress that occurred during the Ireviken event. Marine regressions, which were previously suggested as a causal factor in this extinction episode, on theoretical grounds should have had higher impact on species living in near-shore environments, through the processes of habitat loss which are associated with decreases of shelfal areas. In addition, the significant positive correlations found between skewness of abundance distributions and spectral exponent values and the probability of species survival suggest that community and ecosystem processes (which controlled species abundance fluctuation patterns) were significantly related to selectivity processes of this smaller mass extinction event. PMID:25859854

  3. Calcium-linked increase in coupled cAMP synthesis and hydrolysis is an early event in cholinergic and. beta. -adrenergic stimulation of parotid secretion

    SciTech Connect

    Deeg, M.A.; Graeff, R.M.; Walseth, T.F.; Goldberg, N.D. )

    1988-11-01

    The dynamics and compartmental characteristics of cAMP metabolism were examined by {sup 18}O labeling of cellular adenine nucleotide {alpha} phosphoryls in rat parotid gland stimulated to secrete with {beta}-adrenergic and cholinergic agents. The secretory response occurred in association with a rapidly increased rate of cAMP hydrolysis apparently coordinated with an equivalent increase in the rate of cAMP synthesis, since the cellular concentration of cAMP remained unchanged. The magnitude of this metabolic response was equivalent to the metabolism of 10-75 times the cellular content of cAMP within the first minute of stimulation. This increased metabolic rate occurred only during the early (1-3 min) period of stimulation, in what appeared to be an exclusive cellular compartment distinguished by a unique distribution of {sup 18}O among adenine nucleotide {alpha} phosphoryls. This {sup 18}O distribution contrasted with that produced by forskolin, which increased cellular cAMP concentration and elicited only a delayed response missing the early secretory component. The early acceleration of cAMP metabolism appeared linked to a stimulus-induced increase in intracellular Ca{sup 2+} concentration, since the Ca{sup 2+} ionophore ionomycin produced the same metabolic response in association with secretion. These observations suggest that cAMP metabolism is involved in stimulus-secretion coupling by a Ca{sup 2+}-linked mechanism different from that in which cAMP plays the role of a second messenger.

  4. How to securely replicate services

    NASA Technical Reports Server (NTRS)

    Reiter, Michael; Birman, Kenneth

    1992-01-01

    A method is presented for constructing replicated services that retain their availability and integrity despite several servers and clients corrupted by an intruder, in addition to others failing benignly. More precisely, a service is replicated by n servers in such a way that a correct client will accept a correct server's response if, for some prespecified parameter k, at least k servers are correct and fewer than k servers are corrupt. The issue of maintaining causality among client requests is also addressed. A security breach resulting from an intruder's ability to effect a violation of causality in the sequence of requests processed by the service is illustrated. An approach to counter this problem is proposed that requires fewer than k servers to be corrupt and that is live if at least k+b servers are correct, where b is the assumed maximum total number of corrupt servers in any system run. An important and novel feature of these schemes is that the client need not be able to identify or authenticate even a single server. Instead, the client is required only to possess at most two public keys for the service. The practicality of these schemes is illustrated through a discussion of several issues pertinent to their implementation and use, and their intended role in a secure version of the Isis system is also described.

  5. Transcription regulatory elements are punctuation marks for DNA replication

    E-print Network

    Mirkin, Sergei

    Transcription regulatory elements are punctuation marks for DNA replication Ekaterina V. Mirkin, and approved March 27, 2006 (received for review February 9, 2006) Collisions between DNA replication described collisions between replication forks and elongating RNA polymerases. Although replication

  6. Early Life Exposures and Cancer

    Cancer.gov

    Early-life events and exposures have important consequences for cancer development later in life, however, epidemiological studies of early-life factors and cancer development later in life have had significant methodological challenges.

  7. Human PIF1 helicase supports DNA replication and cell growth under oncogenic-stress

    PubMed Central

    Gagou, Mary E.; Ganesh, Anil; Phear, Geraldine; Robinson, Darren; Petermann, Eva; Cox, Angela; Meuth, Mark

    2014-01-01

    Unwinding duplex DNA is a critical processing step during replication, repair and transcription. Pif1 are highly conserved non-processive 5?->3? DNA helicases with well-established roles in maintenance of yeast genome stability. However, the function of the sole member of Pif1 family in humans remains unclear. Human PIF1 is essential for tumour cell viability, particularly during replication stress, but is dispensable in non-cancerous cells and Pif1 deficient mice. Here we report that suppression of PIF1 function slows replication fork rates and increases arrested forks during normal cycling conditions. Importantly, PIF1-dependent replication impediments impair S-phase progression and reduce proliferation rates of RAS oncogene-transformed fibroblasts, where replication fork slowing is exacerbated, but not parental, non-cancerous cells. Disrupted fork movement upon PIF1-depletion does not enhance double-stranded break formation or DNA damage responses but affects resumption of DNA synthesis after prolonged replication inhibitor exposure, accompanied by diminished new origin firing and mainly S-phase entry. Taken together, we characterised a functional role for human PIF1 in DNA replication that becomes important for cell growth under oncogenic stress. Given that oncogenes induce high levels of replication stress during the early stages of tumorigenesis, this function of PIF1 could become critical during cancer development. PMID:25359767

  8. Managing Single-Stranded DNA during Replication Stress in Fission Yeast

    PubMed Central

    Sabatinos, Sarah A.; Forsburg, Susan L.

    2015-01-01

    Replication fork stalling generates a variety of responses, most of which cause an increase in single-stranded DNA. ssDNA is a primary signal of replication distress that activates cellular checkpoints. It is also a potential source of genome instability and a substrate for mutation and recombination. Therefore, managing ssDNA levels is crucial to chromosome integrity. Limited ssDNA accumulation occurs in wild-type cells under stress. In contrast, cells lacking the replication checkpoint cannot arrest forks properly and accumulate large amounts of ssDNA. This likely occurs when the replication fork polymerase and helicase units are uncoupled. Some cells with mutations in the replication helicase (mcm-ts) mimic checkpoint-deficient cells, and accumulate extensive areas of ssDNA to trigger the G2-checkpoint. Another category of helicase mutant (mcm4-degron) causes fork stalling in early S-phase due to immediate loss of helicase function. Intriguingly, cells realize that ssDNA is present, but fail to detect that they accumulate ssDNA, and continue to divide. Thus, the cellular response to replication stalling depends on checkpoint activity and the time that replication stress occurs in S-phase. In this review we describe the signs, signals, and symptoms of replication arrest from an ssDNA perspective. We explore the possible mechanisms for these effects. We also advise the need for caution when detecting and interpreting data related to the accumulation of ssDNA. PMID:26393661

  9. Chromosomal context and replication properties of ARS plasmids in Schizosaccharomyces pombe.

    PubMed

    Pratihar, Aditya S; Tripathi, Vishnu P; Yadav, Mukesh P; Dubey, Dharani D

    2015-12-01

    Short, specific DNA sequences called as Autonomously Replicating Sequence (ARS) elements function as plasmid as well as chromosomal replication origins in yeasts. As compared to ARSs, different chromosomal origins vary greatly in their efficiency and timing of replication probably due to their wider chromosomal context. The two Schizosaccharomyces pombe ARS elements, ars727 and ars2004, represent two extremities in their chromosomal origin activity - ars727 is inactive and late replicating, while ars2004 is a highly active, early-firing origin. To determine the effect of chromosomal context on the activity of these ARS elements, we have cloned them with their extended chromosomal context as well as in the context of each other in both orientations and analysed their replication efficiency by ARS and plasmid stability assays. We found that these ARS elements retain their origin activity in their extended/altered context. However, deletion of a 133-bp region of the previously reported ars727- associated late replication enforcing element (LRE) caused advancement in replication timing of the resulting plasmid. These results confirm the role of LRE in directing plasmid replication timing and suggest that the plasmid origin efficiency of ars2004 or ars727 remains unaltered by the extended chromosomal context. PMID:26648030

  10. Rolling-circle replication of bacterial plasmids.

    PubMed Central

    Khan, S A

    1997-01-01

    Many bacterial plasmids replicate by a rolling-circle (RC) mechanism. Their replication properties have many similarities to as well as significant differences from those of single-stranded DNA (ssDNA) coliphages, which also replicate by an RC mechanism. Studies on a large number of RC plasmids have revealed that they fall into several families based on homology in their initiator proteins and leading-strand origins. The leading-strand origins contain distinct sequences that are required for binding and nicking by the Rep proteins. Leading-strand origins also contain domains that are required for the initiation and termination of replication. RC plasmids generate ssDNA intermediates during replication, since their lagging-strand synthesis does not usually initiate until the leading strand has been almost fully synthesized. The leading- and lagging-strand origins are distinct, and the displaced leading-strand DNA is converted to the double-stranded form by using solely the host proteins. The Rep proteins encoded by RC plasmids contain specific domains that are involved in their origin binding and nicking activities. The replication and copy number of RC plasmids, in general, are regulated at the level of synthesis of their Rep proteins, which are usually rate limiting for replication. Some RC Rep proteins are known to be inactivated after supporting one round of replication. A number of in vitro replication systems have been developed for RC plasmids and have provided insight into the mechanism of plasmid RC replication. PMID:9409148

  11. Self-replication of DNA rings.

    PubMed

    Kim, Junghoon; Lee, Junwye; Hamada, Shogo; Murata, Satoshi; Ha Park, Sung

    2015-06-01

    Biology provides numerous examples of self-replicating machines, but artificially engineering such complex systems remains a formidable challenge. In particular, although simple artificial self-replicating systems including wooden blocks, magnetic systems, modular robots and synthetic molecular systems have been devised, such kinematic self-replicators are rare compared with examples of theoretical cellular self-replication. One of the principal reasons for this is the amount of complexity that arises when you try to incorporate self-replication into a physical medium. In this regard, DNA is a prime candidate material for constructing self-replicating systems due to its ability to self-assemble through molecular recognition. Here, we show that DNA T-motifs, which self-assemble into ring structures, can be designed to self-replicate through toehold-mediated strand displacement reactions. The inherent design of these rings allows the population dynamics of the systems to be controlled. We also analyse the replication scheme within a universal framework of self-replication and derive a quantitative metric of the self-replicability of the rings. PMID:25961509

  12. Self-replication of DNA rings

    NASA Astrophysics Data System (ADS)

    Kim, Junghoon; Lee, Junwye; Hamada, Shogo; Murata, Satoshi; Ha Park, Sung

    2015-06-01

    Biology provides numerous examples of self-replicating machines, but artificially engineering such complex systems remains a formidable challenge. In particular, although simple artificial self-replicating systems including wooden blocks, magnetic systems, modular robots and synthetic molecular systems have been devised, such kinematic self-replicators are rare compared with examples of theoretical cellular self-replication. One of the principal reasons for this is the amount of complexity that arises when you try to incorporate self-replication into a physical medium. In this regard, DNA is a prime candidate material for constructing self-replicating systems due to its ability to self-assemble through molecular recognition. Here, we show that DNA T-motifs, which self-assemble into ring structures, can be designed to self-replicate through toehold-mediated strand displacement reactions. The inherent design of these rings allows the population dynamics of the systems to be controlled. We also analyse the replication scheme within a universal framework of self-replication and derive a quantitative metric of the self-replicability of the rings.

  13. Pregnancy serum facilitates hepatitis E virus replication in vitro.

    PubMed

    Bi, Yanhong; Yang, Chenchen; Yu, Wenhai; Zhao, Xianchen; Zhao, Chengcheng; He, Zhanlong; Jing, Shenrong; Wang, Huixuan; Huang, Fen

    2015-05-01

    Hepatitis E virus (HEV) infection causes high mortality in pregnant women. However, the pathogenic mechanisms of HEV infection in pregnant women remain unknown. In this study, the roles of pregnancy serum in HEV infection were investigated using an efficient cell culture system. HEV infection was exacerbated by supplementing with pregnancy serum, especially theat in third trimester of pregnancy. Oestrogen receptors (ER-? and ER-?) were activated in cells supplemented with pregnancy serum and were significantly inhibited during HEV infection. Type I IFN, especially IFN-?, showed delayed upregulation in HEV-infected cells supplemented with the serum in the third trimester of pregnancy, which indicated that delayed IFN-? expression may facilitate viral replication. Results suggested that pregnancy serum accelerated HEV replication by suppressing oestrogen receptors and type I IFN in the early stage of infection. PMID:25614592

  14. Speculations on events in the very early universe beyond the standard model: 0th generation stage immediately following the big bang

    E-print Network

    Mladen Georgiev

    2010-02-18

    We suggest that by virtue of the very early processes immediately following the big bang incipient 1st generation particles are created forming periodic strings to confine the quarks. These strings may be described either by the Laplace equation, due to vanishing space charges, or by Poisson-Boltzmann (PB) equation, due to finite charges. We also propose that the supersymmetry created by the big bang is broken through extended vibronic mixing at the end of the 0th generation giving rise to the diversity of atoms and molecules at the later stages of the evolving universe. We choose quark confinement by electrostatic strings supplied by 2D solutions of the PB equation.

  15. The timing of early life events and growth rate estimates of age-0?year group brill Scophthalmus rhombus along the west coast of Ireland.

    PubMed

    Haynes, P S; Brophy, D; McGrath, D

    2014-01-01

    The timing of spawning and hatching, larval durations and growth exhibited by juvenile brill Scophthalmus rhombus captured along the Irish west coast were estimated using otolith microstructure analysis. Scophthalmus rhombus were estimated to have hatched between February and May, with fish settling onto nursery grounds between March and June. Fish collected later on in the season exhibited higher otolith growth rates in comparison to earlier collected fish. This is the first study to describe the early life history of a commercially valuable but understudied flatfish species. PMID:24383806

  16. Monitoring small-crack growth by the replication method

    NASA Technical Reports Server (NTRS)

    Swain, Mary H.

    1992-01-01

    The suitability of the acetate replication method for monitoring the growth of small cracks is discussed. Applications of this technique are shown for cracks growing at the notch root in semicircular-edge-notch specimens of a variety of aluminum alloys and one steel. The calculated crack growth rate versus Delta K relationship for small cracks was compared to that for large cracks obtained from middle-crack-tension specimens. The primary advantage of this techinque is that it provides an opportunity, at the completion of the test, to go backward in time towards the crack initiation event and 'zoom in' on areas of interest on the specimen surface with a resolution of about 0.1 micron. The primary disadvantage is the inability to automate the process. Also, for some materials, the replication process may alter the crack-tip chemistry or plastic zone, thereby affecting crack growth rates.

  17. Responding to the Event Deluge

    NASA Technical Reports Server (NTRS)

    Williams, Roy D.; Barthelmy, Scott D.; Denny, Robert B.; Graham, Matthew J.; Swinbank, John

    2012-01-01

    We present the VOEventNet infrastructure for large-scale rapid follow-up of astronomical events, including selection, annotation, machine intelligence, and coordination of observations. The VOEvent.standard is central to this vision, with distributed and replicated services rather than centralized facilities. We also describe some of the event brokers, services, and software that .are connected to the network. These technologies will become more important in the coming years, with new event streams from Gaia, LOF AR, LIGO, LSST, and many others

  18. Regulation of Unperturbed DNA Replication by Ubiquitylation

    PubMed Central

    Priego Moreno, Sara; Gambus, Agnieszka

    2015-01-01

    Posttranslational modification of proteins by means of attachment of a small globular protein ubiquitin (i.e., ubiquitylation) represents one of the most abundant and versatile mechanisms of protein regulation employed by eukaryotic cells. Ubiquitylation influences almost every cellular process and its key role in coordination of the DNA damage response is well established. In this review we focus, however, on the ways ubiquitylation controls the process of unperturbed DNA replication. We summarise the accumulated knowledge showing the leading role of ubiquitin driven protein degradation in setting up conditions favourable for replication origin licensing and S-phase entry. Importantly, we also present the emerging major role of ubiquitylation in coordination of the active DNA replication process: preventing re-replication, regulating the progression of DNA replication forks, chromatin re-establishment and disassembly of the replisome at the termination of replication forks. PMID:26121093

  19. Self-replicating devices with dipolar colloids

    NASA Astrophysics Data System (ADS)

    Dempster, Joshua; Zhang, Rui; Olvera de La Cruz, Monica

    2014-03-01

    Ubiquitous in nature, self-replication on the nano-scale has been challenging to produce in the laboratory. Recent efforts with DNA tiles have shown great success in correctly replicating tile-sequence templates but require frequent manipulation by the experimenter. We propose a scheme for achieving self-replication with dipolar colloids. Dimers in these systems replicate exponentially over millisecond time scales with no intervention other than periodic energy pulses supplied by external fields. We develop a general formalism governing the rate of self-replication as a function of the interval between pulses. Results from kinetic Monte Carlo simulations show good agreement with the growth rates predicted by simple models of the replication process. We thank the Office of the Director of Defense Research and Engineering (DDR&E) and Air Force Office of Scientific Research (AFOSR) for their support under Award FA9550-10-1-0167.

  20. DNA Replication via Entanglement Swapping

    E-print Network

    Onur Pusuluk; Cemsinan Deliduman

    2011-03-31

    Quantum effects are mainly used for the determination of molecular shapes in molecular biology, but quantum information theory may be a more useful tool to understand the physics of life. Organic molecules and quantum circuits/protocols can be considered as hardware and software of living systems that are co-optimized during evolution. We try to model DNA replication in this sense as a multi-body entanglement swapping with a reliable qubit representation of the nucleotides. In our model molecular recognition of a nucleotide triggers an intrabase entanglement corresponding to a superposition state of different tautomer forms. Then, base pairing occurs by swapping intrabase entanglements with interbase entanglements. We examine possible realizations of quantum circuits to be used to obtain intrabase entanglement and swapping protocols to be employed to obtain interbase entanglement. Finally, we discuss possible ways for computational and experimental verification of the model.

  1. Therapeutic targeting of replicative immortality.

    PubMed

    Yaswen, Paul; MacKenzie, Karen L; Keith, W Nicol; Hentosh, Patricia; Rodier, Francis; Zhu, Jiyue; Firestone, Gary L; Matheu, Ander; Carnero, Amancio; Bilsland, Alan; Sundin, Tabetha; Honoki, Kanya; Fujii, Hiromasa; Georgakilas, Alexandros G; Amedei, Amedeo; Amin, Amr; Helferich, Bill; Boosani, Chandra S; Guha, Gunjan; Ciriolo, Maria Rosa; Chen, Sophie; Mohammed, Sulma I; Azmi, Asfar S; Bhakta, Dipita; Halicka, Dorota; Niccolai, Elena; Aquilano, Katia; Ashraf, S Salman; Nowsheen, Somaira; Yang, Xujuan

    2015-12-01

    One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of persistent cytostasis. This state, termed "senescence," can be triggered by intrinsic cellular processes such as telomere dysfunction and oncogene expression, and by exogenous factors such as DNA damaging agents or oxidative environments. Despite differences in upstream signaling, senescence often involves convergent interdependent activation of tumor suppressors p53 and p16/pRB, but can be induced, albeit with reduced sensitivity, when these suppressors are compromised. Doses of conventional genotoxic drugs required to achieve cancer cell senescence are often much lower than doses required to achieve outright cell death. Additional therapies, such as those targeting cyclin dependent kinases or components of the PI3K signaling pathway, may induce senescence specifically in cancer cells by circumventing defects in tumor suppressor pathways or exploiting cancer cells' heightened requirements for telomerase. Such treatments sufficient to induce cancer cell senescence could provide increased patient survival with fewer and less severe side effects than conventional cytotoxic regimens. This positive aspect is countered by important caveats regarding senescence reversibility, genomic instability, and paracrine effects that may increase heterogeneity and adaptive resistance of surviving cancer cells. Nevertheless, agents that effectively disrupt replicative immortality will likely be valuable components of new combinatorial approaches to cancer therapy. PMID:25869441

  2. Correcting the past: failures to replicate ?.

    PubMed

    Galak, Jeff; Leboeuf, Robyn A; Nelson, Leif D; Simmons, Joseph P

    2012-12-01

    Across 7 experiments (N = 3,289), we replicate the procedure of Experiments 8 and 9 from Bem (2011), which had originally demonstrated retroactive facilitation of recall. We failed to replicate that finding. We further conduct a meta-analysis of all replication attempts of these experiments and find that the average effect size (d = 0.04) is no different from 0. We discuss some reasons for differences between the results in this article and those presented in Bem (2011). PMID:22924750

  3. FOXM1 Upregulation Is an Early Event in Human Squamous Cell Carcinoma and it Is Enhanced by Nicotine during Malignant Transformation

    PubMed Central

    Gemenetzidis, Emilios; Bose, Amrita; Riaz, Adeel M.; Chaplin, Tracy; Young, Bryan D.; Ali, Muhammad; Sugden, David; Thurlow, Johanna K.; Cheong, Sok-Ching; Teo, Soo-Hwang; Wan, Hong; Waseem, Ahmad; Parkinson, Eric K.; Fortune, Farida; Teh, Muy-Teck

    2009-01-01

    Background Cancer associated with smoking and drinking remains a serious health problem worldwide. The survival of patients is very poor due to the lack of effective early biomarkers. FOXM1 overexpression is linked to the majority of human cancers but its mechanism remains unclear in head and neck squamous cell carcinoma (HNSCC). Methodology/Principal Findings FOXM1 mRNA and protein expressions were investigated in four independent cohorts (total 75 patients) consisting of normal, premalignant and HNSCC tissues and cells using quantitative PCR (qPCR), expression microarray, immunohistochemistry and immunocytochemistry. Effect of putative oral carcinogens on FOXM1 transcriptional activity was dose-dependently assayed and confirmed using a FOXM1-specific luciferase reporter system, qPCR, immunoblotting and short-hairpin RNA interference. Genome-wide single nucleotide polymorphism (SNP) array was used to ‘trace’ the genomic instability signature pattern in 8 clonal lines of FOXM1-induced malignant human oral keratinocytes. Furthermore, acute FOXM1 upregulation in primary oral keratinocytes directly induced genomic instability. We have shown for the first time that overexpression of FOXM1 precedes HNSCC malignancy. Screening putative carcinogens in human oral keratinocytes surprisingly showed that nicotine, which is not perceived to be a human carcinogen, directly induced FOXM1 mRNA, protein stabilisation and transcriptional activity at concentrations relevant to tobacco chewers. Importantly, nicotine also augmented FOXM1-induced transformation of human oral keratinocytes. A centrosomal protein CEP55 and a DNA helicase/putative stem cell marker HELLS, both located within a consensus loci (10q23), were found to be novel targets of FOXM1 and their expression correlated tightly with HNSCC progression. Conclusions/Significance This study cautions the potential co-carcinogenic effect of nicotine in tobacco replacement therapies. We hypothesise that aberrant upregulation of FOXM1 may be inducing genomic instability through a program of malignant transformation involving the activation of CEP55 and HELLS which may facilitate aberrant mitosis and epigenetic modifications. Our finding that FOXM1 is upregulated early during oral cancer progression renders FOXM1 an attractive diagnostic biomarker for early cancer detection and its candidate mechanistic targets, CEP55 and HELLS, as indicators of malignant conversion and progression. PMID:19287496

  4. Fractal analysis of replication site images of the human cell nucleus.

    PubMed

    Bhattacharya, S; Malyavantham, K S; Acharya, R; Berezney, R

    2004-01-01

    Epi-fluorescent microscopic images of the mammalian cell nucleus taken during the early, mid and late S (synthetic) phase of the cell cycle suggest that the mass of replicating DNA that belong to the cell nucleus can be characterized as a space filling fractal curve. We reason from a biological standpoint and our understanding of naturally occurring fractals that our microscopic images reveal portions of the spatially complex DNA molecule and present methods for computing the fractal dimensions of the images. Results presented here suggest that our methodology based on fractal properties can distinguish replication of DNA occurring in early versus mid or late S-phase. PMID:17271966

  5. LINEs of evidence: noncanonical DNA replication as an epigenetic determinant

    PubMed Central

    2013-01-01

    LINE-1 (L1) retrotransposons are repetitive elements in mammalian genomes. They are capable of synthesizing DNA on their own RNA templates by harnessing reverse transcriptase (RT) that they encode. Abundantly expressed full-length L1s and their RT are found to globally influence gene expression profiles, differentiation state, and proliferation capacity of early embryos and many types of cancer, albeit by yet unknown mechanisms. They are essential for the progression of early development and the establishment of a cancer-related undifferentiated state. This raises important questions regarding the functional significance of L1 RT in these cell systems. Massive nuclear L1-linked reverse transcription has been shown to occur in mouse zygotes and two-cell embryos, and this phenomenon is purported to be DNA replication independent. This review argues against this claim with the goal of understanding the nature of this phenomenon and the role of L1 RT in early embryos and cancers. Available L1 data are revisited and integrated with relevant findings accumulated in the fields of replication timing, chromatin organization, and epigenetics, bringing together evidence that strongly supports two new concepts. First, noncanonical replication of a portion of genomic full-length L1s by means of L1 RNP-driven reverse transcription is proposed to co-exist with DNA polymerase-dependent replication of the rest of the genome during the same round of DNA replication in embryonic and cancer cell systems. Second, the role of this mechanism is thought to be epigenetic; it might promote transcriptional competence of neighboring genes linked to undifferentiated states through the prevention of tethering of involved L1s to the nuclear periphery. From the standpoint of these concepts, several hitherto inexplicable phenomena can be explained. Testing methods for the model are proposed. Reviewers This article was reviewed by Dr. Philip Zegerman (nominated by Dr. Orly Alter), Dr. I. King Jordan, and Dr. Panayiotis (Takis) Benos. For the complete reviews, see the Reviewers’ Reports section. PMID:24034780

  6. Precise replication of antireflective nanostructures from biotemplates

    NASA Astrophysics Data System (ADS)

    Gao, Hongjun; Liu, Zhongfan; Zhang, Jin; Zhang, Guoming; Xie, Guoyong

    2007-03-01

    The authors report herein a new type of nanonipple structures on the cicada's eye and the direct structural replication of the complex micro- and nanostructures for potential functional emulation. A two-step direct molding process is developed to replicate these natural micro- and nanostructures using epoxy resin with high fidelity, which demonstrates a general way of fabricating functional nanostructures by direct replication of natural biotemplates via a suitable physicochemical process. Measurements of spectral reflectance showed that this kind of replicated nanostructure has remarkable antireflective property, suggestive of its potential applications to optical devices.

  7. A Solution NMR Investigation into the Early Events of Amelogenin Nanosphere Self-Assembly Initiated with Sodium Chloride or Calcium Chloride

    SciTech Connect

    Buchko, Garry W.; Tarasevich, Barbara J.; Bekhazi, Jacky G.; Snead, Malcolm L.; Shaw, Wendy J.

    2008-12-08

    Using solution-state NMR spectroscopy, new insights into the early intermolecular interactions stabilizing amelogenin supramolecular assembly and the potential role of calcium ions have been discovered. Two-dimensional 1H-15N spectra were recorded for 15N-labeled amelogenin as a function of increasing Ca2+ concentration starting from monomeric conditions. Evidence for protein-protein interactions were observed between residues E18 and E40 in the N-terminus. At higher Ca2+ concentrations there was concurrent involvement of residues in both the N- (Y12-Q56) and the C-terminus (Q144-T171). Neither specific residues nor their stepwise interaction have previously been identified in the initial stages of nanosphere assembly.

  8. Sertoli cell differentiation in rhesus monkey (Macaca mulatta) is an early event in puberty and precedes attainment of the adult complement of undifferentiated spermatogonia.

    PubMed

    Simorangkir, D R; Ramaswamy, S; Marshall, G R; Roslund, R; Plant, T M

    2012-04-01

    In primates, the time course of Sertoli cell proliferation and differentiation during puberty and its relationship with the expansion of undifferentiated type A spermatogonia that occurs at this critical stage of development are poorly defined. Mid and late juvenile and early and late pubertal male rhesus monkeys were studied. Testes were immersion fixed, embedded in paraffin, and sectioned at 5??m. Sertoli cell number per testis, S-phase labeling (BrdU), and growth fraction (Ki67 labeling) were determined and correlated with corresponding parameters for undifferentiated type A spermatogonia (A dark and A pale). Dual fluorescence labeling was used in addition to histochemistry to monitor spermatogonial differentiation during the peripubertal period using GFR?-1 and cKIT as markers. While the adult complement of Sertoli cells/testis was attained in early pubertal monkeys after only a few weeks of exposure to the elevated gonadotropin secretion characteristic of this developmental stage, the number of undifferentiated type A spermatogonia several months later in mid pubertal monkeys was only 50% of that in adult testes. Both A dark and A pale spermatogonia exhibited high S-phase BrdU labeling at all stages of juvenile and pubertal development. Spermatogonial differentiation, as reflected histochemically and by relative changes in GFR?-1 and cKIT expression, was not observed until after the initiation of puberty. In the rhesus monkey and maybe in other higher primates including human, the pubertal proliferation of undifferentiated spermatogonia is insidious and proceeds in the wake of a surge in Sertoli cell proliferation following termination of the juvenile stage of development. PMID:22232743

  9. Palaeo-earthquake events during the late Early Palaeozoic in the central Tarim Basin (NW China): evidence from deep drilling cores

    NASA Astrophysics Data System (ADS)

    He, Bizhu; Qiao, Xiufu; Jiao, Cunli; Xu, Zhiqin; Cai, Zhihui; Guo, Xianpu; Zhang, Yinli

    2014-07-01

    Various millimetre-, centimetre- and metre-scale soft-sediment deformation structures (SSDS) have been identified in the Upper Ordovician and Lower-Middle Silurian from deep drilling cores in the Tarim Basin (NW China). These structures include liquefied-sand veins, liquefaction-induced breccias, boudinage-like structures, load and diapir- or flame-like structures, dish and mixed-layer structures, hydroplastic convolutions and seismic unconformities. The deformed layers are intercalated by undeformed layers of varying thicknesses that are petrologically and sedimentologically similar to the deformed layers. The SSDS developed in a shelf environment during the early Late Ordovician and formed initially under shear tensile stress conditions, as indicated by boudinage-like structures; during the latest Ordovician, SSDS formed under a com-pressional regime. The SSDS in the Lower-Middle Silurian consist mainly of mixed layers and sand veins; they formed in shoreline and tidal-flat settings with liquefaction features indicating an origin under a compressional stress regime. By Silurian times, the centre of tectonic activity had shifted to the south-eastern part of the basin. The SSDS occur at different depths in wells that are close to the syn-sedimentary Tazhong 1 Fault (TZ1F) and associated reversed-thrust secondary faults. Based on their characteristics, the inferred formation mechanism and the spatial association with faults, the SSDS are interpreted as seismites. The Tazhong 1 fault was a seismogenic fault during the later Ordovician, whereas the reversed-direction secondary faults became active in the Early-Middle Silurian. Multiple palaeo-earthquake records reflect pulses and cyclicity, which supports secondary tectonic activity within the main tectonic movement. The range of SSDS structures reflects different developments of tectonic activity with time for the various tectonic units of the centralbasin. The effects of the strong palaeo-earthquake activity coincide with uplift, fault activity and syn-tectonic sedimentation in the study area during the Late Ordovician to Middle Silurian.

  10. Reversal of DNA methylation with 5-azacytidine alters chromosome replication patterns in human lymphocyte and fibroblast cultures.

    PubMed

    Shafer, D A; Priest, J H

    1984-05-01

    Prior studies demonstrated that developmental or induced methylation of DNA can inactivate associated gene loci. Such DNA methylation can be reversed and specific genes reactivated by treatment with 5-azacytidine (5- azaC ). The present cytogenetic studies using replication banding methods show that 5- azaC treatment also results in an increase or decrease in replication staining at one or more band locations in human lymphocyte and fibroblast chromosomes. New replication band locations are not formed. These changes in replication staining, which reflect changes in timing of replication, are different between these two tissues. However, in both tissues, the delayed onset of replication in the heterocyclic, inactive X is shortened by 5- azaC . A correlation is thus suggested between the induced temporal change to earlier DNA replication, and induced hypomethylation and gene activation. The temporal effect on chromosome replication in 5- azaC -treated cells depends on the portion of the S-period studied. Toward the beginning of S, early-replication patterns are increased in both lymphocytes and fibroblasts. Toward the end of S, late-replication patterns are increased only in lymphocytes, suggesting a differential effect of 5- azaC in: (1) early-vs. late-S, and (2) lymphocytes vs. fibroblasts. Generally, 5- azaC has its greatest effect on the inactive chromosome regions that are typically late-replicating prior to 5- azaC treatment. These observed changes in replication band staining suggest that DNA methylation may modify regional groups of genes in concert. PMID:6203402

  11. Co-directional replication-transcription conflicts lead to replication restart

    E-print Network

    Merrikh, Houra

    Head-on encounters between the replication and transcription machineries on the lagging DNA strand can lead to replication fork arrest and genomic instability1, 2. To avoid head-on encounters, most genes, especially essential ...

  12. Replicative Intermediates of Human Papillomavirus Type 11 in Laryngeal Papillomas: Site of Replication Initiation and Direction of Replication

    NASA Astrophysics Data System (ADS)

    Auborn, K. J.; Little, R. D.; Platt, T. H. K.; Vaccariello, M. A.; Schildkraut, C. L.

    1994-07-01

    We have examined the structures of replication intermediates from the human papillomavirus type 11 genome in DNA extracted from papilloma lesions (laryngeal papillomas). The sites of replication initiation and termination utilized in vivo were mapped by using neutral/neutral and neutral/alkaline two-dimensional agarose gel electrophoresis methods. Initiation of replication was detected in or very close to the upstream regulatory region (URR; the noncoding, regulatory sequences upstream of the open reading frames in the papillomavirus genome). We also show that replication forks proceed bidirectionally from the origin and converge 180circ opposite the URR. These results demonstrate the feasibility of analysis of replication of viral genomes directly from infected tissue.

  13. Both Chromosome Decondensation and Condensation Are Dependent on DNA Replication in C. elegans Embryos

    PubMed Central

    Sonneville, Remi; Craig, Gillian; Labib, Karim; Gartner, Anton; Blow, J. Julian

    2015-01-01

    Summary During cell division, chromatin alternates between a condensed state to facilitate chromosome segregation and a decondensed form when DNA replicates. In most tissues, S phase and mitosis are separated by defined G1 and G2 gap phases, but early embryogenesis involves rapid oscillations between replication and mitosis. Using Caenorhabditis elegans embryos as a model system, we show that chromosome condensation and condensin II concentration on chromosomal axes require replicated DNA. In addition, we found that, during late telophase, replication initiates on condensed chromosomes and promotes the rapid decondensation of the chromatin. Upon replication initiation, the CDC-45-MCM-GINS (CMG) DNA helicase drives the release of condensin I complexes from chromatin and the activation or displacement of inactive MCM-2–7 complexes, which together with the nucleoporin MEL-28/ELYS tethers condensed chromatin to the nuclear envelope, thereby promoting chromatin decondensation. Our results show how, in an early embryo, the chromosome-condensation cycle is functionally linked with DNA replication. PMID:26166571

  14. Increased frequencies of CD11b(+) CD33(+) CD14(+) HLA-DR(low) myeloid-derived suppressor cells are an early event in melanoma patients.

    PubMed

    Rudolph, Berenice M; Loquai, Carmen; Gerwe, Alexander; Bacher, Nicole; Steinbrink, Kerstin; Grabbe, Stephan; Tuettenberg, Andrea

    2014-03-01

    Myeloid-derived suppressor cells (MDSC) are a heterogeneous cell population characterized by immunosuppressive activity. Elevated levels of MDSC in peripheral blood are found in inflammatory diseases as well as in malignant tumors where they are supposed to be major contributors to mechanisms of tumor-associated tolerance. We investigated the frequency and function of MDSC in peripheral blood of melanoma patients and observed an accumulation of CD11b(+) CD33(+) CD14(+) HLA-DR(low) MDSC in all stages of disease (I-IV), including early stage I patients. Disease progression and enhanced tumor burden did not result in a further increase in frequencies or change in phenotype of MDSC. By investigation of specific MDSC-associated cytokines in patients' sera, we found an accumulation of IL-8 in all stages of disease. T-cell proliferation assays revealed that MDSC critically contribute to suppressed antigen-specific T-cell reactivity and thus might explain the frequently observed transient effects of immunotherapeutic strategies in melanoma patients. PMID:24495013

  15. A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis

    PubMed Central

    Palamiuc, Lavinia; Schlagowski, Anna; Ngo, Shyuan T; Vernay, Aurelia; Dirrig-Grosch, Sylvie; Henriques, Alexandre; Boutillier, Anne-Laurence; Zoll, Joffrey; Echaniz-Laguna, Andoni; Loeffler, Jean-Philippe; René, Frédérique

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is the most common fatal motor neuron disease in adults. Numerous studies indicate that ALS is a systemic disease that affects whole body physiology and metabolic homeostasis. Using a mouse model of the disease (SOD1G86R), we investigated muscle physiology and motor behavior with respect to muscle metabolic capacity. We found that at 65 days of age, an age described as asymptomatic, SOD1G86R mice presented with improved endurance capacity associated with an early inhibition in the capacity for glycolytic muscle to use glucose as a source of energy and a switch in fuel preference toward lipids. Indeed, in glycolytic muscles we showed progressive induction of pyruvate dehydrogenase kinase 4 expression. Phosphofructokinase 1 was inhibited, and the expression of lipid handling molecules was increased. This mechanism represents a chronic pathologic alteration in muscle metabolism that is exacerbated with disease progression. Further, inhibition of pyruvate dehydrogenase kinase 4 activity with dichloroacetate delayed symptom onset while improving mitochondrial dysfunction and ameliorating muscle denervation. In this study, we provide the first molecular basis for the particular sensitivity of glycolytic muscles to ALS pathology. PMID:25820275

  16. A Stochastic Model of Nonenzymatic Nucleic Acid Replication: ``Elongators'' Sequester Replicators

    E-print Network

    Fernando, Chrisantha

    A Stochastic Model of Nonenzymatic Nucleic Acid Replication: ``Elongators'' Sequester Replicators / Accepted: 22 January 2007 [Reviewing Editor: Dr. Niles Lehman] Abstract. The origin of nucleic acid template replication is a major unsolved problem in science. A novel stochastic model of nucleic acid

  17. Florbetaben PET in the Early Diagnosis of Alzheimer's Disease: A Discrete Event Simulation to Explore Its Potential Value and Key Data Gaps

    PubMed Central

    Guo, Shien; Getsios, Denis; Hernandez, Luis; Cho, Kelly; Lawler, Elizabeth; Altincatal, Arman; Lanes, Stephan; Blankenburg, Michael

    2012-01-01

    The growing understanding of the use of biomarkers in Alzheimer's disease (AD) may enable physicians to make more accurate and timely diagnoses. Florbetaben, a beta-amyloid tracer used with positron emission tomography (PET), is one of these diagnostic biomarkers. This analysis was undertaken to explore the potential value of florbetaben PET in the diagnosis of AD among patients with suspected dementia and to identify key data that are needed to further substantiate its value. A discrete event simulation was developed to conduct exploratory analyses from both US payer and societal perspectives. The model simulates the lifetime course of disease progression for individuals, evaluating the impact of their patient management from initial diagnostic work-up to final diagnosis. Model inputs were obtained from specific analyses of a large longitudinal dataset from the New England Veterans Healthcare System and supplemented with data from public data sources and assumptions. The analyses indicate that florbetaben PET has the potential to improve patient outcomes and reduce costs under certain scenarios. Key data on the use of florbetaben PET, such as its influence on time to confirmation of final diagnosis, treatment uptake, and treatment persistency, are unavailable and would be required to confirm its value. PMID:23326754

  18. Lake dwellers occupation gap in Lake Geneva (France-Switzerland) possibly explained by an earthquake-mass movement-tsunami event during Early Bronze Age

    NASA Astrophysics Data System (ADS)

    Kremer, Katrina; Marillier, François; Hilbe, Michael; Simpson, Guy; Dupuy, David; Yrro, Ble J. F.; Rachoud-Schneider, Anne-Marie; Corboud, Pierre; Bellwald, Benjamin; Wildi, Walter; Girardclos, Stéphanie

    2014-01-01

    High-resolution seismic and sediment core data from the ‘Grand Lac’ basin of Lake Geneva reveal traces of repeated slope instabilities with one main slide-evolved mass-flow (minimum volume 0.13 km3) that originated from the northern lateral slope of the lake near the city of Lausanne. Radiocarbon dating of organic remains sampled from the top of the main deposit gives an age interval of 1865-1608 BC. This date coincides with the age interval for a mass movement event described in the ‘Petit Lac’ basin of Lake Geneva (1872-1622 BC). Because multiple mass movements took place at the same time in different parts of the lake, we consider the most likely trigger mechanism to be a strong earthquake (Mw 6) that occurred in the period between 1872 and 1608 BC. Based on numerical simulations, we show the major deposit near Lausanne would have generated a tsunami with local wave heights of up to 6 m. The combined effects of the earthquake and the following tsunami provide a possible explanation for a gap in lake dwellers occupation along the shores of Lake Geneva revealed by dendrochronological dating of two palafitte archaeological sites.

  19. Replication and Robustness in Developmental Research

    ERIC Educational Resources Information Center

    Duncan, Greg J.; Engel, Mimi; Claessens, Amy; Dowsett, Chantelle J.

    2014-01-01

    Replications and robustness checks are key elements of the scientific method and a staple in many disciplines. However, leading journals in developmental psychology rarely include explicit replications of prior research conducted by different investigators, and few require authors to establish in their articles or online appendices that their key…

  20. Diversified Caching for Replicated Web Search Engines

    E-print Network

    Yiu, Man Lung

    Diversified Caching for Replicated Web Search Engines Chuanfei Xu, Bo Tang, Man Lung Yiu Department lists. Furthermore, the huge capacity of modern hard disks renders it feasible to replicate inverted be the cache content of Si. Given a query workload Q (i.e., a sequence of queries), we measure the query

  1. Switching a replication-defective adenoviral vector into a replication-competent, oncolytic adenovirus.

    PubMed

    Nakashima, Hiroshi; Chiocca, E Antonio

    2014-01-01

    The adenovirus immediate early gene E1A initiates the program of viral gene transcription and reprograms multiple aspects of cell function and behavior. For adenoviral (Ad) vector-mediated gene transfer and therapy approaches, where replication-defective (RD) gene transfer is required, E1A has thus been the primary target for deletions. For oncolytic gene therapy for cancer, where replication-competent (RC) Ad viral gene expression is needed, E1A has been either mutated or placed under tumor-specific transcriptional control. A novel Ad vector that initially infected target tumor cells in an RD manner for transgene expression but that could be "switched" into an RC, oncolytic state when needed might represent an advance in vector technology. Here, we report that we designed such an Ad vector (proAd?24.GFP), where initial Ad replication is silenced by a green fluorescent protein (GFP) transgene that blocks cytomegalovirus (CMV)-mediated transcription of E1A. This vector functions as a bona fide E1A-deleted RD vector in infected tumor cells. However, because the silencing GFP transgene is flanked by FLP recombination target (FRT) sites, we show that it can be efficiently excised by Flp recombinase site-specific recombination, either when Flp is expressed constitutively in cells or when it is provided in trans by coinfection with a second RD herpes simplex virus (HSV) amplicon vector. This switches the RD Ad, proAd?24.GFP, into a fully RC, oncolytic Ad (rAd?24) that lyses tumor cells in culture and generates oncolytic progeny virions. In vivo, coinfection of established flank tumors with the RD proAd?24.GFP and the RD Flp-bearing HSV1 amplicon leads to generation of RC, oncolytic rAd?24. In an orthotopic human glioma xenograft tumor model, coinjection of the RD proAd?24.GFP and the RD Flp-bearing HSV1 amplicon also led to a significant increase in animal survival, compared to controls. Therefore, Flp-FRT site-specific recombination can be applied to switch RD Ad into fully oncolytic RC Ad for tumor therapy and is potentially applicable to a variety of gene therapy approaches. PMID:24155386

  2. Switching a Replication-Defective Adenoviral Vector into a Replication-Competent, Oncolytic Adenovirus

    PubMed Central

    Nakashima, Hiroshi

    2014-01-01

    The adenovirus immediate early gene E1A initiates the program of viral gene transcription and reprograms multiple aspects of cell function and behavior. For adenoviral (Ad) vector-mediated gene transfer and therapy approaches, where replication-defective (RD) gene transfer is required, E1A has thus been the primary target for deletions. For oncolytic gene therapy for cancer, where replication-competent (RC) Ad viral gene expression is needed, E1A has been either mutated or placed under tumor-specific transcriptional control. A novel Ad vector that initially infected target tumor cells in an RD manner for transgene expression but that could be “switched” into an RC, oncolytic state when needed might represent an advance in vector technology. Here, we report that we designed such an Ad vector (proAd?24.GFP), where initial Ad replication is silenced by a green fluorescent protein (GFP) transgene that blocks cytomegalovirus (CMV)-mediated transcription of E1A. This vector functions as a bona fide E1A-deleted RD vector in infected tumor cells. However, because the silencing GFP transgene is flanked by FLP recombination target (FRT) sites, we show that it can be efficiently excised by Flp recombinase site-specific recombination, either when Flp is expressed constitutively in cells or when it is provided in trans by coinfection with a second RD herpes simplex virus (HSV) amplicon vector. This switches the RD Ad, proAd?24.GFP, into a fully RC, oncolytic Ad (rAd?24) that lyses tumor cells in culture and generates oncolytic progeny virions. In vivo, coinfection of established flank tumors with the RD proAd?24.GFP and the RD Flp-bearing HSV1 amplicon leads to generation of RC, oncolytic rAd?24. In an orthotopic human glioma xenograft tumor model, coinjection of the RD proAd?24.GFP and the RD Flp-bearing HSV1 amplicon also led to a significant increase in animal survival, compared to controls. Therefore, Flp-FRT site-specific recombination can be applied to switch RD Ad into fully oncolytic RC Ad for tumor therapy and is potentially applicable to a variety of gene therapy approaches. PMID:24155386

  3. Evidence that replication fork components catalyze establishment of cohesion between sister chromatids

    PubMed Central

    Carson, Dena R.; Christman, Michael F.

    2001-01-01

    Accurate chromosome segregation requires that replicated sister chromatids are held together until anaphase, when their “cohesion” is dissolved, and they are pulled to opposite spindle poles by microtubules. Establishment of new cohesion between sister chromatids in the next cell cycle is coincident with replication fork passage. Emerging evidence suggests that this temporal coupling is not just a coincident timing of independent events, but rather that the establishment of cohesion is likely to involve the active participation of replication-related activities. These include PCNA, a processivity clamp for some DNA polymerases, Trf4/Pol ? (formerly Trf4/Pol?), a novel and essential DNA polymerase, and a modified Replication Factor C clamp–loader complex. Here we describe recent advances in how cohesion establishment is linked to replication, highlight important unanswered questions in this new field, and describe a “polymerase switch” model for how cohesion establishment is coupled to replication fork progression. Building the bridges between newly synthesized sister chromatids appears to be a fundamental but previously unrecognized function of the eukaryotic replication machinery. PMID:11459963

  4. Ordered replication of DNA sequences: synthesis of mouse satellite and adjacent main band sequences.

    PubMed

    Dooley, D C; Ozer, H L

    1979-03-01

    The replication of mouse satellite DNA was delayed when synchronized 3T3 cells were exposed to low concentrations of hydroxyurea during S phase, It appears that the onset of satellite replication is not a time dependent event, but instead requires that a certain amount of main band DNA be synthesized first. Using hydroxyapatite chromatography and S1 nuclease digestion, a procedure was developed to quantitate the synthesis of both satellite and neighboring main band sequences. The replication kinetics of satellite determined by this method agree with previous estimates. Main band sequences adjacent to satellite appear to replicate in concert with satellite DNA. The results are discussed and related to the limitations of the techniques utilized. PMID:438296

  5. Biological Evolution of Replicator Systems: Towards a Quantitative Approach

    NASA Astrophysics Data System (ADS)

    Martin, Osmel; Horvath, J. E.

    2013-04-01

    The aim of this work is to study the features of a simple replicator chemical model of the relation between kinetic stability and entropy production under the action of external perturbations. We quantitatively explore the different paths leading to evolution in a toy model where two independent replicators compete for the same substrate. To do that, the same scenario described originally by Pross (J Phys Org Chem 17:312-316, 2004) is revised and new criteria to define the kinetic stability are proposed. Our results suggest that fast replicator populations are continually favored by the effects of strong stochastic environmental fluctuations capable to determine the global population, the former assumed to be the only acting evolution force. We demonstrate that the process is continually driven by strong perturbations only, and that population crashes may be useful proxies for these catastrophic environmental fluctuations. As expected, such behavior is particularly enhanced under very large scale perturbations, suggesting a likely dynamical footprint in the recovery patterns of new species after mass extinction events in the Earth's geological past. Furthermore, the hypothesis that natural selection always favors the faster processes may give theoretical support to different studies that claim the applicability of maximum principles like the Maximum Metabolic Flux (MMF) or Maximum Entropy Productions Principle (MEPP), seen as the main goal of biological evolution.

  6. The mechanism of DNA replication termination in vertebrates.

    PubMed

    Dewar, James M; Budzowska, Magda; Walter, Johannes C

    2015-09-17

    Eukaryotic DNA replication terminates when replisomes from adjacent replication origins converge. Termination involves local completion of DNA synthesis, decatenation of daughter molecules and replisome disassembly. Termination has been difficult to study because termination events are generally asynchronous and sequence nonspecific. To overcome these challenges, we paused converging replisomes with a site-specific barrier in Xenopus egg extracts. Upon removal of the barrier, forks underwent synchronous and site-specific termination, allowing mechanistic dissection of this process. We show that DNA synthesis does not slow detectably as forks approach each other, and that leading strands pass each other unhindered before undergoing ligation to downstream lagging strands. Dissociation of the replicative CMG helicase (comprising CDC45, MCM2-7 and GINS) occurs only after the final ligation step, and is not required for completion of DNA synthesis, strongly suggesting that converging CMGs pass one another and dissociate from double-stranded DNA. This termination mechanism allows rapid completion of DNA synthesis while avoiding premature replisome disassembly. PMID:26322582

  7. Phospholipid biosynthesis and poliovirus genome replication, two coupled phenomena.

    PubMed Central

    Guinea, R; Carrasco, L

    1990-01-01

    Poliovirus infection leads to an increase of phospholipid synthesis and the proliferation of new membranes, giving rise to a great number of cytoplasmic vesicles in the infected cells. Viral RNA replication is physically associated with these newly-synthesized membranes. Cerulenin, an inhibitor of lipid biosynthesis, effectively blocks the growth of poliovirus in HeLa cells. The presence of cerulenin after virus entry prevents the synthesis of poliovirus proteins. However, if this antibiotic is added at later stages of the virus replication cycle, it has no effect on viral translation itself, nor on the proteolytic processing and myristoylation of poliovirus proteins. The synthesis of viral, but not cellular RNA is selectively inhibited by cerulenin. Analysis of the viral RNA made in poliovirus-infected cells by specific minus-or plus-stranded RNA probes suggests a selective blockade by cerulenin of plus-strand RNA synthesis. Finally, the synthesis of phospholipids and the proliferation of membranes does not take place if cerulenin is added to the culture medium. These findings indicate that continuous phospholipid synthesis is required for efficient poliovirus genome replication and provide new insights towards the understanding of the molecular events that occur during poliovirus growth. Images Fig. 1. Fig. 3. Fig. 4. Fig. 6. PMID:2161336

  8. Inferring Where and When Replication Initiates from Genome-Wide Replication Timing Data

    NASA Astrophysics Data System (ADS)

    Baker, A.; Audit, B.; Yang, S. C.-H.; Bechhoefer, J.; Arneodo, A.

    2012-06-01

    Based on an analogy between DNA replication and one dimensional nucleation-and-growth processes, various attempts to infer the local initiation rate I(x,t) of DNA replication origins from replication timing data have been developed in the framework of phase transition kinetics theories. These works have all used curve-fit strategies to estimate I(x,t) from genome-wide replication timing data. Here, we show how to invert analytically the Kolmogorov-Johnson-Mehl-Avrami model and extract I(x,t) directly. Tests on both simulated and experimental budding-yeast data confirm the location and firing-time distribution of replication origins.

  9. Diagnostic usefulness of cognitive auditory event-related p300 subcomponents in patients with Alzheimers disease?

    PubMed

    Juckel, Georg; Clotz, Frauke; Frodl, Thomas; Kawohl, Wolfram; Hampel, Harald; Pogarell, Oliver; Hegerl, Ulrich

    2008-06-01

    Early diagnosis of Alzheimers disease (AD) would be of great clinical value. Auditory event-related P300 mainly generated in temporoparietal regions is related to the pathophysiology of AD. A former study revealed that reliable separation of P300 subcomponents by dipole source analysis increased sensitivity (86.7%) and specificity (76.7%) in correctly detecting AD patients from healthy subjects. Aim of the present study was to replicate this interesting finding on a different sample. Auditory event-related P300 was recorded in unmedicated patients with mild to moderate AD and age- and sex-matched healthy volunteers. The subcomponents of the P300, P3a and P3b, were determined by dipole source analysis (Brain Electric Source Analysis program). As in the first study, AD patients were again characterized by a diminished P3b amplitude and longer P3a latency and reaction time. Using these three parameters, sensitivity was 81.3% to detect patients with AD from healthy controls with a specificity of 83.3%. This successful replication of the first study suggests that recording and determining P300 subcomponents together with other putative neurobiological markers may be useful to enhance the individual diagnostic accuracy in AD at an early stage. PMID:18469731

  10. On the duration of magnetochrons C24r and C25n and the timing of early Eocene global warming events: Implications from the Ocean Drilling Program Leg 208 Walvis Ridge depth transect

    NASA Astrophysics Data System (ADS)

    Westerhold, Thomas; Röhl, Ursula; Laskar, Jacques; Raffi, Isabella; Bowles, Julie; Lourens, Lucas J.; Zachos, James C.

    2007-04-01

    Five sections drilled in multiple holes over a depth transect of more than 2200 m at the Walvis Ridge (SE Atlantic) during Ocean Drilling Program (ODP) Leg 208 resulted in the first complete early Paleogene deep-sea record. Here we present high-resolution stratigraphic records spanning a ~4.3 million yearlong interval of the late Paleocene to early Eocene. This interval includes the Paleocene-Eocene thermal maximum (PETM) as well as the Eocene thermal maximum (ETM) 2 event. A detailed chronology was developed with nondestructive X-ray fluorescence (XRF) core scanning records and shipboard color data. These records were used to refine the shipboard-derived spliced composite depth for each site and with a record from ODP Site 1051 were then used to establish a continuous time series over this interval. Extensive spectral analysis reveals that the early Paleogene sedimentary cyclicity is dominated by precession modulated by the short (100 kyr) and long (405 kyr) eccentricity cycles. Counting of precession-related cycles at multiple sites results in revised estimates for the duration of magnetochrons C24r and C25n. Direct comparison between the amplitude modulation of the precession component derived from XRF data and recent models of Earth's orbital eccentricity suggests that the onset of the PETM and ETM2 are related to a 100-kyr eccentricity maximum. Both events are approximately a quarter of a period offset from a maximum in the 405-kyr eccentricity cycle, with the major difference that the PETM is lagging and ETM2 is leading a 405-kyr eccentricity maximum. Absolute age estimates for the PETM, ETM2, and the magnetochron boundaries that are consistent with recalibrated radiometric ages and recent models of Earth's orbital eccentricity cannot be precisely determined at present because of too large uncertainties in these methods. Nevertheless, we provide two possible tuning options, which demonstrate the potential for the development of a cyclostratigraphic framework based on the stable 405-kyr eccentricity cycle for the entire Paleogene.

  11. Tethering of SUUR and HP1 proteins results in delayed replication of euchromatic regions in Drosophila melanogaster polytene chromosomes.

    PubMed

    Pokholkova, Galina V; Koryakov, Dmitry E; Pindyurin, Alexey V; Kozhevnikova, Elena N; Belyakin, Stepan N; Andreyenkov, Oleg V; Belyaeva, Elena S; Zhimulev, Igor F

    2015-06-01

    We analyze how artificial targeting of Suppressor of Under-Replication (SUUR) and HP1 proteins affects DNA replication in the "open," euchromatic regions. Normally these regions replicate early in the S phase and display no binding of either SUUR or HP1. These proteins were expressed as fusions with DNA-binding domain of GAL4 and recruited to multimerized UAS integrated in three euchromatic sites of the polytene X chromosome: 3B, 8D, and 18B. Using PCNA staining as a marker of ongoing replication, we showed that targeting of SUUR(GAL4DBD) and HP1(GAL4DBD) results in delayed replication of appropriate euchromatic regions. Specifically, replication at these regions starts early, much like in the absence of the fusion proteins; however, replication completion is significantly delayed. Notably, delayed replication was insufficient to induce underreplication. Recruitment of SUUR(GAL4DBD) and HP1(GAL4DBD) had distinct effects on expression of a mini-white reporter, found near UAS. Whereas SUUR(GAL4DBD) had no measurable influence on mini-white expression, HP1(GAL4DBD) targeting silenced mini-white, even in the absence of functional SU(VAR)3-9. Furthermore, recruitment of SUUR(GAL4DBD) and HP1(GAL4DBD) had distinct effects on the protein composition of target regions. HP1(GAL4DBD) but not SUUR(GAL4DBD) could displace an open chromatin marker, CHRIZ, from the tethering sites. PMID:25398563

  12. An unusual early Holocene diatom event north of the Getz Ice Shelf (Amundsen Sea): Implications for West Antarctic Ice Sheet development

    NASA Astrophysics Data System (ADS)

    Esper, O.; Gersonde, R.; Hillenbrand, C.; Kuhn, G.; Smith, J.

    2011-12-01

    Modern global change affects not only the polar north but also, and to increasing extent, the southern high latitudes, especially the Antarctic regions covered by the West Antarctic Ice Sheet (WAIS). Consequently, knowledge of the mechanisms controlling past WAIS dynamics and WAIS behaviour at the last deglaciation is critical to predict its development in a future warming world. Geological and palaeobiological information from major drainage areas of the WAIS, like the Amundsen Sea Embayment, shed light on the history of the WAIS glaciers. Sediment records obtained from a deep inner shelf basin north of Getz Ice Shelf document a deglacial warming in three phases. Above a glacial diamicton and a sediment package barren of microfossils that document sediment deposition by grounded ice and below an ice shelf or perennial sea ice cover (possibly fast ice), respectively, a sediment section with diatom assemblages dominated by sea ice taxa indicates ice shelf retreat and seasonal ice-free conditions. This conclusion is supported by diatom-based summer temperature reconstructions. The early retreat was followed by a phase, when exceptional diatom ooze was deposited around 12,500 cal. years B.P. [1]. Microscopical inspection of this ooze revealed excellent preservation of diatom frustules of the species Corethron pennatum together with vegetative Chaetoceros, thus an assemblage usually not preserved in the sedimentary record. Sediments succeeding this section contain diatom assemblages indicating rather constant Holocene cold water conditions with seasonal sea ice. The deposition of the diatom ooze can be related to changes in hydrographic conditions including strong advection of nutrients. However, sediment focussing in the partly steep inner shelf basins cannot be excluded as a factor enhancing the thickness of the ooze deposits. It is not only the presence of the diatom ooze but also the exceptional preservation and the species composition of the diatom assemblage, which point to specific scenarios involving e.g. changes in the food web that can be related to warmer surface water temperatures. Such warming of shelf waters may be related with an overshooting Atlantic Meridional Overturning Circulation (AMOC) and strong injection of warmer North Atlantic Deep Water into the Southern Ocean water masses at Termination I as reported by [2]. Such finding may highlight the effects of AMOC changes on Antarctic ice shelf extent and coastal ecosystems. [1] Hillenbrand et al., 2010. J. Quat. Sci. 25 (3), 280-295. [2] Barker et al., 2010. Nature Geosci. 3, 567-571.

  13. A whole genome RNAi screen identifies replication stress response genes.

    PubMed

    Kavanaugh, Gina; Ye, Fei; Mohni, Kareem N; Luzwick, Jessica W; Glick, Gloria; Cortez, David

    2015-11-01

    Proper DNA replication is critical to maintain genome stability. When the DNA replication machinery encounters obstacles to replication, replication forks stall and the replication stress response is activated. This response includes activation of cell cycle checkpoints, stabilization of the replication fork, and DNA damage repair and tolerance mechanisms. Defects in the replication stress response can result in alterations to the DNA sequence causing changes in protein function and expression, ultimately leading to disease states such as cancer. To identify additional genes that control the replication stress response, we performed a three-parameter, high content, whole genome siRNA screen measuring DNA replication before and after a challenge with replication stress as well as a marker of checkpoint kinase signalling. We identified over 200 replication stress response genes and subsequently analyzed how they influence cellular viability in response to replication stress. These data will serve as a useful resource for understanding the replication stress response. PMID:26454783

  14. Replication forks reverse at high frequency upon replication stress in Physarum polycephalum.

    PubMed

    Maric, Chrystelle; Bénard, Marianne

    2014-12-01

    The addition of hydroxyurea after the onset of S phase allows replication to start and permits the successive detecting of replication-dependent joint DNA molecules and chicken foot structures in the synchronous nuclei of Physarum polycephalum. We find evidence for a very high frequency of reversed replication forks upon replication stress. The formation of these reversed forks is dependent on the presence of joint DNA molecules, the impediment of the replication fork progression by hydroxyurea, and likely on the propensity of some replication origins to reinitiate replication to counteract the action of this compound. As hydroxyurea treatment enables us to successively detect the appearance of joint DNA molecules and then of reversed replication forks, we propose that chicken foot structures are formed both from the regression of hydroxyurea-frozen joint DNA molecules and from hydroxyurea-stalled replication forks. These experiments underscore the transient nature of replication fork regression, which becomes detectable due to the hydroxyurea-induced slowing down of replication fork progression. PMID:24951952

  15. Semi-Passive Replication Xavier Defago Andre Schiper Nicole Sergent

    E-print Network

    Défago, Xavier

    Semi-Passive Replication Xavier D´efago Andr´e Schiper Nicole Sergent D´epartement d This paper presents the semi-passive replication tech- nique ­ a variant of passive replication ­ that can on a primary. Passive replication is a popular replication technique since it can tolerate non

  16. Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements

    PubMed Central

    Liu, Pengfei; Erez, Ayelet; Sreenath Nagamani, Sandesh C.; Dhar, Shweta U.; Ko?odziejska, Katarzyna E.; Dharmadhikari, Avinash V.; Cooper, M. Lance; Wiszniewska, Joanna; Zhang, Feng; Withers, Marjorie A.; Bacino, Carlos A.; Campos-Acevedo, Luis Daniel; Delgado, Mauricio R.; Freedenberg, Debra; Garnica, Adolfo; Grebe, Theresa A.; Hernández-Almaguer, Dolores; Immken, LaDonna; Lalani, Seema R.; McLean, Scott D.; Northrup, Hope; Scaglia, Fernando; Strathearn, Lane; Trapane, Pamela; Kang, Sung-Hae L.; Patel, Ankita; Cheung, Sau Wai; Hastings, P. J.; Stankiewicz, Pawe?; Lupski, James R.; Bi, Weimin

    2011-01-01

    SUMMARY Complex genomic rearrangements (CGR) consisting of two or more breakpoint junctions have been observed in genomic disorders. Recently, a chromosome catastrophe phenomenon termed chromothripsis, in which numerous genomic rearrangements are apparently acquired in one single catastrophic event, was described in multiple cancers. Here we show that constitutionally acquired CGRs share similarities with cancer chromothripsis. In the 17 CGR cases investigated we observed localization and multiple copy number changes including deletions, duplications and/or triplications, as well as extensive translocations and inversions. Genomic rearrangements involved varied in size and complexities; in one case, array comparative genomic hybridization revealed 18 copy number changes. Breakpoint sequencing identified characteristic features, including small templated insertions at breakpoints and microhomology at breakpoint junctions, which have been attributed to replicative processes. The resemblance between CGR and chromothripsis suggests similar mechanistic underpinnings. Such chromosome catastrophic events appear to reflect basic DNA metabolism operative throughout an organism’s life cycle. PMID:21925314

  17. Initiation of bacteriophage lambda DNA replication in vitro with purified lambda replication proteins.

    PubMed Central

    Wold, M S; Mallory, J B; Roberts, J D; LeBowitz, J H; McMacken, R

    1982-01-01

    We have developed a soluble enzyme system that replicates exogenously added plasmid DNA (lambda dv) bearing the replication origin of the bacteriophage lambda chromosome. The system contains pure phage lambda O and P replication proteins and a partially purified mixture of Escherichia coli replication proteins [the enzyme system of Fuller, R.S., Kaguni, J.M. & Kornberg, A. (1981) Proc. Natl. Acad. Sci. USA 78, 7370-7374). The features of lambda dv replication in this system closely resemble the known characteristics of phage lambda DNA replication in vivo. The system (i) depends completely on exogenously supplied DNA, (ii) specifically replicates supercoiled plasmid DNA that contains a lambda replication origin, (iii) depends on both the lambda O protein and the lambda P protein, (iv) depends on RNA polymerase, (v) depends on host replication proteins (e.g., primase, dnaB protein, and several others that function in the priming of DNA synthesis in E. coli) as judged by antibody inhibitions, and (vi) replicates as much as 32% of added lambda dv plasmid DNA through a single complete round to generate catenated daughter molecules. Furthermore, replication of lambda dv DNA in vitro requires DNA gyrase and an ATP-regenerating system. It is notable that addition of lambda O and P proteins to the mixture of E. coli replication proteins inhibits replication of plasmids bearing the origin of the E. coli chromosome. Exploitation of this enzyme system should allow a detailed investigation of the biochemical mechanisms involved in bacteriophage lambda DNA replication and its regulation. Images PMID:6216478

  18. Cell cycle progression requires the CDC-48UFD 1/NPL 4 complex for efficient DNA replication

    E-print Network

    Gartner, Anton

    replication, which is important for cell cycle progression and genome stability. ATL-1/ATR C. elegans CDC-48/p in mitosis have been addressed by several studies. Early observations in yeast and recent findings using Xenopus egg extracts suggested that Cdc48/p97 regulates spindle disassembly during exit from mitosis (6, 7

  19. Stimulus-response uncoupling in the neutrophil. Adenosine A2-receptor occupancy inhibits the sustained, but not the early, events of stimulus transduction in human neutrophils by a mechanism independent of actin-filament formation.

    PubMed Central

    Cronstein, B N; Haines, K A

    1992-01-01

    Generation of superoxide anion (O2-) in response to occupancy of neutrophil chemoattractant receptors requires both early events ('triggering') and sustained signals ('activation'). We have previously demonstrated that occupancy of adenosine A2 receptors inhibits O2- generation by neutrophils. In parallel, adenosine-receptor occupancy promotes association of bound N-formylmethionyl-leucyl-phenylalanine (fMLP) receptors with the cytoskeleton, a process associated with termination of neutrophil activation (stimulus-response uncoupling). We undertook this study to determine whether inhibition of neutrophil function by adenosine-receptor occupancy requires intact actin filaments and to examine the effect of adenosine-receptor occupancy on the stimulated generation of intracellular signals involved in neutrophil triggering and activation. Occupancy of adenosine A2 receptors by 5'-N-ethylcarboxamidoadenosine (NECA, 1 microM) significantly increased (130 +/- 1% of control, P less than 0.001, n = 3) association of [3H]fMLP with cytoskeletal preparations. Cytochalasin B (5 micrograms/ml), an agent which disrupts actin filaments, completely blocked association of [3H]fMLP with cytoskeletal preparations, as previously reported. However, NECA markedly increased association of [3H]fMLP with the cytoskeleton even in the presence of cytochalasin B (P less than 0.0002). Moreover, NECA did not significantly affect either the early (30s) or the late (5 min) formation of actin filaments after stimulation by chemoattractant (fMLP, 0.1-100 nM). Cytochalasin B markedly inhibited actin-filament formation by stimulated neutrophils, and NECA did not reverse the effect of cytochalasin B on actin-filament formation. Adenosine-receptor occupancy did not affect the rapid peak in diacylglycerol generation (less than or equal to 15 s) from either [3H]arachidonate- or [14C]glycerol-labelled phospholipid pools. However, as would be predicted if occupancy of the adenosine receptor was a signal for early termination of cell activation, NECA (1 microM) markedly diminished the slow sustained generation of diacylglycerol. These results suggest that adenosine-A2-receptor occupancy does not affect triggering of the neutrophil, but that occupancy of adenosine receptors is an early signal for the termination of neutrophil activation, i.e. the 'premature' finish of signal transduction. Moreover, these data indicate that at least two pathways are available for increasing the association of ligated chemoattractant receptors with the cytoskeleton of neutrophils: F-actin-dependent and -independent. PMID:1311169

  20. Mechanisms for Initiating Cellular DNA Replication

    PubMed Central

    Costa, Alessandro; Hood, Iris V.; Berger, James M.

    2015-01-01

    The initiation of DNA replication represents a committing step to cell proliferation. Appropriate replication onset depends on multiprotein complexes that help properly distinguish origin regions, generate nascent replication bubbles, and promote replisome formation. This review describes initiation systems employed by bacteria, archaea, and eukaryotes, with a focus on comparing and contrasting molecular mechanisms among organisms. Although commonalities can be found in the functional domains and strategies used to carry out and regulate initiation, many key participants have markedly different activities and appear to have evolved convergently. Despite significant advances in the field, major questions still persist in understanding how initiation programs are executed at the molecular level. PMID:23746253

  1. Replication and Analysis of Ebbinghaus’ Forgetting Curve

    PubMed Central

    Murre, Jaap M. J.; Dros, Joeri

    2015-01-01

    We present a successful replication of Ebbinghaus’ classic forgetting curve from 1880 based on the method of savings. One subject spent 70 hours learning lists and relearning them after 20 min, 1 hour, 9 hours, 1 day, 2 days, or 31 days. The results are similar to Ebbinghaus' original data. We analyze the effects of serial position on forgetting and investigate what mathematical equations present a good fit to the Ebbinghaus forgetting curve and its replications. We conclude that the Ebbinghaus forgetting curve has indeed been replicated and that it is not completely smooth but most probably shows a jump upwards starting at the 24 hour data point. PMID:26148023

  2. Prebiotic chemistry and nucleic acid replication

    NASA Technical Reports Server (NTRS)

    Orgel, L. E.; Lohrmann, R.

    1974-01-01

    Recent work is reviewed on some reactions that could have occurred on the primitive earth and that could have played a part in the evolution of a self-replicating system. The transition from the primitive atmosphere to the simplest replicating molecules is considered in four stages: (1) the formation of a 'prebiotic soup' of organic precursors, including the purine and pyrimidine bases and the pentose sugars; (2) the condensation of these precursors and inorganic phosphate to form monomeric nucleotides and activated nucleotide derivatives; (3) the polymerization of nucleotide derivatives to oligonucleotides; and (4) the complementary replication of oligonucleotides in a template-directed process that depends on Watson-Crick base pairing.

  3. Inferring Where and When Replication Initiates from Genome-Wide Replication Timing Data S. C.-H. Yang (),2

    E-print Network

    Bechhoefer, John

    Inferring Where and When Replication Initiates from Genome-Wide Replication Timing Data A. Baker,1 29 June 2012; publisher error corrected 3 July 2012) Based on an analogy between DNA replication Iðx; tÞ of DNA replication origins from replication timing data have been developed in the framework

  4. A transcription and translation-coupled DNA replication system using rolling-circle replication

    PubMed Central

    Sakatani, Yoshihiro; Ichihashi, Norikazu; Kazuta, Yasuaki; Yomo, Tetsuya

    2015-01-01

    All living organisms have a genome replication system in which genomic DNA is replicated by a DNA polymerase translated from mRNA transcribed from the genome. The artificial reconstitution of this genome replication system is a great challenge in in vitro synthetic biology. In this study, we attempted to construct a transcription- and translation-coupled DNA replication (TTcDR) system using circular genomic DNA encoding phi29 DNA polymerase and a reconstituted transcription and translation system. In this system, phi29 DNA polymerase was translated from the genome and replicated the genome in a rolling-circle manner. When using a traditional translation system composition, almost no DNA replication was observed, because the tRNA and nucleoside triphosphates included in the translation system significantly inhibited DNA replication. To minimize these inhibitory effects, we optimized the composition of the TTcDR system and improved replication by approximately 100-fold. Using our system, genomic DNA was replicated up to 10 times in 12?hours at 30?°C. This system provides a step toward the in vitro construction of an artificial genome replication system, which is a prerequisite for the construction of an artificial cell. PMID:26013404

  5. Using autonomous replication to physically and genetically define human origins of replication

    SciTech Connect

    Krysan, P.J.

    1993-01-01

    The author previously developed a system for studying autonomous replication in human cells involving the use of sequences from the Epstein-Barr virus (EBV) genome to provide extrachromosomal plasmids with a nuclear retention function. Using this system, it was demonstrated that large fragments of human genomic DNA could be isolated which replicate autonomously in human cells. In this study the DNA sequences which function as origins of replication in human cells are defined physically and genetically. These experiments demonstrated that replication initiates at multiple locations distributed throughout the plasmid. Another line of experiments addressed the DNA sequence requirements for autonomous replication in human cells. These experiments demonstrated that human DNA fragments have a higher replication activity than bacterial fragments do. It was also found, however, that the bacterial DNA sequence could support efficient replication if enough copies of it were present on the plasmid. These findings suggested that autonomous replication in human cells does not depend on extensive, specific DNA sequences. The autonomous replication system which the author has employed for these experiments utilizes a cis-acting sequence from the EBV origin and the trans-acting EBNA-1 protein to provide plasmids with a nuclear retention function. It was therefore relevant to verify that the autonomous replication of human DNA fragments did not depend on the replication activity associated with the EBV sequences utilized for nuclear retention. To accomplish this goal, the author demonstrated that plasmids carrying the EBV sequences and large fragments of human DNA could support long-term autonomous replication in hamster cells, which are not permissive for EBV replication.

  6. Movement of Replicating DNA through a Stationary Replisome

    E-print Network

    Lemon, Katherine P.

    We found that DNA is replicated at a central stationary polymerase, and each replicated region moves away from the replisome. In Bacillus subtilis, DNA polymerase is predominantly located at or near midcell. When replication ...

  7. Brief announcement: Optimistic Algorithms for Partial Database Replication

    E-print Network

    Pedone, Fernando

    Brief announcement: Optimistic Algorithms for Partial Database Replication Nicolas Schiper1 Introduction Database replication protocols based on group communication have re- cently received a lot database replication. Most of the complexity involved in synchronizing database replicas is handled

  8. Chromosomal Arrangement of Phosphorelay Genes Couples Sporulation and DNA Replication

    E-print Network

    Rulkov, Nikolai F.

    Article Chromosomal Arrangement of Phosphorelay Genes Couples Sporulation and DNA Replication replication d Negative feedback leads to pulsatile activation of sporulation master regulator d Pulsed response couples sporulation and DNA replication d Gene translocations eliminating pulses lead

  9. Developmental regulation of DNA replication in Drosophila melanogaster

    E-print Network

    Park, Eugenia Agnes

    2006-01-01

    In mitotic cell cycles, the genome must be replicated fully in each cell cycle to ensure the normal complement of chromosomes. Failure to replicate chromosomes fully or a failure to limit replication to once-per-cell-cycle ...

  10. Replication–transcription conflicts in bacteria

    E-print Network

    Merrikh, Houra

    DNA replication and transcription use the same template and occur concurrently in bacteria. The lack of temporal and spatial separation of these two processes leads to their conflict, and failure to deal with this conflict ...

  11. Universal super-replication of unitary gates

    E-print Network

    G. Chiribella; Y. Yang; C. Huang

    2015-02-20

    Quantum states obey an asymptotic no-cloning theorem, stating that no deterministic machine can reliably replicate generic sequences of identically prepared pure states. In stark contrast, we show that generic sequences of unitary gates can be replicated deterministically at nearly quadratic rates, with an error vanishing on most inputs except for an exponentially small fraction. The result is not in contradiction with the no-cloning theorem, since the impossibility of deterministically transforming pure states into unitary gates prevents the application of the gate replication protocol to states. In addition to gate replication, we show that $N$ parallel uses of a completely unknown unitary gate can be compressed into a single gate acting on $O(\\log N)$ qubits, leading to an exponential reduction of the amount of quantum communication needed to implement the gate remotely.

  12. Statistical physics of self-replication

    E-print Network

    England, Jeremy L.

    Self-replication is a capacity common to every species of living thing, and simple physical intuition dictates that such a process must invariably be fueled by the production of entropy. Here, we undertake to make this ...

  13. Autogenesis: the evolution of replicative systems.

    PubMed

    Csányi, V; Kampis, G

    1985-05-21

    Questions concerning the nature and origin of living systems and the hierarchy of their evolutionary processes are considered, and several problems which arise in connection with formerly developed theories--the autopoiesis of Maturana & Varela, the POL theory of Haukioja and the earlier developed evolutionary theory of Csányi--are discussed. The organization of living systems, the use of informational terms and the question how reproduction can enter into their characterization, problems of autonomy and identity are included in the list. It is suggested that replication--a copying process achieved by a special network of interrelatedness of components and component-producing processes that produces the same network as that which produced them--characterizes the living organization. The information "used" in this copying process, whether it is stored by special means or distributed in the whole system, is called replicative information. A theoretical model is introduced for the spontaneous emergence of replicative organization, called autogenesis. Autogenesis commences in a system by an organized "small" subsystem, referred to as AutoGenetic System Precursor (AGSP), which conveys replicative information to the system. During autogenesis, replicative information increases in system and compartment(s) form. A compartment is the co-replicating totality of components. The end state of autogenesis is an invariantly self-replicating organization which is unable to undergo further intrinsic organizational changes. It is suggested that replicative unities--such as living organisms--evolve via autogenesis. Levels of evolution emerge as a consequence of the relative autonomy of the autogenetic unities. On the next level they can be considered as components endowed with functions and a new autogenetic process can commence. Thus evolution proceeds towards its end state through the parallel autogenesis of the various levels. In terms of applications, ontogenesis is dealt with in detail as an autogenetic process as is the autogenesis of the biosphere and the global system. PMID:4033156

  14. Evidence for an Early Cretaceous mineralizing event above the basement/sediment unconformity in the intracratonic Paris Basin: paragenetic sequence and Sm-Nd dating of the world-class Pierre-Perthuis stratabound fluorite deposit

    NASA Astrophysics Data System (ADS)

    Gigoux, Morgane; Delpech, Guillaume; Guerrot, Catherine; Pagel, Maurice; Augé, Thierry; Négrel, Philippe; Brigaud, Benjamin

    2015-04-01

    World-class stratabound fluorite deposits are spatially associated with the basement/sediment unconformity of the intracratonic Paris Basin and the Morvan Massif in Burgundy (France). The reserves are estimated to be about 5.5 Mt of fluorite within six fluorite deposits. In this study, we aim to determine the age of the major fluorite mineralization event of the Pierre-Perthuis deposit (1.4 Mt fluorite) by a combined study of the paragenetic mineral sequence and Sm-Nd dating on fluorite crystals. Fluorite occurs as isolated cubes or filling geodes in a Triassic, silicified, dolomitic formation. Three fluorite stages associated with sphalerite, pyrite, galena, barite, and quartz have been distinguished using optical, cathodoluminescence, and scanning electron microscopes. Seven crystals of the geodic fluorite stage were analyzed for their rare earth element (REE) contents and their 147Sm/144Nd and 143Nd/144Nd isotopic compositions. The normalized REE distribution displays homogeneous bell-shaped patterns for all the geodic fluorite samples with a Mid-REE enrichment over the Light-REE and Heavy-REE. The 147Sm/144Nd varies from 0.3108 to 0.5504 and the 143Nd/144Nd from 0.512313 to 0.512518. A six-point Sm-Nd isochron defines an age of 130 ± 15 Ma (initial 143Nd/144Nd = 0.512054, MSWD = 0.21). This Sm-Nd isochron provides the first age for the stratabound fluorite sediment-hosted deposit, related to an unconformity in the Paris Basin, and highlights a major Early Cretaceous fluid circulation event mainly above the basement/sediment unconformity during a flexural deformation of the Paris Basin, which relates to the rifting of the Bay of Biscay and the formation of the Ligurian Sea in the Western Europe domain.

  15. Commercial Building Partnerships Replication and Diffusion

    SciTech Connect

    Antonopoulos, Chrissi A.; Dillon, Heather E.; Baechler, Michael C.

    2013-09-16

    This study presents findings from survey and interview data investigating replication efforts of Commercial Building Partnership (CBP) partners that worked directly with the Pacific Northwest National Laboratory (PNNL). PNNL partnered directly with 12 organizations on new and retrofit construction projects, which represented approximately 28 percent of the entire U.S. Department of Energy (DOE) CBP program. Through a feedback survey mechanism, along with personal interviews, PNNL gathered quantitative and qualitative data relating to replication efforts by each organization. These data were analyzed to provide insight into two primary research areas: 1) CBP partners’ replication efforts of technologies and approaches used in the CBP project to the rest of the organization’s building portfolio (including replication verification), and, 2) the market potential for technology diffusion into the total U.S. commercial building stock, as a direct result of the CBP program. The first area of this research focused specifically on replication efforts underway or planned by each CBP program participant. Factors that impact replication include motivation, organizational structure and objectives firms have for implementation of energy efficient technologies. Comparing these factors between different CBP partners revealed patterns in motivation for constructing energy efficient buildings, along with better insight into market trends for green building practices. The second area of this research develops a diffusion of innovations model to analyze potential broad market impacts of the CBP program on the commercial building industry in the United States.

  16. Design and Implementation of Replicated Object Layer

    NASA Technical Reports Server (NTRS)

    Koka, Sudhir

    1996-01-01

    One of the widely used techniques for construction of fault tolerant applications is the replication of resources so that if one copy fails sufficient copies may still remain operational to allow the application to continue to function. This thesis involves the design and implementation of an object oriented framework for replicating data on multiple sites and across different platforms. Our approach, called the Replicated Object Layer (ROL) provides a mechanism for consistent replication of data over dynamic networks. ROL uses the Reliable Multicast Protocol (RMP) as a communication protocol that provides for reliable delivery, serialization and fault tolerance. Besides providing type registration, this layer facilitates distributed atomic transactions on replicated data. A novel algorithm called the RMP Commit Protocol, which commits transactions efficiently in reliable multicast environment is presented. ROL provides recovery procedures to ensure that site and communication failures do not corrupt persistent data, and male the system fault tolerant to network partitions. ROL will facilitate building distributed fault tolerant applications by performing the burdensome details of replica consistency operations, and making it completely transparent to the application.Replicated databases are a major class of applications which could be built on top of ROL.

  17. Replication of Epstein–Barr Viral DNA

    PubMed Central

    Hammerschmidt, Wolfgang; Sugden, Bill

    2013-01-01

    Epstein–Barr virus (EBV) is a paradigm for human tumor viruses: it is the first virus recognized to cause cancer in people; it causes both lymphomas and carcinomas; yet these tumors arise infrequently given that most people in the world are infected with the virus. EBV is maintained extrachromosomally in infected normal and tumor cells. Eighty-four percent of these viral plasmids replicate each S phase, are licensed, require a single viral protein for their synthesis, and can use two functionally distinct origins of DNA replication, oriP, and Raji ori. Eighty-eight percent of newly synthesized plasmids are segregated faithfully to the daughter cells. Infectious viral particles are not synthesized under these conditions of latent infection. This plasmid replication is consistent with survival of EBV’s host cells. Rare cells in an infected population either spontaneously or following exogenous induction support EBV’s lytic cycle, which is lethal for the cell. In this case, the viral DNA replicates 100-fold or more, uses a third kind of viral origin of DNA replication, oriLyt, and many viral proteins. Here we shall describe the three modes of EBV’s replication as a function of the viral origins used and the viral and cellular proteins that mediate the DNA synthesis from these origins focusing, where practical, on recent advances in our understanding. PMID:23284049

  18. Replication and robustness in developmental research.

    PubMed

    Duncan, Greg J; Engel, Mimi; Claessens, Amy; Dowsett, Chantelle J

    2014-11-01

    Replications and robustness checks are key elements of the scientific method and a staple in many disciplines. However, leading journals in developmental psychology rarely include explicit replications of prior research conducted by different investigators, and few require authors to establish in their articles or online appendices that their key results are robust across estimation methods, data sets, and demographic subgroups. This article makes the case for prioritizing both explicit replications and, especially, within-study robustness checks in developmental psychology. It provides evidence on variation in effect sizes in developmental studies and documents strikingly different replication and robustness-checking practices in a sample of journals in developmental psychology and a sister behavioral science-applied economics. Our goal is not to show that any one behavioral science has a monopoly on best practices, but rather to show how journals from a related discipline address vital concerns of replication and generalizability shared by all social and behavioral sciences. We provide recommendations for promoting graduate training in replication and robustness-checking methods and for editorial policies that encourage these practices. Although some of our recommendations may shift the form and substance of developmental research articles, we argue that they would generate considerable scientific benefits for the field. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID:25243330

  19. A developmental checkpoint couples the initiation of sporulation to DNA replication in Bacillus subtilis.

    PubMed Central

    Ireton, K; Grossman, A D

    1994-01-01

    Spore formation in Bacillus subtilis requires the generation of two distinct cell types, each with an active chromosome that becomes committed to a defined program of gene expression. Here we show that a developmental checkpoint couples the initiation of sporulation, and the subsequent formation of these two cell types, to DNA replication early during development. Inhibiting the initiation of chromosomal replication prevents the onset of sporulation and inhibits expression of several genes that are normally induced early during development. This defect in gene expression is due to inhibition of the multi-component phosphorylation pathway needed to activate the developmental transcription factor encoded by spo0A. The target affected by inhibiting the initiation of replication is neither Spo0A nor the major kinase, KinA, needed for production of Spo0A approximately P. Rather, the target appears to be one of the proteins that transfers phosphate from the kinase to the Spo0A transcription factor. The signal that couples activity of the phosphorelay to the initiation of DNA replication is different from the previously described DNA damage signal that inhibits the phosphorelay during SOS induction in a recA-dependent response. Thus, DNA replication as well as DNA damage signals control production of Spo0A approximately P and initiation of sporulation. PMID:8156995

  20. Genetics and early disturbances of breathing control.

    PubMed

    Gaultier, Claude; Amiel, Jeanne; Dauger, Stéphane; Trang, Ha; Lyonnet, Stanislas; Gallego, Jorge; Simonneau, Michel

    2004-05-01

    Early disturbances in breathing control, including apneas of prematurity and apparently life-threatening events, account for some cases of sudden infant death syndrome and for a rare disorder called congenital central hypoventilation syndrome (CCHS). Data suggesting a genetic basis for CCHS have been obtained. Recently, we found heterozygous de novo mutations of the PHOX2B gene in 18 of 29 individuals with CCHS. Most mutations consisted of five to nine alanine expansions within a 20-residue polyalanine tract, probably resulting from nonhomologous recombination. Other mutations, generally inherited from one of the parents, in the coding regions of genes involved in the endothelin and RET signaling pathways and in the brain-derived-neurotrophic factor (BDNF) gene have been found in a few CCHS patients. Interestingly, all these genes are involved in the development of neural crest cells. Targeted disruption of these genes in mice has provided information on the pathophysiological mechanisms underlying CCHS. Despite the identification of these genes involved in breathing control, none of the genetically engineered mice developed to date replicate the full human CCHS respiratory phenotype. Recent insights into the genetic basis for CCHS may shed light on the genetics of other early disturbances in breathing control, such as apnea of prematurity and sudden infant death syndrome. PMID:14739359

  1. Hematopoietic cancer cell lines can support replication of Sabin poliovirus type 1.

    PubMed

    Oosterhoff, Dinja; van de Weerd, Gerard; van Eikenhorst, Gerco; de Gruijl, Tanja D; van der Pol, Leo A; Bakker, Wilfried A M

    2015-01-01

    Viral vaccines can be produced in adherent or in suspension cells. The objective of this work was to screen human suspension cell lines for the capacity to support viral replication. As the first step, it was investigated whether poliovirus can replicate in such cell lines. Sabin poliovirus type 1 was serially passaged on five human cell lines, HL60, K562, KG1, THP-1, and U937. Sabin type 1 was capable of efficiently replicating in three cell lines (K562, KG1, and U937), yielding high viral titers after replication. Expression of CD155, the poliovirus receptor, did not explain susceptibility to replication, since all cell lines expressed CD155. Furthermore, we showed that passaged virus replicated more efficiently than parental virus in KG1 cells, yielding higher virus titers in the supernatant early after infection. Infection of cell lines at an MOI of 0.01 resulted in high viral titers in the supernatant at day 4. Infection of K562 with passaged Sabin type 1 in a bioreactor system yielded high viral titers in the supernatant. Altogether, these data suggest that K562, KG1, and U937 cell lines are useful for propagation of poliovirus. PMID:25815312

  2. Hematopoietic Cancer Cell Lines Can Support Replication of Sabin Poliovirus Type 1

    PubMed Central

    van Eikenhorst, Gerco; de Gruijl, Tanja D.; van der Pol, Leo A.; Bakker, Wilfried A. M.

    2015-01-01

    Viral vaccines can be produced in adherent or in suspension cells. The objective of this work was to screen human suspension cell lines for the capacity to support viral replication. As the first step, it was investigated whether poliovirus can replicate in such cell lines. Sabin poliovirus type 1 was serially passaged on five human cell lines, HL60, K562, KG1, THP-1, and U937. Sabin type 1 was capable of efficiently replicating in three cell lines (K562, KG1, and U937), yielding high viral titers after replication. Expression of CD155, the poliovirus receptor, did not explain susceptibility to replication, since all cell lines expressed CD155. Furthermore, we showed that passaged virus replicated more efficiently than parental virus in KG1 cells, yielding higher virus titers in the supernatant early after infection. Infection of cell lines at an MOI of 0.01 resulted in high viral titers in the supernatant at day 4. Infection of K562 with passaged Sabin type 1 in a bioreactor system yielded high viral titers in the supernatant. Altogether, these data suggest that K562, KG1, and U937 cell lines are useful for propagation of poliovirus. PMID:25815312

  3. RNA virus replication depends on enrichment of phosphatidylethanolamine at replication sites in subcellular membranes.

    PubMed

    Xu, Kai; Nagy, Peter D

    2015-04-01

    Intracellular membranes are critical for replication of positive-strand RNA viruses. To dissect the roles of various lipids, we have developed an artificial phosphatidylethanolamine (PE) vesicle-based Tomato bushy stunt virus (TBSV) replication assay. We demonstrate that the in vitro assembled viral replicase complexes (VRCs) in artificial PE vesicles can support a complete cycle of replication and asymmetrical RNA synthesis, which is a hallmark of (+)-strand RNA viruses. Vesicles containing ?85% PE and ?15% additional phospholipids are the most efficient, suggesting that TBSV replicates within membrane microdomains enriched for PE. Accordingly, lipidomics analyses show increased PE levels in yeast surrogate host and plant leaves replicating TBSV. In addition, efficient redistribution of PE leads to enrichment of PE at viral replication sites. Expression of the tombusvirus p33 replication protein in the absence of other viral compounds is sufficient to promote intracellular redistribution of PE. Increased PE level due to deletion of PE methyltransferase in yeast enhances replication of TBSV and other viruses, suggesting that abundant PE in subcellular membranes has a proviral function. In summary, various (+)RNA viruses might subvert PE to build membrane-bound VRCs for robust replication in PE-enriched membrane microdomains. PMID:25810252

  4. RNA virus replication depends on enrichment of phosphatidylethanolamine at replication sites in subcellular membranes

    PubMed Central

    Xu, Kai; Nagy, Peter D.

    2015-01-01

    Intracellular membranes are critical for replication of positive-strand RNA viruses. To dissect the roles of various lipids, we have developed an artificial phosphatidylethanolamine (PE) vesicle-based Tomato bushy stunt virus (TBSV) replication assay. We demonstrate that the in vitro assembled viral replicase complexes (VRCs) in artificial PE vesicles can support a complete cycle of replication and asymmetrical RNA synthesis, which is a hallmark of (+)-strand RNA viruses. Vesicles containing ?85% PE and ?15% additional phospholipids are the most efficient, suggesting that TBSV replicates within membrane microdomains enriched for PE. Accordingly, lipidomics analyses show increased PE levels in yeast surrogate host and plant leaves replicating TBSV. In addition, efficient redistribution of PE leads to enrichment of PE at viral replication sites. Expression of the tombusvirus p33 replication protein in the absence of other viral compounds is sufficient to promote intracellular redistribution of PE. Increased PE level due to deletion of PE methyltransferase in yeast enhances replication of TBSV and other viruses, suggesting that abundant PE in subcellular membranes has a proviral function. In summary, various (+)RNA viruses might subvert PE to build membrane-bound VRCs for robust replication in PE-enriched membrane microdomains. PMID:25810252

  5. Defining multiple, distinct, and shared spatiotemporal patterns of DNA replication and endoreduplication from 3D image analysis of developing maize (Zea mays L.) root tip nuclei.

    PubMed

    Bass, Hank W; Hoffman, Gregg G; Lee, Tae-Jin; Wear, Emily E; Joseph, Stacey R; Allen, George C; Hanley-Bowdoin, Linda; Thompson, William F

    2015-11-01

    Spatiotemporal patterns of DNA replication have been described for yeast and many types of cultured animal cells, frequently after cell cycle arrest to aid in synchronization. However, patterns of DNA replication in nuclei from plants or naturally developing organs remain largely uncharacterized. Here we report findings from 3D quantitative analysis of DNA replication and endoreduplication in nuclei from pulse-labeled developing maize root tips. In both early and middle S phase nuclei, flow-sorted on the basis of DNA content, replicative labeling was widely distributed across euchromatic regions of the nucleoplasm. We did not observe the perinuclear or perinucleolar replicative labeling patterns characteristic of middle S phase in mammals. Instead, the early versus middle S phase patterns in maize could be distinguished cytologically by correlating two quantitative, continuous variables, replicative labeling and DAPI staining. Early S nuclei exhibited widely distributed euchromatic labeling preferentially localized to regions with weak DAPI signals. Middle S nuclei also exhibited widely distributed euchromatic labeling, but the label was preferentially localized to regions with strong DAPI signals. Highly condensed heterochromatin, including knobs, replicated during late S phase as previously reported. Similar spatiotemporal replication patterns were observed for both mitotic and endocycling maize nuclei. These results revealed that maize euchromatin exists as an intermingled mixture of two components distinguished by their condensation state and replication timing. These different patterns might reflect a previously described genome organization pattern, with "gene islands" mostly replicating during early S phase followed by most of the intergenic repetitive regions replicating during middle S phase. PMID:26394866

  6. Mutations in the M112/M113-Coding Region Facilitate Murine Cytomegalovirus Replication in Human Cells?

    PubMed Central

    Schumacher, Uwe; Handke, Wiebke; Jurak, Igor; Brune, Wolfram

    2010-01-01

    Cytomegaloviruses, representatives of the Betaherpesvirinae, cause opportunistic infections in immunocompromised hosts. They infect various cells and tissues in their natural host but are highly species specific. For instance, human cytomegalovirus (HCMV) does not replicate in mouse cells, and human cells are not permissive for murine cytomegalovirus (MCMV) infection. However, the underlying molecular mechanisms are so far poorly understood. In the present study we isolated and characterized a spontaneously occurring MCMV mutant that has gained the capacity to replicate rapidly and to high titers in human cells. Compared to the parental wild-type (wt) virus, this mutant formed larger nuclear replication compartments and replicated viral DNA more efficiently. It also disrupted promyelocytic leukemia (PML) protein nuclear domains with greater efficiency but caused less apoptosis than did wt MCMV. Sequence analysis of the mutant virus genome revealed mutations in the M112/M113-coding region. This region is homologous to the HCMV UL112-113 region and encodes the viral early 1 (E1) proteins, which are known to play an important role in viral DNA replication. By introducing the M112/M113 mutations into wt MCMV, we demonstrated that they are sufficient to facilitate MCMV replication in human cells and are, at least in part, responsible for the efficient replication capability of the spontaneously adapted virus. However, additional mutations probably contribute as well. These results reveal a previously unrecognized role of the viral E1 proteins in regulating viral replication in different cells and provide new insights into the mechanisms of the species specificity of cytomegaloviruses. PMID:20519391

  7. Mutations in the M112/M113-coding region facilitate murine cytomegalovirus replication in human cells.

    PubMed

    Schumacher, Uwe; Handke, Wiebke; Jurak, Igor; Brune, Wolfram

    2010-08-01

    Cytomegaloviruses, representatives of the Betaherpesvirinae, cause opportunistic infections in immunocompromised hosts. They infect various cells and tissues in their natural host but are highly species specific. For instance, human cytomegalovirus (HCMV) does not replicate in mouse cells, and human cells are not permissive for murine cytomegalovirus (MCMV) infection. However, the underlying molecular mechanisms are so far poorly understood. In the present study we isolated and characterized a spontaneously occurring MCMV mutant that has gained the capacity to replicate rapidly and to high titers in human cells. Compared to the parental wild-type (wt) virus, this mutant formed larger nuclear replication compartments and replicated viral DNA more efficiently. It also disrupted promyelocytic leukemia (PML) protein nuclear domains with greater efficiency but caused less apoptosis than did wt MCMV. Sequence analysis of the mutant virus genome revealed mutations in the M112/M113-coding region. This region is homologous to the HCMV UL112-113 region and encodes the viral early 1 (E1) proteins, which are known to play an important role in viral DNA replication. By introducing the M112/M113 mutations into wt MCMV, we demonstrated that they are sufficient to facilitate MCMV replication in human cells and are, at least in part, responsible for the efficient replication capability of the spontaneously adapted virus. However, additional mutations probably contribute as well. These results reveal a previously unrecognized role of the viral E1 proteins in regulating viral replication in different cells and provide new insights into the mechanisms of the species specificity of cytomegaloviruses. PMID:20519391

  8. Event Perception

    PubMed Central

    Radvansky, Gabriel; Zacks, Jeffrey M.

    2012-01-01

    Events are central elements of human experience. Formally, they can be individuated in terms of the entities that compose them, the features of those entities, and the relations amongst entities. Psychologically, representations of events capture their spatiotemporal location, the people and objects involved, and the relations between these elements. Here, we present an account of the nature of psychological representations of events and how they are constructed and updated. Event representations are like images in that they are isomorphic to the situations they represent. However, they are like models or language in that they are constructed of components rather than being holistic. Also, they are partial representations that leave out some elements and abstract others. Representations of individual events are informed by schematic knowledge about general classes of events. Event representations are constructed in a process that segments continuous activity into discrete events. The construction of a series of event representations forms a basis for predicting the future, planning for that future, and imagining alternatives. PMID:23082236

  9. Dynamic and Nucleolin-Dependent Localization of Human Cytomegalovirus UL84 to the Periphery of Viral Replication Compartments and Nucleoli

    PubMed Central

    Bender, Brian J.

    2014-01-01

    ABSTRACT Protein-protein and protein-nucleic acid interactions within subcellular compartments are required for viral genome replication. To understand the localization of the human cytomegalovirus viral replication factor UL84 relative to other proteins involved in viral DNA synthesis and to replicating viral DNA in infected cells, we created a recombinant virus expressing a FLAG-tagged version of UL84 (UL84FLAG) and used this virus in immunofluorescence assays. UL84FLAG localization differed at early and late times of infection, transitioning from diffuse distribution throughout the nucleus to exclusion from the interior of replication compartments, with some concentration at the periphery of replication compartments with newly labeled DNA and the viral DNA polymerase subunit UL44. Early in infection, UL84FLAG colocalized with the viral single-stranded DNA binding protein UL57, but colocalization became less prominent as infection progressed. A portion of UL84FLAG also colocalized with the host nucleolar protein nucleolin at the peripheries of both replication compartments and nucleoli. Small interfering RNA (siRNA)-mediated knockdown of nucleolin resulted in a dramatic elimination of UL84FLAG from replication compartments and other parts of the nucleus and its accumulation in the cytoplasm. Reciprocal coimmunoprecipitation of viral proteins from infected cell lysates revealed association of UL84, UL44, and nucleolin. These results indicate that UL84 localization during infection is dynamic, which is likely relevant to its functions, and suggest that its nuclear and subnuclear localization is highly dependent on direct or indirect interactions with nucleolin. IMPORTANCE The protein-protein interactions among viral and cellular proteins required for replication of the human cytomegalovirus (HCMV) DNA genome are poorly understood. We sought to understand how an enigmatic HCMV protein critical for virus replication, UL84, localizes relative to other viral and cellular proteins required for HCMV genome replication and replicating viral DNA. We found that UL84 localizes with viral proteins, viral DNA, and the cellular nucleolar protein nucleolin in the subnuclear replication compartments in which viral DNA replication occurs. Unexpectedly, we also found localization of UL84 with nucleolin in nucleoli and showed that the presence of nucleolin is involved in localization of UL84 to the nucleus. These results add to previous work showing the importance of nucleolin in replication compartment architecture and viral DNA synthesis and are relevant to understanding UL84 function. PMID:25078694

  10. Optical tweezers reveal how proteins alter replication

    NASA Astrophysics Data System (ADS)

    Chaurasiya, Kathy

    Single molecule force spectroscopy is a powerful method that explores the DNA interaction properties of proteins involved in a wide range of fundamental biological processes such as DNA replication, transcription, and repair. We use optical tweezers to capture and stretch a single DNA molecule in the presence of proteins that bind DNA and alter its mechanical properties. We quantitatively characterize the DNA binding mechanisms of proteins in order to provide a detailed understanding of their function. In this work, we focus on proteins involved in replication of Escherichia coli (E. coli ), endogenous eukaryotic retrotransposons Ty3 and LINE-1, and human immunodeficiency virus (HIV). DNA polymerases replicate the entire genome of the cell, and bind both double-stranded DNA (dsDNA) and single-stranded DNA (ssDNA) during DNA replication. The replicative DNA polymerase in the widely-studied model system E. coli is the DNA polymerase III subunit alpha (DNA pol III alpha). We use optical tweezers to determine that UmuD, a protein that regulates bacterial mutagenesis through its interactions with DNA polymerases, specifically disrupts alpha binding to ssDNA. This suggests that UmuD removes alpha from its ssDNA template to allow DNA repair proteins access to the damaged DNA, and to facilitate exchange of the replicative polymerase for an error-prone translesion synthesis (TLS) polymerase that inserts nucleotides opposite the lesions, so that bacterial DNA replication may proceed. This work demonstrates a biophysical mechanism by which E. coli cells tolerate DNA damage. Retroviruses and retrotransposons reproduce by copying their RNA genome into the nuclear DNA of their eukaryotic hosts. Retroelements encode proteins called nucleic acid chaperones, which rearrange nucleic acid secondary structure and are therefore required for successful replication. The chaperone activity of these proteins requires strong binding affinity for both single- and double-stranded nucleic acids. We use single molecule DNA stretching to show that the nucleocapsid protein (NC) of the yeast retrotransposon Ty3, which is likely to be an ancestor of HIV NC, has optimal nucleic acid chaperone activity with only a single zinc finger. We also show that the chaperone activity of the ORF1 protein is responsible for successful replication of the mouse LINE-1 retrotransposon. LINE-1 is also 17% of the human genome, where it generates i