Science.gov

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

    PubMed

    Stenfeldt, Carolina; Pacheco, Juan M; Rodriguez, Luis L; Arzt, Jonathan

    2014-01-01

    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, intra-oropharyngeal, inoculation. The earliest detectable event was primary infection in the lingual and paraepiglottic tonsils at 6 hours post inoculation (hpi) characterized by regional localization of viral RNA, viral antigen, and infectious virus. At this time FMDV antigen was localized in cytokeratin-positive epithelial cells and CD172a-expressing leukocytes of the crypt epithelium of the paraepiglottic tonsils. De novo replication of FMDV was first detected in oropharyngeal swab samples at 12 hpi and viremia occurred at 18-24 hpi, approximately 24 hours prior to the appearance of vesicular lesions. From 12 through 78 hpi, microscopic detection of FMDV was consistently localized to cytokeratin-positive cells within morphologically characteristic segments of oropharyngeal tonsil crypt epithelium. During this period, leukocyte populations expressing CD172a, SLA-DQ class II and/or CD8 were found in close proximity to infected epithelial cells, but with little or no co-localization with viral proteins. Similarly, M-cells expressing cytokeratin-18 did not co-localize with FMDV proteins. Intra-epithelial micro-vesicles composed of acantholytic epithelial cells expressing large amounts of structural and non-structural FMDV proteins were present within crypts of the tonsil of the soft palate during peak clinical infection. These findings inculpate the paraepiglottic tonsils as the primary site of FMDV infection in pigs exposed via the gastrointestinal tract. Furthermore, the continuing replication of FMDV in the oropharyngeal tonsils during viremia and peak clinical infection with no concurrent amplification of virus occurring in the lower respiratory tract indicates that these sites are the major source of shedding of FMDV from pigs. PMID:25184288

  3. Early Events in the Pathogenesis of Foot-and-Mouth Disease in Pigs; Identification of Oropharyngeal Tonsils as Sites of Primary and Sustained Viral Replication

    PubMed Central

    Stenfeldt, Carolina; Pacheco, Juan M.; Rodriguez, Luis L.; Arzt, Jonathan

    2014-01-01

    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, intra-oropharyngeal, inoculation. The earliest detectable event was primary infection in the lingual and paraepiglottic tonsils at 6 hours post inoculation (hpi) characterized by regional localization of viral RNA, viral antigen, and infectious virus. At this time FMDV antigen was localized in cytokeratin-positive epithelial cells and CD172a-expressing leukocytes of the crypt epithelium of the paraepiglottic tonsils. De novo replication of FMDV was first detected in oropharyngeal swab samples at 12 hpi and viremia occurred at 18–24 hpi, approximately 24 hours prior to the appearance of vesicular lesions. From 12 through 78 hpi, microscopic detection of FMDV was consistently localized to cytokeratin-positive cells within morphologically characteristic segments of oropharyngeal tonsil crypt epithelium. During this period, leukocyte populations expressing CD172a, SLA-DQ class II and/or CD8 were found in close proximity to infected epithelial cells, but with little or no co-localization with viral proteins. Similarly, M-cells expressing cytokeratin-18 did not co-localize with FMDV proteins. Intra-epithelial micro-vesicles composed of acantholytic epithelial cells expressing large amounts of structural and non-structural FMDV proteins were present within crypts of the tonsil of the soft palate during peak clinical infection. These findings inculpate the paraepiglottic tonsils as the primary site of FMDV infection in pigs exposed via the gastrointestinal tract. Furthermore, the continuing replication of FMDV in the oropharyngeal tonsils during viremia and peak clinical infection with no concurrent amplification of virus occurring in the lower respiratory tract indicates that these sites are the major source of shedding of FMDV from pigs. PMID:25184288

  4. 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.

  5. 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

  6. A CI-Independent Form of Replicative Inhibition: Turn Off of Early Replication of Bacteriophage Lambda

    PubMed Central

    Hayes, Sidney; Horbay, Monique A.; Hayes, Connie

    2012-01-01

    Several earlier studies have described an unusual exclusion phenotype exhibited by cells with plasmids carrying a portion of the replication region of phage lambda. Cells exhibiting this inhibition phenotype (IP) prevent the plating of homo-immune and hybrid hetero-immune lambdoid phages. We have attempted to define aspects of IP, and show that it is directed to rep? phages. IP was observed in cells with plasmids containing a ? DNA fragment including oop, encoding a short OOP micro RNA, and part of the lambda origin of replication, ori?, defined by iteron sequences ITN1-4 and an adjacent high AT-rich sequence. Transcription of the intact oop sequence from its promoter, pO is required for IP, as are iterons ITN34, but not the high AT-rich portion of ori?. The results suggest that IP silencing is directed to theta mode replication initiation from an infecting rep? genome, or an induced rep? prophage. Phage mutations suppressing IP, i.e., Sip, map within, or adjacent to cro or in O, or both. Our results for plasmid based IP suggest the hypothesis that there is a natural mechanism for silencing early theta-mode replication initiation, i.e. the buildup of ? genomes with oop+ ori?+ sequence. PMID:22590552

  7. 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

  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 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.

  10. 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.

  11. 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

  12. Meaning of early polyomavirus-BK replication post kidney transplant.

    PubMed

    Mitterhofer, A P; Pietropaolo, V; Barile, M; Tinti, F; Fioriti, D; Mischitelli, M; Limonta, A; Meule, A; Ferretti, G; Poli, L; Chiarini, F; Berloco, P B; Taliani, G

    2010-05-01

    Polyomavirus BK (BKV) infection is ubiquitous in the human population. Under immunosuppression, BKV can undergo reactivation resulting in viral replication. What really happens in the early hours posttransplantation is not clearly defined; the meaning of early viremia and viruria is not clear. BKV viremia is considered a marker of infection. The aim of our study was to investigate the prevalence of early BKV infection in kidney transplant patients, to evaluate the relationship to infections at 3 and 6 months and the association with recipient, donor, and graft features. We enrolled 36 kidney transplanted patients from May 2006 to April 2007. BKV load was measured on plasma and urine samples by Q-PCR at 12 hours (T(0)/early) as well as 3 (T(3)) and 6 (T(6)) months thereafter. A high percentage of BKV infections were detectable in the first hours after transplantation (33.3%), which remained unchanged to month 6 post transplantation. Moreover, patients who were positive at T(0) had a high probability of remaining positive thereafter. The number of copies in plasma samples tended to increase at 3 months and to decrease thereafter, whereas the urine viral load tended to steadily increase. Among BKV-positive patients, we identified 2 groups according to viremic state at T(0): 9 patients (group A); who were already positive and remained so to T(6) 5 and 3 patients who turned positive at 3 or at 6 months, respectively (group B). Group A included 75% of positive patients at T(0) and 90% of positive patients at either T(3) or T(6) (P = .007). The most important contribution of our study was to highlight the presence of BKV infection in renal transplant recipients from the first hours posttransplantation. This condition seemed to be the most important risk factor for persistent infection in the first 6 months. PMID:20534245

  13. 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.

  14. Early Word Comprehension in Infants: Replication and Extension

    PubMed Central

    Bergelson, Elika; Swingley, Daniel

    2014-01-01

    A handful of recent experimental reports have shown that infants of 6 to 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 named in a sentence, they look at the named video at above-chance rates. We demonstrate anew that infants understand common words by 6-9 months, and that performance increases substantially around 14 months. The results imply that 6-9 month olds failure to understand words not referring to objects (verbs, adjectives, performatives) in a similar prior study is not attributable to the use of dynamic video depictions. Thus, 6-9 month olds experience of spoken language includes some understanding of common words for concrete objects, but relatively impoverished comprehension of other words. PMID:26664329

  15. Early Events in Ionic Liquid Radiation Chemistry

    SciTech Connect

    Wishart, J.F.; Cook, A.; Rimmer, R.D.; Gohdo, M.

    2010-09-14

    Ionic liquids are interesting and useful materials whose solvation time scales are up to thousands of times longer than in conventional solvents. The extended lifetimes of pre-solvated electrons and other energetic species in ionic liquids has profound consequences for the radiolytic product distributions and reactivity patterns. We use a newly developed, multiplexed variation of pulse-probe spectroscopy to measure the kinetics of the early dynamical and reactive events in ionic liquids.

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

    PubMed

    Simes, 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. 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

  18. Genome-wide sequence and functional analysis of early replicating DNA in normal human fibroblasts

    PubMed Central

    Cohen, Stephanie M; Furey, Terrence S; Doggett, Norman A; Kaufman, David G

    2006-01-01

    Background The replication of mammalian genomic DNA during the S phase is a highly coordinated process that occurs in a programmed manner. Recent studies have begun to elucidate the pattern of replication timing on a genomic scale. Using a combination of experimental and computational techniques, we identified a genome-wide set of the earliest replicating sequences. This was accomplished by first creating a cosmid library containing DNA enriched in sequences that replicate early in the S phase of normal human fibroblasts. Clone ends were then sequenced and aligned to the human genome. Results By clustering adjacent or overlapping early replicating clones, we identified 1759 "islands" averaging 100 kb in length, allowing us to perform the most detailed analysis to date of DNA characteristics and genes contained within early replicating DNA. Islands are enriched in open chromatin, transcription related elements, and Alu repetitive elements, with an underrepresentation of LINE elements. In addition, we found a paucity of LTR retroposons, DNA transposon sequences, and an enrichment in all classes of tandem repeats, except for dinucleotides. Conclusion An analysis of genes associated with islands revealed that nearly half of all genes in the WNT family, and a number of genes in the base excision repair pathway, including four of ten DNA glycosylases, were associated with island sequences. Also, we found an overrepresentation of members of apoptosis-associated genes in very early replicating sequences from both fibroblast and lymphoblastoid cells. These data suggest that there is a temporal pattern of replication for some functionally related genes. PMID:17134498

  19. Evidence that a single replication fork proceeds from early to late replicating domains in the IgH locus in a non-B cell line.

    PubMed

    Ermakova, O V; Nguyen, L H; Little, R D; Chevillard, C; Riblet, R; Ashouian, N; Birshtein, B K; Schildkraut, C L

    1999-03-01

    In non-B cell lines, like the murine erythroleukemia cell line (MEL), the most distal IgH constant region gene, C alpha, replicates early in S; other heavy chain constant region genes, joining and diversity segments, and the most proximal Vh gene replicate successively later in S in a 3' to 5' direction proportional to their distance from C alpha. In MEL, replication forks detected in the IgH locus also proceed in the same 3' to 5' direction for approximately 400 kb, beginning downstream of the IgH 3' regulatory region and continuing to the D region, as well as within the Vh81X gene. Downstream of the initiation region is an early replicating domain, and upstream of Vh81X is a late replicating domain. Hence, the gradual transition between early and late replicated domains can be achieved by a single replication fork. PMID:10198634

  20. Dynamics of the Genome during Early Xenopus laevis Development: Karyomeres As Independent Units of Replication

    PubMed Central

    Lemaitre, Jean-Marc; Géraud, Gérard; Méchali, Marcel

    1998-01-01

    During Xenopus laevis early development, the genome is replicated in less than 15 min every 30 min. We show that during this period, DNA replication proceeds in an atypical manner. Chromosomes become surrounded by a nuclear membrane lamina forming micronuclei or karyomeres. This genomic organization permits that prereplication centers gather on condensed chromosomes during anaphase and that DNA replication initiates autonomously in karyomeres at early telophase before nuclear reconstruction and mitosis completion. The formation of karyomeres is not dependent on DNA replication but requires mitotic spindle formation and the normal segregation of chromosomes. Thus, during early development, chromosomes behave as structurally and functionally independent units. The formation of a nuclear envelope around each chromosome provides an in vivo validation of its role in regulating initiation of DNA replication, enabling the rate of replication to accelerate and S phase to overlap M phase without illegitimate reinitiation. The abrupt disappearance of this atypical organization within one cell cycle after thirteen divisions defines a novel developmental transition at the blastula stage, which may affect both the replication and the transcription programs of development. PMID:9732278

  1. 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.

  2. Early and late modes of DNA replication in ultraviolet irradated Syrian hamster embryo cells

    SciTech Connect

    Doniger, J.; DiPaolo, J.A.

    1980-08-01

    The nature of DNA replication in UV irradiated Syrian hamster embryo cells (HEC) was investigated by measuring the size distribution of nascent daughter strand DNA. During the early mode, nascent strands are made in smaller pieces than in nonirradiated cells. The late mode begins when nascent strands recover to normal size. This was observed in HEC 5 h post-UV. When the late mode is operational, nascent strands elongate to parental size in <2 h, whereas >3 h are required during early mode function. Evidence from split dose experiments demonstrates that the recovery of the size of nascent strands is not due to enhanced gap filling. Furthermore, pyrimidine dimers are probably recognized differently by the replication complex during early and late mode DNA synthesis. The late mode of replication could account for the ability of HEC to survive UV irradiation even though they are inefficient in both excision and postreplication repair.

  3. Replication protein A safeguards genome integrity by controlling NER incision events

    PubMed Central

    Overmeer, René M.; Moser, Jill; Volker, Marcel; Kool, Hanneke; Tomkinson, Alan E.; van Zeeland, Albert A.

    2011-01-01

    Single-stranded DNA gaps that might arise by futile repair processes can lead to mutagenic events and challenge genome integrity. Nucleotide excision repair (NER) is an evolutionarily conserved repair mechanism, essential for removal of helix-distorting DNA lesions. In the currently prevailing model, NER operates through coordinated assembly of repair factors into pre- and post-incision complexes; however, its regulation in vivo is poorly understood. Notably, the transition from dual incision to repair synthesis should be rigidly synchronized as it might lead to accumulation of unprocessed repair intermediates. We monitored NER regulatory events in vivo using sequential UV irradiations. Under conditions that allow incision yet prevent completion of repair synthesis or ligation, preincision factors can reassociate with new damage sites. In contrast, replication protein A remains at the incomplete NER sites and regulates a feedback loop from completion of DNA repair synthesis to subsequent damage recognition, independently of ATR signaling. Our data reveal an important function for replication protein A in averting further generation of DNA strand breaks that could lead to mutagenic and recombinogenic events. PMID:21282463

  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. Early replication dynamics of sex-linked mitochondrial DNAs in the doubly uniparental inheritance species Ruditapes philippinarum (Bivalvia Veneridae).

    PubMed

    Guerra, D; Ghiselli, F; Milani, L; Breton, S; Passamonti, M

    2016-03-01

    Mitochondrial homoplasmy, which is maintained by strictly maternal inheritance and a series of bottlenecks, is thought to be an adaptive condition for metazoans. Doubly uniparental inheritance (DUI) is a unique mode of mitochondrial transmission found in bivalve species, in which two distinct mitochondrial genome (mtDNA) lines are present, one inherited through eggs (F) and one through sperm (M). During development, the two lines segregate in a sex- and tissue-specific manner: females lose M during embryogenesis, whereas males actively segregate it in the germ line. These two pivotal events are still poorly characterized. Here we investigated mtDNA replication dynamics during embryogenesis and pre-adulthood of the venerid Ruditapes philippinarum using real-time quantitative PCR. We found that both mtDNAs do not detectably replicate during early embryogenesis, and that the M line might be lost from females around 24 h of age. A rise in mtDNA copy number was observed before the first reproductive season in both sexes, with the M mitochondrial genome replicating more than the F in males, and we associate these boosts to the early phase of gonad production. As evidence indicates that DUI relies on the same molecular machine of mitochondrial maternal inheritance that is common in most animals, our data are relevant not only to DUI but also to shed light on how differential segregations of mtDNA variants, in the same nuclear background, may be controlled during development. PMID:26626575

  6. DNA Replication Origin Interference Increases the Spacing between Initiation Events in Human Cells

    PubMed Central

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

    2006-01-01

    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. 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

  8. Early growth response-1 facilitates enterovirus 71 replication by direct binding to the viral genome RNA.

    PubMed

    Song, Yu; Cheng, Xin; Yang, Xiaoxia; Zhao, Rong; Wang, Peili; Han, Yang; Luo, Zhen; Cao, Yanhua; Zhu, Chengliang; Xiong, Ying; Liu, Yingle; Wu, Kailang; Wu, Jianguo

    2015-05-01

    Enterovirus 71 (EV71) infections can cause hand, foot and mouth disease (HFMD), meningoencephalitis, neonatal sepsis, and even fatal encephalitis in children. Unfortunately, there is currently no effective treatment for EV71 infection due to the lack of understanding of viral replication and infection; and viral infections have emerged as an imperative global hazard. Thus, it is extremely important to understand the mechanism of EV71 replication in order to prevent and control the diseases associated with EV71 infections. Early growth response-1 (EGR1) is a multifunctional transcription factor that regulates diverse biological functions, including inflammation, apoptosis, differentiation, tumorigenesis, and even viral infection. Here, we provide new insight into the role of EV71 infection in regulating EGR1 production; and reveal a novel mechanism by which EGR1 facilitates EV71 replication. We demonstrate that EV71 activates EGR1 expression during infection by stimulating the protein kinase A/protein kinase C?/phosphoinositide 3-kinase/Akt (PKA/PKC?/PI3K/Akt) cascade. We further reveal that EV71-activated EGR1, in turn, regulates the internal ribosomal entry site (IRES) of EV71 to enhance viral replication. In addition, EGR1 facilitates EV71 replication by binding directly to stem-loops I and IV of EV71 5'-untranslated region (5'UTR) with its first two zinc fingers. Moreover, EGR1 protein co-localizes with EV71 RNA in the cytoplasm of infected cells to facilitate viral replication. Our results reveal an important new role of EGR1 in viral infection, provide new insight into the novel mechanism underlying the regulation of EV71 replication, and suggest a potential application of EGR1 in the control of EV71 infection. PMID:25724735

  9. Neurogenesis requires TopBP1 to prevent catastrophic replicative DNA damage in early progenitors

    PubMed Central

    Lee, Youngsoo; Katyal, Sachin; Downing, Susanna M.; Zhao, Jingfeng; Russell, Helen R.; McKinnon, Peter J.

    2012-01-01

    The rapid proliferation of progenitors during neurogenesis requires a stringent genomic maintenance program to ensure transmission of genetic fidelity. However the essential factors that govern neural progenitor genome integrity are unknown. Here we report that conditional inactivation of mouse TopBP1, a protein linked to DNA replication, and a key activator of the DNA damage response kinase ATR (ataxia telangiectasia and rad3 related) is critical for maintenance of early-born neural progenitors. During cortical development TopBP1 prevented replication-associated DNA damage in Emx1-progenitors which otherwise resulted in profound tissue ablation. Importantly, disrupted neurogenesis in TopBP1-depleted tissues was substantially rescued by p53- but not ATM-inactivation. Our data establish that TopBP1 is essential for preventing replication-associated DNA strand breaks, but is not essential per se for DNA replication. Thus, TopBP1 is crucial for maintaining genome integrity in the early progenitors that drive neurogenesis. PMID:22522401

  10. 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.

  11. Remote Acculturation of Early Adolescents in Jamaica towards European American Culture: A Replication and Extension

    PubMed Central

    Ferguson, Gail M.; Bornstein, Marc H.

    2015-01-01

    Remote acculturation is a modern form of non-immigrant acculturation identified among early adolescents in Jamaica as “Americanization”. This study aimed to replicate the original remote acculturation findings in a new cohort of early adolescents in Jamaica (n = 222; M = 12.08 years) and to extend our understanding of remote acculturation by investigating potential vehicles of indirect and intermittent intercultural contact. Cluster analyses replicated prior findings: Relative to Traditional Jamaican adolescents (62%), Americanized Jamaican adolescents (38%) reported stronger European American cultural orientation, lower Jamaican orientation, lower family obligations, and greater conflict with parents. More U.S. media (girls) and less local media and local sports (all) were the primary vehicles of intercultural contact predicting higher odds of Americanization. U.S. food, U.S. tourism, and transnational communication were also linked to U.S. orientation. Findings have implications for acculturation research and for practice and policy targeting Caribbean youth and families. PMID:25709142

  12. Early Jurassic mass extinction: A global long-term event

    NASA Astrophysics Data System (ADS)

    Little, Crispin T. S.; Benton, Michael J.

    1995-06-01

    The end-Pliensbachian extinction event (187 Ma) has been interpreted 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 spanned five ammonite zones during the late Pliensbachian and the early Toarcian, an interval of 7.5 m.y., and were distributed unequally in the Boreal, Tethyan, and Austral realms. Detailed sampling of invertebrate macrofaunas through complete expanded sequences in northwest Europe shows that most species extinctions occurred in the early Toarcian, following a regional anoxic event. The Early Jurassic mass-extinction event took place over a long time scale, and it was global in extent.

  13. Coupling of Saccharomyces cerevisiae early meiotic gene expression to DNA replication depends upon RPD3 and SIN3.

    PubMed Central

    Lamb, T M; Mitchell, A P

    2001-01-01

    It has been established that meiotic recombination and chromosome segregation are inhibited when meiotic DNA replication is blocked. Here we demonstrate that early meiotic gene (EMG) expression is also inhibited by a block in replication. Since early meiotic genes are required to promote meiotic recombination and DNA division, the low expression of these genes may contribute to the block in meiotic progression. We have identified three Hur- (HU reduced recombination) mutants that fail to couple meiotic recombination and gene expression with replication. One of these mutations is in RPD3, a gene required to maintain meiotic gene repression in mitotic cells. Complete deletions of RPD3 and the repression adapter SIN3 permitted recombination and early meiotic gene expression when replication was inhibited with hydroxyurea (HU). Biochemical analysis showed that the Rpd3p-Sin3p-Ume6p repression complex does exist in meiotic cells. These observations suggest that repression of early meiotic genes by SIN3 and RPD3 is critical for the normal response to inhibited replication. A second response to inhibited replication has also been discovered. HU-inhibited replication reduced the accumulation of phospho-Ume6p in meiotic cells. Phosphorylation of Ume6p normally promotes interaction with the meiotic activator Ime1p, thereby activating EMG expression. Thus, inhibited replication may also reduce the Ume6p-dependent activation of EMGs. Taken together, our data suggest that both active repression and reduced activation combine to inhibit EMG expression when replication is inhibited. PMID:11156977

  14. DNA replication and order of cell cycle events: a role for protein isoprenylation?

    PubMed

    Galli, I; Uchiyama, M; Wang, T S

    1997-09-01

    When the aya1+ gene is mutated, Schizosaccharomyces pombe cells become unable to react appropriately to a delay in DNA replication. Instead of stalling the cell cycle to allow completion of DNA synthesis, they proceed unperturbed towards mitosis and attempt to segregate the still unreplicated chromosomes. As a result, the genetic material segregates unevenly and the nuclei assume a mitotic catastrophe phenotype, characterized by torn chromosomes (cut), anucleated cells and scattered chromosomes. Interestingly, the aya1 phenotype can be suppressed by overexpression of either the catalytic subunit of S. pombe DNA polymerase alpha or of a novel protein called hur1 +p. The latter bears significant homology to the core of the human Rab escort protein, which belongs to a family of factors necessary to the post-translational isoprenylation of proteins like Ras, Rab and lamin B. When isoprenylation is chemically inhibited with R-limonene (a monoterpene derived from orange rind), wild type S. pombe cells become insensitive to an S phase delay, in a manner strongly reminiscent of aya1 mutants. Moreover, overexpression of hur1 +p in wild type cells rescues the failing checkpoint function. We propose that there is a strong correlation between the aya1 phenotype, S-M phase checkpoint function, and isoprenylation events in fission yeast. PMID:9348105

  15. Abnormal early cleavage events predict early embryo demise: sperm oxidative stress and early abnormal cleavage.

    PubMed

    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

  16. 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

  17. The human oncoprotein MDM2 induces replication stress eliciting early intra-S-phase checkpoint response and inhibition of DNA replication origin firing.

    PubMed

    Frum, Rebecca A; Singh, Shilpa; Vaughan, Catherine; Mukhopadhyay, Nitai D; Grossman, Steven R; Windle, Brad; Deb, Sumitra; Deb, Swati Palit

    2014-01-01

    Conventional paradigm ascribes the cell proliferative function of the human oncoprotein mouse double minute2 (MDM2) primarily to its ability to degrade p53. Here we report that in the absence of p53, MDM2 induces replication stress eliciting an early S-phase checkpoint response to inhibit further firing of DNA replication origins. Partially synchronized lung cells cultured from p53-/-:MDM2 transgenic mice enter S phase and induce S-phase checkpoint response earlier than lung cells from p53-/- mice and inhibit firing of DNA replication origins. MDM2 activates chk1 phosphorylation, elevates mixed lineage lymphoma histone methyl transferase levels and promotes checkpoint-dependent tri-methylation of histone H3 at lysine 4, known to prevent firing of late replication origins at the early S phase. In the absence of p53, a condition that disables inhibition of cyclin A expression by MDM2, MDM2 increases expression of cyclin D2 and A and hastens S-phase entry of cells. Consistently, inhibition of cyclin-dependent kinases, known to activate DNA replication origins during firing, inhibits MDM2-mediated induction of chk1 phosphorylation indicating the requirement of this activity in MDM2-mediated chk1 phosphorylation. Our data reveal a novel pathway, defended by the intra-S-phase checkpoint, by which MDM2 induces unscheduled origin firing and accelerates S-phase entry of cells in the absence of p53. PMID:24163099

  18. Reversible inhibition of poxvirus replication by cycloheximide during the early phase of infection.

    PubMed

    Chen, X; Rsel, J; Dunker, R; Goldschmidt, R; Maurer-Schultze, B; Jungwirth, C

    1983-01-30

    Infection of primary chick embryo fibroblasts with Vaccinia WR, IHD-W, and cowpox virus even at high m.o.i. does not cause drastic early inhibition of host cell protein synthesis. This contrasts with the infection by these viruses of many eucaryotic cells. Cellular protein synthesis of mouse L cells is also only partially inhibited after infection with cowpox virus up to a m.o.i. of 2500 e.b. As predicted by Moss and Filler (1970, J. Virol. 5, 99-108) no irreversible inhibition of poxvirus replication is observed in these cells following the addition of cycloheximide early after infection. The viral cores which accumulate in chick embryo fibroblasts in the presence of cycloheximide are further uncoated after removal of the protein synthesis inhibitor. These poxvirus host cell systems can be used to identify in vivo immediate and putative delayed early viral gene products. Formation of progeny virus, viral DNA synthesis, the sequential formation of viral proteins, and sensitivity to interferon has been demonstrated in chick embryo fibroblasts after reversal of the cycloheximide block. These studies indicate a synchronized replication cycle of poxvirus after reversal of the cycloheximide block. PMID:6186078

  19. Characteristics of early, long recovery VLF scattering events

    NASA Astrophysics Data System (ADS)

    Kotovsky, D. A.; Moore, R. C.

    2013-12-01

    Experimental observations of early, long recovery VLF events (LOREs) and their causative radio atmospherics (sferics) are analyzed -- 49 events are presented, including over-sea and over-land events. We demonstrate that the phasor addition of ambient and scattered VLF fields may lead to amplitude and phase changes that have different perturbation characteristics (onset duration, recovery time, etc.), and conclude that VLF perturbations are best categorized by their associated normalized scattered field phasor. Additionally, we present observations which demonstrate that normalized scattered field characteristics can depend upon the receiving antenna orientation.

  20. Method for early detection of cooling-loss events

    SciTech Connect

    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.

  1. 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.

  2. 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.

  3. Short-range inversions: rethinking organelle genome stability: template switching events during DNA replication destabilize organelle genomes.

    PubMed

    Tremblay-Belzile, Samuel; Lepage, tienne; Zampini, ric; Brisson, Normand

    2015-10-01

    In the organelles of plants and mammals, recent evidence suggests that genomic instability stems in large part from template switching events taking place during DNA replication. Although more than one mechanism may be responsible for this, some similarities exist between the different proposed models. These can be separated into two main categories, depending on whether they involve a single-strand-switching or a reciprocal-strand-switching event. Single-strand-switching events lead to intermediates containing Y junctions, whereas reciprocal-strand-switching creates Holliday junctions. Common features in all the described models include replication stress, fork stalling and the presence of inverted repeats, but no single element appears to be required in all cases. We review the field, and examine the ideas that several mechanisms may take place in any given genome, and that the presence of palindromes or inverted repeats in certain regions may favor specific rearrangements. PMID:26222836

  4. Traumatic Events and Children: How Early Childhood Educators Can Help.

    ERIC Educational Resources Information Center

    Alat, Kazim

    2002-01-01

    Examines the range of children's responses to traumatic events and identifies common symptoms of posttraumatic stress disorder (PTSD). Identifies protective and risk factors for PTSD. Discusses ways early childhood educators can provide a sense of security and regularity in their classrooms and use classroom activities to facilitate coping with…

  5. 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

  6. 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

  7. The human autoantigen MCP1 is required during early stages of DNA replication.

    PubMed

    Bronze-da-Rocha, E; Nóvoa, A; Cunha, C; do Carmo-Fonseca, M; Staines, N A; Sunkel, C E

    2000-01-01

    Metaphase chromosome protein 1 (MCP1) is a nuclear autoantigen that is associated with condensed chromosomes throughout mitosis. During interphase, this antigen shows a speckle distribution in the nucleus, excluding the nucleolus. Additionally, MCP1 binds tightly to the scaffold/matrix component of nuclei and isolated chromosomes. In order to determine the in-vivo localization of the antigen, we have expressed MCP1 fused to EGFP in tissue culture cells. The results demonstrate that MCP1 is located in the nucleus during interphase and during mitosis associates tightly to condensed chromosomes. Furthermore, microinjection of specific antibody confirms these results. We have used a specific monoclonal antibody (mAb 402) against MCP1 to assess the function of this antigen during cell cycle progression. HeLa and Ptk-2 cells that were microinjected into the nucleus and/or cytoplasm at G1/S and very early S phase were not able to progress and complete DNA replication. However, injection of mAb 402 at mid or late S phase does not prevent completion of DNA replication and subsequent progression into mitosis. Microinjection of mAb 402 in Ptk-2 cells synchronized in mitosis did not interfere with progression of mitosis and cells divided. Our results suggest that MCP1 is required at the G1/S transition and during early S phase. PMID:11196133

  8. Initiation of simian virus 40 DNA replication in vitro: aphidicolin causes accumulation of early-replicating intermediates and allows determination of the initial direction of DNA synthesis.

    PubMed Central

    Decker, R S; Yamaguchi, M; Possenti, R; DePamphilis, M L

    1986-01-01

    Aphidicolin, a specific inhibitor of DNA polymerase alpha, provided a novel method for distinguishing between initiation of DNA synthesis at the simian virus 40 (SV40) origin of replication (ori) and continuation of replication beyond ori. In the presence of sufficient aphidicolin to inhibit total DNA synthesis by 50%, initiation of DNA replication in SV40 chromosomes or ori-containing plasmids continued in vitro, whereas DNA synthesis in the bulk of SV40 replicative intermediate DNA (RI) that had initiated replication in vivo was rapidly inhibited. This resulted in accumulation of early RI in which most nascent DNA was localized within a 600- to 700-base-pair region centered at ori. Accumulation of early RI was observed only under conditions that permitted initiation of SV40 ori-dependent, T-antigen-dependent DNA replication and only when aphidicolin was added to the in vitro system. Increasing aphidicolin concentrations revealed that DNA synthesis in the ori region was not completely resistant to aphidicolin but simply less sensitive than DNA synthesis at forks that were farther away. Since DNA synthesized in the presence of aphidicolin was concentrated in the 300 base pairs on the early gene side of ori, we conclude that the initial direction of DNA synthesis was the same as that of early mRNA synthesis, consistent with the model proposed by Hay and DePamphilis (Cell 28:767-779, 1982). The data were also consistent with initiation of the first DNA chains in ori by CV-1 cell DNA primase-DNA polymerase alpha. Synthesis of pppA/G(pN)6-8(pdN)21-23 chains on a single-stranded DNA template by a purified preparation of this enzyme was completely resistant to aphidicolin, and further incorporation of deoxynucleotide monophosphates was inhibited. Therefore, in the presence of aphidicolin, this enzyme could initiate RNA-primed DNA synthesis at ori first in the early gene direction and then in the late gene direction, but could not continue DNA synthesis for an extended distance. Images PMID:3025613

  9. On the Relativistic Electron Injection Event in Early April 2010

    NASA Astrophysics Data System (ADS)

    Blake, J. B.; OBrien, P.; Rodriguez, J. V.; Green, J. C.

    2011-12-01

    Beginning in early 2008, the MeV electron population in the Earth's radiation belts began declining and reached an unprecedented low in the autumn. This minimum continued until early April 2010 when a large relativistic electron injection event occurred. An extraordinary feature of this event was that high intensities of multi-MeV electrons extended out to beyond L=7, and the energy spectrum was very hard, extending to several MeV. Observations are available from many spacecraft including HEO1 & HEO3, ICO-F2, SAMPEX, and GOES. Also data are available from several GOES spacecraft including observations with the HEPAD sensors that give clear evidence that the electron energies extended to above 10 MeV. These data and other information on the state of the magnetosphere suggest that loss processes were subdued during this time period, enabling the magnetospheric electron accelerator to operate effectively over an extended time period

  10. Protein-mediated Selective Enclosure of Early Replicators Inside of Membranous Vesicles: First Step Towards Cell Membranes

    NASA Astrophysics Data System (ADS)

    Laiterä, Tiina; Lehto, Kirsi

    2009-12-01

    Containment in cell membranes is essential for all contemporary life, and apparently even the earliest life forms had to be somehow contained. It has been postulated that random enclosure of replicating molecules inside of spontaneously assembled vesicles would have formed the initial cellular ancestors. However, completely random re-formation or division of such primitive vesicles would have abolished the heritability of their contents, nullifying any selective advantage to them. We propose that the containment of the early replicators in membranous vesicles was adopted only after the invention of genetically encoded proteins, and that selective enclosure of target molecules was mediated by specific proteins. A similar containment process is still utilised by various RNA- and retroviruses to isolate their replication complexes from the host’s intracellular environment. Such selective encapsulation would have protected the replicators against competitor and parasitic sequences, and provided a strong positive selection within the replicator communities.

  11. Early viral replication in lymph nodes provides HIV with a means by which to escape NK-cell-mediated control.

    PubMed

    Luteijn, Rutger; Sciaranghella, Gaia; van Lunzen, Jan; Nolting, Anne; Dugast, Anne-Sophie; Ghebremichael, Musie S; Altfeld, Marcus; Alter, Galit

    2011-09-01

    Acute HIV infection is marked by dramatic viral replication associated with preferential replication within secondary lymphoid tissues, such as lymph nodes (LNs), that is rapidly but incompletely contained to a viral setpoint. Accumulating evidence supports a role for natural killer (NK) cells in the early control of HIV infection; however, little is known about the location of their antiviral control. Given that HIV replicates profusely in LNs during early infection, we sought to define whether changes occurred in the NK cell infiltrate within these sites during the first year of HIV infection. Surprisingly, NK cell numbers and distribution were unaltered during early HIV infection. LN NK cells expressed decreased inhibitory receptors, were more highly activated, and expressed elevated TRAIL, potentially conferring a superior capacity for NK cells to become activated and control infection. Most noticeably, KIR(+) NK cells were rarely detected in the LN during HIV infection, associated with diminished migratory capacity in the setting of reduced expression of CX3CR1 and CXCR1. Thus, incomplete control of HIV viral replication during early disease may be due to the inefficient recruitment of KIR(+) NK cells to this vulnerable site, providing HIV a niche where it can replicate unabated by early NK-cell-mediated innate pressure. PMID:21630248

  12. 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

  13. Early steps of replication of moloney murine leukemia virus in resting lymphocytes.

    PubMed

    Pironi, L; Bouill, P; Auclair, C; Guillosson, J J; Nafziger, J

    1999-09-30

    We explored the role of cell type in the early steps of replication of Moloney murine leukemia virus (Mo-MLV) by comparing viral entry and reverse transcription in physiologically quiescent peripheral blood B and T lymphocytes. Virus entry was identical in both cell types. In contrast to previous results, full-length viral DNA was synthesized in resting B lymphocytes, but in agreement with earlier reports, reverse transcription was abortive in resting T lymphocytes. The addition of exogenous nucleosides in the culture medium of resting T lymphocytes allowed reverse transcription to proceed in these cells, without inducing cell cycling. These data suggest that the difference in the ability of quiescent T and B lymphocytes to sustain reverse transcription of Mo-MLV can be explained by a difference in the dNTP pool sizes of these two populations of quiescent cells. PMID:10502519

  14. Changes in Transcription and Metabolism During the Early Stage of Replicative Cellular Senescence in Budding Yeast*

    PubMed Central

    Kamei, Yuka; Tamada, Yoshihiro; Nakayama, Yasumune; Fukusaki, Eiichiro; Mukai, Yukio

    2014-01-01

    Age-related damage accumulates and a variety of biological activities and functions deteriorate in senescent cells. However, little is known about when cellular aging behaviors begin and what cellular aging processes change. Previous research demonstrated age-related mRNA changes in budding yeast by the 18th to 20th generation, which is the average replicative lifespan of yeast (i.e. about half of the population is dead by this time point). Here, we performed transcriptional and metabolic profiling for yeast at early stages of senescence (4th, 7th, and 11th generation), that is, for populations in which most cells are still alive. Transcriptional profiles showed up- and down-regulation for ?20% of the genes profiled after the first four generations, few further changes by the 7th generation, and an additional 12% of the genes were up- and down-regulated after 11 generations. Pathway analysis revealed that these 11th generation cells had accumulated transcripts coding for enzymes involved in sugar metabolism, the TCA cycle, and amino acid degradation and showed decreased levels of mRNAs coding for enzymes involved in amino acid biosynthetic pathways. These observations were consistent with the metabolomic profiles of aging cells: an accumulation of pyruvic acid and TCA cycle intermediates and depletion of most amino acids, especially branched-chain amino acids. Stationary phase-induced genes were highly expressed after 11 generations even though the growth medium contained adequate levels of nutrients, indicating deterioration of the nutrient sensing and/or signaling pathways by the 11th generation. These changes are presumably early indications of replicative senescence. PMID:25294875

  15. Changes in transcription and metabolism during the early stage of replicative cellular senescence in budding yeast.

    PubMed

    Kamei, Yuka; Tamada, Yoshihiro; Nakayama, Yasumune; Fukusaki, Eiichiro; Mukai, Yukio

    2014-11-14

    Age-related damage accumulates and a variety of biological activities and functions deteriorate in senescent cells. However, little is known about when cellular aging behaviors begin and what cellular aging processes change. Previous research demonstrated age-related mRNA changes in budding yeast by the 18th to 20th generation, which is the average replicative lifespan of yeast (i.e. about half of the population is dead by this time point). Here, we performed transcriptional and metabolic profiling for yeast at early stages of senescence (4th, 7th, and 11th generation), that is, for populations in which most cells are still alive. Transcriptional profiles showed up- and down-regulation for ∼20% of the genes profiled after the first four generations, few further changes by the 7th generation, and an additional 12% of the genes were up- and down-regulated after 11 generations. Pathway analysis revealed that these 11th generation cells had accumulated transcripts coding for enzymes involved in sugar metabolism, the TCA cycle, and amino acid degradation and showed decreased levels of mRNAs coding for enzymes involved in amino acid biosynthetic pathways. These observations were consistent with the metabolomic profiles of aging cells: an accumulation of pyruvic acid and TCA cycle intermediates and depletion of most amino acids, especially branched-chain amino acids. Stationary phase-induced genes were highly expressed after 11 generations even though the growth medium contained adequate levels of nutrients, indicating deterioration of the nutrient sensing and/or signaling pathways by the 11th generation. These changes are presumably early indications of replicative senescence. PMID:25294875

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

    PubMed

    Ohlberger, Jan; Langangen, ystein

    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

  17. Early immunologic events at the tick-host interface.

    PubMed

    Heinze, Dar M; Carmical, J Russ; Aronson, Judith F; Thangamani, Saravanan

    2012-01-01

    Ixodes species ticks are competent vectors of tick-borne viruses including tick-borne encephalitis and Powassan encephalitis. Tick saliva has been shown to facilitate and enhance viral infection. This likely occurs by saliva-mediated modulation of host responses into patterns favorable for viral infection and dissemination. Because of the rapid kinetics of tick-borne viral transmission, this modulation must occur as early as tick attachment and initiation of feeding. In this study, cutaneous bite-site lesions were analyzed using Affymetrix mouse genome 430A 2.0 arrays and histopathology at 1, 3, 6, and 12 hours after uninfected Ixodes scapularis nymphal tick attachment. At 1 and 3 hrs after attachment, the gene expression profile is markedly different than at later time points. Upregulated gene ontology term clusters enriched at 1 and 3 hrs were related to post-translational modification. At 6 and 12 hrs, cytoskeletal rearrangements, DNA replication/cell division, inflammation, and chemotaxis were prominent clusters. At 6 and 12 hrs, extracellular matrix, signaling, and DNA binding clusters were downregulated. Histopathological analysis shows minimal inflammation at 1 and 3 hrs but an appreciable neutrophil infiltrate at 6 and 12 hrs. In addition, putative hyperemia, localized necrosis, and increased ECM deposition were identified. Putting the gene expression and histopathology analysis together suggests early tick feeding is characterized by modulation of host responses in resident cells that merges into a nascent, neutrophil-driven immune response by 12 hrs post-attachment. PMID:23077588

  18. Characteristics of Lightning Associated with Long Recovery Early VLF Events

    NASA Astrophysics Data System (ADS)

    Kotovsky, D. A.; Moore, R. C.; Zhu, Y.; Pilkey, J. T.; Caicedo, J. A.; Hare, B.; Rakov, V. A.; Jordan, D. M.; Uman, M. A.

    2014-12-01

    A recently discovered category of long recovery, early VLF scattering events (LOREs) indicate that the quasi-electostatic and electromagnetic radiation fields from lightning discharges are capable of producing long lasting disturbances (up to tens of minutes) in the D-region of the ionosphere. Analysis of causative VLF radio atmospherics of 52 LOREs reveals that >76% exhibit detectable precursor radiation just prior to (typically within 4 msec of) the causative lightning return stroke. In contrast, such radiation is detected for <22% of 52 regular recovery early events, and <21% of 142 National Lightning Detection Network recorded discharges (peak current magnitude >50 kA, within 1500 km of the nearest receiver). By comparison with electric field measurements and lightning mapping array data, preliminary breakdown in natural, negative cloud-to-ground flashes is shown to produce VLF precursor radiation similar in most observable respects to those associated with VLF scattering events. It is thereby inferred that strong preliminary breakdown (and fast stepped leaders) are predominant features of discharges capable of producing long lasting D-region disturbances.

  19. Adenoviral early region 4 is required for efficient viral DNA replication and for late gene expression.

    PubMed Central

    Weinberg, D H; Ketner, G

    1986-01-01

    H2dl808 is a defective deletion mutant of human adenovirus 2 lacking most of transcriptional early region 4. Although the mutant can be grown in the complementing cell line W162, it is defective in human cell lines normally used to propagate adenovirus. In such nonpermissive cells, H2dl808 exhibits a severe defect in late gene expression, accumulating very small amounts of viral late messages and producing correspondingly small amounts of viral late proteins. H2dl808 also exhibits a defect in viral DNA synthesis: 24 h after infection, H2dl808-infected nonpermissive cells contain five- to sevenfold less viral DNA than those cells infected with wild-type adenovirus. H2dl808-infected nonpermissive cells eventually accumulate a significant amount of viral DNA. However, the rate of synthesis of viral proteins late in mutant infection remains much lower than that observed in wild-type infection at a time when DNA accumulation is comparable. Thus, the mutant's late protein synthesis defect is probably not due solely to its reduced accumulation of viral DNA. Finally, H2dl808 is much less efficient than wild-type virus in the inhibition of host cell protein synthesis in infections of nonpermissive cells. These observations imply roles for early region 4 products in several aspects of the viral growth cycle, including DNA replication, late gene expression, and host cell shutoff. Images PMID:3485200

  20. 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.

  1. 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

  2. Role of early signalling events in plant-insect interactions.

    PubMed

    Zebelo, Simon A; Maffei, Massimo E

    2015-02-01

    The response of plants to the stress caused by herbivores involves several different defence mechanisms. These responses begin at the plant cell plasma membrane, where insect herbivores interact physically by causing mechanical damage and chemically by introducing elicitors or by triggering plant-derived signalling molecules. The earliest plant responses to herbivore contact are represented by ion flux unbalances generated in the plant cell plasma membrane at the damaged site. Differences in the charge distribution generate plasma transmembrane potential (V m) variation, the first event, which eventually leads to the initiation of signal transduction pathways and gene expression. Calcium signalling and the generation of reactive oxygen and nitrogen species are early events closely related to V m variations. This review provides an update on recent developments and advances in plant early signalling in response to herbivory, with particular emphasis on the electrophysiological variations of the plasma membrane potential, calcium signalling, cation channel activity, production of reactive oxygen and nitrogen species, and formation of a systemically moving signal from wounded tissues. The roles of calcium-dependent protein kinases and calcineurin signalling are also discussed. PMID:25429000

  3. Pentacyclic triterpenes in birch bark extract inhibit early step of herpes simplex virus type 1 replication.

    PubMed

    Heidary Navid, M; Laszczyk-Lauer, M N; Reichling, J; Schnitzler, P

    2014-09-25

    Antiviral agents frequently applied for treatment of herpesvirus infections include acyclovir and its derivatives. The antiviral effect of a triterpene extract of birch bark and its major pentacyclic triterpenes, i.e. betulin, lupeol and betulinic acid against acyclovir-sensitive and acyclovir-resistant HSV type 1 strains was examined. The cytotoxic effect of a phytochemically defined birch bark triterpene extract (TE) as well as different pentacyclic triterpenes was analyzed in cell culture, and revealed a moderate cytotoxicity on RC-37 cells. TE, betulin, lupeol and betulinic acid exhibited high levels of antiviral activity against HSV-1 in viral suspension tests with IC50 values ranging between 0.2 and 0.5 ?g/ml. Infectivity of acyclovir-sensitive and clinical isolates of acyclovir-resistant HSV-1 strains was significantly reduced by all tested compounds and a direct concentration- and time-dependent antiherpetic activity could be demonstrated. In order to determine the mode of antiviral action, TE and the compounds were added at different times during the viral infection cycle. Addition of these drugs to uninfected cells prior to infection or to herpesvirus-infected cells during intracellular replication had low effect on virus multiplication. Minor virucidal activity of triterpenes was observed, however both TE and tested compounds exhibited high anti-herpetic activity when viruses were pretreated with these drugs prior to infection. Pentacyclic triterpenes inhibit acyclovir-sensitive and acyclovir-resistant clinical isolates of HSV-1 in the early phase of infection. PMID:25172789

  4. 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.

  5. 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

  6. Replication RCT of Early Universal Prevention Effects on Young Adult Substance Misuse

    PubMed Central

    Spoth, Richard; Trudeau, Linda; Redmond, Cleve; Shin, Chungyeol

    2014-01-01

    Objective For many substances, more frequent and problematic use occurs in young adulthood; these types of use are predicted by the timing of initiation during adolescence. We replicated and extended an earlier study examining whether delayed substance initiation during adolescence, resulting from universal preventive interventions implemented in middle school, reduces problematic use in young adulthood. Method Participants were middle school students from 36 Iowa schools randomly assigned to the Strengthening Families Program plus Life Skills Training (SFP 10–14 + LST), LST-only, or a control condition. Self-report questionnaires were collected at 11 time points, including four during young adulthood. The intercept (average level) and rate of change (slope) in young adult frequency measures (drunkenness, alcohol-related problems, cigarettes, and illicit drugs) across ages 19–22 were modeled as outcomes influenced by growth factors describing substance initiation during adolescence. Analyses entailed testing a two-step hierarchical latent growth curve model; models included the effects of baseline risk, intervention condition assignment, and their interaction. Results Analyses showed significant indirect intervention effects on the average levels of all young adult outcomes, through effects on adolescent substance initiation growth factors, along with intervention by risk interaction effects favoring the higher-risk subsample. Additional direct effects on young adult use were observed in some cases. Relative reduction rates were larger for the higher-risk subsample at age 22, ranging from 5.8% to 36.4% on outcomes showing significant intervention effects. Conclusions Universal preventive interventions implemented during early adolescence have the potential to decrease the rates of substance use and associated problems, into young adulthood. PMID:24821095

  7. Classifying onset durations of early VLF events: Scattered field analysis and new insights

    NASA Astrophysics Data System (ADS)

    Kotovsky, D. A.; Moore, R. C.

    2015-08-01

    The physical processes responsible for a variety of early VLF scattering events have not yet been satisfactorily identified. Properly categorizing the early VLF event type is imperative to understand the causative physical processes involved. In this paper, the onset durations of 26 exceptionally high signal-to-noise ratio early VLF scattering events are analyzed, using scattered fields to classify events. New observations of events that exhibit "slow" amplitude changes, but "fast" scattered field changes are presented, which call into question previous analyses of early/slow events. We separately identify and analyze three early VLF events that definitively exhibit slow scattered field behavior. Additionally, we identify a significant number of events which have onset durations between the current definitions of fast and slow. Four events are observed which unambiguously exhibit a rapid initial rotation of the scattered field phasor during the first few seconds of the recovery stage. Possible physical mechanisms are discussed.

  8. 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

  9. 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

  10. Importance of bacterial replication and alveolar macrophage-independent clearance mechanisms during early lung infection with Streptococcus pneumoniae.

    PubMed

    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; Brown, Jeremy S

    2015-03-01

    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

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

    PubMed Central

    Camberlein, Emilie; Cohen, Jonathan M.; Jos, 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

  12. RNA Interference-Mediated Targeting of Human Cytomegalovirus Immediate-Early or Early Gene Products Inhibits Viral Replication with Differential Effects on Cellular Functions

    PubMed Central

    E, Xiaofei; Stadler, Bradford M.; Debatis, Michelle; Wang, Shixia; Lu, Shan

    2012-01-01

    Viral drug toxicity, resistance, and an increasing immunosuppressed population warrant continued research into new avenues for limiting diseases associated with human cytomegalovirus (HCMV). In this study, a small interfering RNA (siRNA), siX3, was designed to target coding sequences within shared exon 3 of UL123 and UL122 transcripts encoding IE1 and IE2 immediate-early proteins of HCMV. Pretreatment of cells with siX3 reduced the levels of viral protein expression, DNA replication, and progeny virus production compared to control siRNA. Two siRNAs against UL54 and overlapping transcripts (UL55-57) were compared to siX3 in HCMV infection and were also found to be effective at inhibiting HCMV replication. Further investigation into the effects of the siRNAs on viral replication showed that pretreatment with each of the siRNAs resulted in an inhibition in the formation of mature replication compartments. The ability of these siRNAs to prevent or reduce certain cytopathic effects associated with HCMV infection was also examined. Infected cells pretreated with siX3, but not siUL54, retained promyelocytic leukemia (PML) protein in cellular PML bodies, an essential component of this host intrinsic antiviral defense. DNA damage response proteins, which are localized in nuclear viral replication compartments, were reduced in the siX3- and siUL54-treated cells. siX3, but not siUL54, prevented DNA damage response signaling early after infection. Therapeutic efficacy was demonstrated by treating cells with siRNAs after HCMV replication had commenced. Together, these findings suggest that siRNAs targeting exon 3 of the major IE genes or the UL54-57 transcripts be further studied for their potential development into anti-HCMV therapeutics. PMID:22438545

  13. RNA interference-mediated targeting of human cytomegalovirus immediate-early or early gene products inhibits viral replication with differential effects on cellular functions.

    PubMed

    Xiaofei, E; Stadler, Bradford M; Debatis, Michelle; Wang, Shixia; Lu, Shan; Kowalik, Timothy F

    2012-05-01

    Viral drug toxicity, resistance, and an increasing immunosuppressed population warrant continued research into new avenues for limiting diseases associated with human cytomegalovirus (HCMV). In this study, a small interfering RNA (siRNA), siX3, was designed to target coding sequences within shared exon 3 of UL123 and UL122 transcripts encoding IE1 and IE2 immediate-early proteins of HCMV. Pretreatment of cells with siX3 reduced the levels of viral protein expression, DNA replication, and progeny virus production compared to control siRNA. Two siRNAs against UL54 and overlapping transcripts (UL55-57) were compared to siX3 in HCMV infection and were also found to be effective at inhibiting HCMV replication. Further investigation into the effects of the siRNAs on viral replication showed that pretreatment with each of the siRNAs resulted in an inhibition in the formation of mature replication compartments. The ability of these siRNAs to prevent or reduce certain cytopathic effects associated with HCMV infection was also examined. Infected cells pretreated with siX3, but not siUL54, retained promyelocytic leukemia (PML) protein in cellular PML bodies, an essential component of this host intrinsic antiviral defense. DNA damage response proteins, which are localized in nuclear viral replication compartments, were reduced in the siX3- and siUL54-treated cells. siX3, but not siUL54, prevented DNA damage response signaling early after infection. Therapeutic efficacy was demonstrated by treating cells with siRNAs after HCMV replication had commenced. Together, these findings suggest that siRNAs targeting exon 3 of the major IE genes or the UL54-57 transcripts be further studied for their potential development into anti-HCMV therapeutics. PMID:22438545

  14. Modulation of early cellular events in wound healing in mice.

    PubMed

    Kenyon, A J; Michaels, E B

    1983-02-01

    Wound healing experiments were conducted in random-bred Swiss mice to determine the effect on antimicrobial surfactants and macrophage stimulators on wound measurements, histologic repair, and wound breaking strengths. In selection of mice, Sendai virus antibody-positive mice healed more slowly than did mice with no detectable titer to Sendai virus. Studies were conducted with Sendai virus-free mice that had C31G (an antimicrobial surfactant), alkyl amine oxide, zymosan, glucan, or phosphate-buffered isotonic saline solution instilled into full-thickness incised wounds. The early events in the repair process indicated a greater degree of inflammatory response comprised mainly of polymorphonuclear leukocytes with subsequent large numbers of monocytes in C31G and alkyl amine oxide-treated wounds. Although zymosan did not induce as large a number of monocytes, the degree of fibroplasia was as great as in wounds in which numbers were higher. The effect of zymosan could be blocked by the addition of N-alpha-p-tosyl-L-lysine chloromethyl ketone to wounds. Wound breaking strength 3 days after surgery was greatest for glucan-treated mice (134 +/- 37 g) whereas that in C31G-treated mice (77 +/- 31 g) was less than that of the controls (92 +/- 37 g). By day 7, there was no significant difference in breaking strength between control and glucan-treated wounds; however, C31G-treated wounds remained substantially weaker than control wounds. PMID:6299147

  15. Sigma-1 receptor regulates early steps of viral RNA replication at the onset of hepatitis C virus infection.

    PubMed

    Friesland, Martina; Mingorance, Lidia; Chung, Josan; Chisari, Francis V; Gastaminza, Pablo

    2013-06-01

    Hepatitis C virus (HCV) genome replication is thought to occur in a membranous cellular compartment derived from the endoplasmic reticulum (ER). The molecular mechanisms by which these membrane-associated replication complexes are formed during HCV infection are only starting to be unraveled, and both viral and cellular factors contribute to their formation. In this study, we describe the discovery of nonopioid sigma-1 receptor (S1R) as a cellular factor that mediates the early steps of viral RNA replication. S1R is a cholesterol-binding protein that resides in lipid-rich areas of the ER and in mitochondrion-associated ER membranes (MAMs). Several functions have been ascribed to this ER-resident chaperone, many of which are related to Ca(2+) signaling at the MAMs and lipid storage and trafficking. Downregulation of S1R expression by RNA interference (RNAi) in Huh-7 cells leads to a proportional decrease in susceptibility to HCV infection, as shown by reduced HCV RNA accumulation and intra- and extracellular infectivity in single-cycle infection experiments. Similar RNAi studies in persistently infected cells indicate that S1R expression is not rate limiting for persistent HCV RNA replication, as marked reduction in S1R in these cells does not lead to any decrease in HCV RNA or viral protein expression. However, subgenomic replicon transfection experiments indicate that S1R expression is rate limiting for HCV RNA replication without impairing primary translation. Overall, our data indicate that the initial steps of HCV infection are regulated by S1R, a key component of MAMs, suggesting that these structures could serve as platforms for initial RNA replication during HCV infection. PMID:23536676

  16. Replication of proto-oncogenes early during the S phase in mammalian cell lines.

    PubMed Central

    Iqbal, M A; Chinsky, J; Didamo, V; Schildkraut, C L

    1987-01-01

    Members of several classes of proto-oncogenes replicate during the first third of S-phase in two human (K562 erythroleukemia and HeLa), one Chinese hamster (CHO) and eight mouse cell lines. These cell lines exhibit a variety of specialized functions characteristic of pre-B and B cells, T cells and erythroid cells. The proto-oncogenes studied include fos, myc, myb, abl, fes, fms, mos, raf, rel, sis, Ha-ras, Ki-ras, and N-ras. In K562 cells, amplified and rearranged c-abl genes show a pattern of temporal replication during S that is similar to the pattern observed for the 5' breakpoint cluster region (bcr) and the amplified C lambda light chain immunoglobulin genes. The c-Ki-ras related sequences in CHO cells provide one example of late replicating proto-oncogene sequences that are present in multiple copies. The cellular gene N-myc replicates late during S in some of these cell lines. In three pre-B cell lines in which N-myc specific transcripts have been detected, N-myc replicates earlier in the S phase than in the other cell lines studied here. Images PMID:3469620

  17. 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 20years ago (S. Yamada and M. Shimizu, Virology 199:366375, 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

  18. 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

  19. Baculovirus resistance in codling moth (Cydia pomonella L.) caused by early block of virus replication.

    PubMed

    Asser-Kaiser, Sabine; Radtke, Pit; El-Salamouny, Said; Winstanley, Doreen; Jehle, Johannes A

    2011-02-20

    An up to 10,000-fold resistance against the biocontrol agent Cydia pomonella granulovirus (CpGV) was observed in field populations of codling moth, C. pomonella, in Europe. Following different experimental approaches, a modified peritrophic membrane, a modified midgut receptor, or a change of the innate immune response could be excluded as possible resistance mechanisms. When CpGV replication was traced by quantitative PCR in different tissues of susceptible and resistant insects after oral and intra-hemocoelic infection, no virus replication could be detected in any of the tissues of resistant insects, suggesting a systemic block prior to viral DNA replication. This conclusion was corroborated by fluorescence microscopy using a modified CpGV (bacCpGV(hsp-eGFP)) carrying enhanced green fluorescent gene (eGFP), which showed that infection in resistant insects did not spread. In conclusion, the different lines of evidence indicate that CpGV can enter but not replicate in the cells of resistant codling moth larvae. PMID:21190707

  20. 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

  1. 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…

  2. Early trafficking and intracellular replication of Legionella longbeachaea within an ER-derived late endosome-like phagosome.

    PubMed

    Asare, Rexford; Abu Kwaik, Yousef

    2007-06-01

    Legionella pneumophila is the predominant cause of Legionnaires' disease in the USA and Europe in contrast to Legionella longbeachaea, which is the leading cause of the disease in Western Australia. The ability of L. pneumophila to replicate intracellularly is triggered at the post-exponential phase along with expression of other virulence traits, such as motility. We show that while motility of L. longbeachaea is triggered upon growth transition into post-exponential phase, its ability to proliferate intracellularly is totally independent of the bacterial growth phase. Within macrophages, L. pneumophila replicates in a phagosome that excludes early and late endocytic markers and is surrounded by the rough endoplasmic reticulum (RER). In contrast, the L. longbeachaea phagosome colocalizes with the early endosomal marker early endosomal antigen 1 (EEA1) and the late endosomal markers lysosomal associated membrane glycoprotein 2 (LAMP-2) and mannose 6-phosphate receptor (M6PR), and is surrounded by the RER. The L. longbeachaea phagosome does not colocalize with the vacuolar ATPase (vATPase) proton pump, and the lysosomal luminal protease Cathepsin D, or the lysosomal tracer Texas red Ovalbumin (TROV). Intracellular proliferation of L. longbeachaea occurs in LAMP-2-positive phagosomes that are remodelled by the RER. Despite their distinct trafficking, both L. longbeachaea and L. pneumophila can replicate in communal phagosomes whose biogenesis is predominantly modulated by L. longbeachaea into LAMP-2-positive phagosomes. In addition, the L. pneumophila dotA mutant is rescued for intracellular replication if it co-inhabits the phagosome with L. longbeachaea. During late stages of infection, L. longbeachaea escape into the cytoplasm, prior to lysis of the macrophage, similar to L. pneumophila. We conclude that the L. longbeachaea phagosome matures to a non-acidified late endosome-like stage that is remodelled by the RER, indicating an idiosyncratic trafficking of L. longbeachaea compared with other intracellular pathogens, and a divergence in its intracellular lifestyle from L. pneumophila. In addition, re-routing biogenesis of the L. pneumophila phagosome into a late endosome controlled by L. longbeachaea has no effect on intracellular replication. PMID:17309675

  3. Replication stress in early S phase generates apparent micronuclei and chromosome rearrangement in fission yeast

    PubMed Central

    Sabatinos, Sarah A.; Ranatunga, Nimna S.; Yuan, Ji-Ping; Green, Marc D.; Forsburg, Susan L.

    2015-01-01

    DNA replication stress causes genome mutations, rearrangements, and chromosome missegregation, which are implicated in cancer. We analyze a fission yeast mutant that is unable to complete S phase due to a defective subunit of the MCM helicase. Despite underreplicated and damaged DNA, these cells evade the G2 damage checkpoint to form ultrafine bridges, fragmented centromeres, and uneven chromosome segregations that resembles micronuclei. These micronuclei retain DNA damage markers and frequently rejoin with the parent nucleus. Surviving cells show an increased rate of mutation and chromosome rearrangement. This first report of micronucleus-like segregation in a yeast replication mutant establishes underreplication as an important factor contributing to checkpoint escape, abnormal chromosome segregation, and chromosome instability. PMID:26246602

  4. 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

  5. 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 ɛHf(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 ɛHf(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.

  6. 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.

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

    NASA Astrophysics Data System (ADS)

    Weber, Arthur L.

    1989-03-01

    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.

  8. Early Responsivity to Moral Events: Physiological and Behavioral Correlates?

    ERIC Educational Resources Information Center

    Lamb, Sharon; And Others

    This study investigated toddlers' reactions to morally related events to determine whether age was a factor in emotional reaction, whether the middle of the second year was a salient time for the emergence of emotional reactions to such events, and whether heart rate change could be used as a new measure of moral responsivity. While their heart

  9. Early events in hepatitis B virus infection: From the cell surface to the nucleus.

    PubMed

    Hayes, C Nelson; Zhang, Yizhou; Makokha, Grace Naswa; Hasan, Md Zobaer; Omokoko, Magot D; Chayama, Kazuaki

    2016-02-01

    While most adults are able to clear acute hepatitis B virus (HBV) infection, chronic HBV infection is recalcitrant to current therapy because of the persistence of covalently closed circular DNA in the nucleus. Complete clearance of the virus in these patients is rare, and long-term therapy with interferon and/or nucleoside analogues may be required in an attempt to suppress viral replication and prevent progressive liver damage. The difficulty of establishing HBV infection in cell culture and experimental organisms has hindered efforts to elucidate details of the HBV life cycle, but it has also revealed the importance of the cellular microenvironment required for HBV binding and entry. Recent studies have demonstrated an essential role of sodium-taurocholate cotransporting polypeptide as a functional receptor in HBV infection, which has facilitated the development of novel infection systems and opened the way for more detailed understanding of the early steps of HBV infection as well as a potential new therapeutic target. However, many gaps remain in understanding of how HBV recognizes and attaches to hepatocytes prior to binding to sodium-taurocholate cotransporting polypeptide, as well as events that are triggered after binding, including entry into the cell, intracellular transport, and passage through the nuclear pore complex. This review summarizes current knowledge of the initial stages of HBV infection leading to the establishment of covalently closed circular DNA in the nucleus. PMID:26414381

  10. 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

  11. Effect of Exposure to UV-C Irradiation and Monochloramine on Adenovirus Serotype 2 Early Protein Expression and DNA Replication?

    PubMed Central

    Sirikanchana, Kwanrawee; Shisler, Joanna L.; Marias, Benito J.

    2008-01-01

    The mechanisms of adenovirus serotype 2 inactivation with either UV light (with a narrow emission spectrum centered at 254 nm) or monochloramine were investigated by assessing the potential inhibition of two key steps of the adenovirus life cycle, namely, E1A protein synthesis and viral genomic replication. E1A early protein synthesis was assayed by using immunoblotting, while the replication of viral DNA was analyzed by using slot blotting. Disinfection experiments were performed in phosphate buffer solutions at pH 8 and room temperature (UV) or 20C (monochloramine). Experimental results revealed that normalized E1A levels at 12 h postinfection (p.i.) were statistically the same as the corresponding decrease in survival ratio for both UV and monochloramine disinfection. Normalized DNA levels at 24 h p.i. were also found to be statistically the same as the corresponding decrease in survival ratio for monochloramine disinfection. In contrast, for UV disinfection, genomic DNA levels were much lower than E1A or survival ratios, possibly as a result of a delay in DNA replication for UV-treated virions compared to that for controls. Future efforts will determine the pre-E1A synthesis step in the adenovirus life cycle affected by exposure to UV and monochloramine, with the goal of identifying the viral molecular target of these two disinfectants. PMID:18424543

  12. Early Events in Cell Spreading as a Model for Quantitative Analysis of Biomechanical Events

    PubMed Central

    Wolfenson, Haguy; Iskratsch, Thomas; Sheetz, MichaelP.

    2014-01-01

    In this review, we focus on the early events in the process of fibroblast spreading on fibronectin matrices of different rigidities. We present a focused position piece that illustrates the many different tests that a cell makes of its environment before it establishes mature matrix adhesions. When a fibroblast is placed on fibronectin-coated glass surfaces at 37C, it typically spreads and polarizes within 20-40min primarily through ?v?3 integrin binding to fibronectin. In that short period, the cell goes through three major phases that involve binding, integrin activation, spreading, and mechanical testing of the surface. The advantage of using the model system of cell spreading from the unattached state is that it is highly reproducible and the stages that the cell undergoes can thus be studied in a highly quantitative manner, in both space and time. The mechanical and biochemical parameters that matter in this example are often surprising because of both the large number of tests that occur and the precision of the tests. We discuss our current understanding of those tests, the decision tree that is involved in this process, and an extension to the behavior of the cells at longer time periods when mature adhesions develop. Because many other matrices and integrins are involved in cell-matrix adhesion, this model system gives us a limited view of a subset of cellular behaviors that can occur. However, by defining one cellular process at a molecular level, we know more of what to expect when defining other processes. Because each cellular process will involve some different proteins, a molecular understanding of multiple functions operating within a given cell can lead to strategies to selectively block a function. PMID:25468330

  13. 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…

  14. 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...

  15. Prolidase Is Required for Early Trafficking Events during Influenza A Virus Entry

    PubMed Central

    Pohl, Marie O.; Edinger, Thomas O.

    2014-01-01

    ABSTRACT Influenza A virus (IAV) entry is a multistep process that requires the interaction of the virus with numerous host factors. In this study, we demonstrate that prolidase (PEPD) is a cellular factor required by IAV for successful entry into target cells. PEPD was selected as a candidate during an entry screen performed on nonvalidated primary hits from previously published genome-wide small interfering RNA (siRNA) screens. siRNA-mediated depletion of PEPD resulted in the decreased growth of IAV during mono- and multicycle growth. This growth defect was independent of cell type or virus strain. Furthermore, IAV restriction was apparent as early as 3 h postinfection, and experiments in the absence of protein biosynthesis revealed that the nuclear import of viral ribonucleoprotein complexes (vRNPs) was already blocked in the absence of PEPD. These results led us to investigate which step during entry was affected. Receptor expression, IAV attachment, or IAV internalization was not dependent on the presence of PEPD. However, when looking at the distribution of incoming IAV particles in PEPD-knockdown cells, we found a localization pattern that differed from that in control cells: IAV mostly localized to the cell periphery, and consequently, viral particles displayed reduced colocalization with early and late endosome markers and fusion between viral and endosomal membranes was strongly reduced. Finally, experiments using a competitive inhibitor of PEPD catalytic activity suggested that the enzymatic function of the dipeptidase is required for its proviral effect on IAV entry. In sum, this study establishes PEPD as a novel entry factor required for early endosomal trafficking of IAV. IMPORTANCE Influenza A virus (IAV) continues to be a constant threat to public health. As IAV relies on its host cell for replication, the identification of host factors required by the virus is of importance. First, such studies often reveal novel functions of cellular factors and can extend our knowledge of cellular processes. Second, we can further our understanding of processes that are required for the entry of IAV into target cells. Third, the identification of host factors that contribute to IAV entry will increase the number of potential targets for the development of novel antiviral drugs that are of urgent need. Our study identifies prolidase (PEPD) to be a novel entry factor required by IAV for correct routing within the endosomal compartment following virus internalization. Thereby, we link PEPD, which has been shown to play a role during collagen recycling and growth factor signaling, to early events of viral infection. PMID:25031340

  16. Aneuploidy as an Early Mechanistic Event in Metal Carcinogenesis

    PubMed Central

    Wise, Sandra S.; Wise, John Pierce

    2014-01-01

    Aneuploidy has recently been proposed as an initiating event for carcinogenesis. There is significant evidence that carcinogenic metals induce aneuploidy. Here we review the mechanisms for how carcinogenic metals may induce aneuploidy and the evidence that carcinogenic metals induce an aneugenic effect which can destabilize the genome leading to genomic instability and cancer. PMID:21118142

  17. 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...

  18. Effects of Early or Overexpression of the Autographa californica Multiple Nucleopolyhedrovirus orf94 (ODV-e25) on Virus Replication

    PubMed Central

    Luo, Xiao-Chun; Wang, Shan-Shan; Zhang, Jie; Qian, Duo-Duo; Wang, Si-Min; Li, Lu-Lin

    2013-01-01

    odv-e25(e25) is one of the core genes of baculoviruses. To investigate how it functions in the replication cycle of a baculovirus, a number of Autographa californica multiple nucleopolyhedrovirus recombinants with e25 under control of the promoter of immediate early gene ie1, or the promoter of the very late hyperexpressed gene p10, were constructed using a bacmid system, and the effects of early expression or overexpression of e25 on replication of the virus were evaluated. Microscopy and titration assays demonstrated that bacmids with e25 under control of ie1 promoter were unable to produce budded viruses; and that the recombinant viruses with e25 under control of p10 promoter generated budded virus normally, but formation of occlusion bodies were dramatically reduced and delayed in the infected cells. Electron microscopy showed that there were no mature virions or intact nucleocapsids present in the cells transfected with a recombinant bacmid with e25 under control of ie1 promoter. Quantitative real-time PCR analysis demonstrated that alteration of the e25 promoter did not affect viral DNA synthesis. The reporter gene expression from the promoter of the major capsid protein gene vp39 was reduced 63% by early expression of e25. Confocal microscopy revealed that E25 was predominantly localized in nuclei by 24 hours post infection with wild-type virus, but it remained in the cytoplasm in the cells transfected with a recombinant bacmid with e25 under control of the ie1 promoter, suggesting that the transport of E25 into nuclei was regulated in a specific and strict time dependent manner. PMID:23825525

  19. Opportunity, Community, and Early Adolescent Pregnancy: A Replication of Research with Older Teenaged Girls.

    ERIC Educational Resources Information Center

    Bickel, Robert; McDonough, Meghan; Williams, Tony

    1999-01-01

    Attempts to broaden the analytic categories for understanding early-adolescent pregnancy, suggesting an antidote to the methodological individualism that emphasizes individual and family characteristics by using broader contextual factors. Seemingly imprudent behaviors can be rendered interpretably rational when placed in social context. Without

  20. Early Events in the Pathogenesis of Avian Salmonellosis

    PubMed Central

    Henderson, S. Christine; Bounous, Denise I.; Lee, Margie D.

    1999-01-01

    Salmonellae are gastrointestinal pathogens of man and animals. However, strains that are host-specific avian pathogens are often avirulent in mammals, and those which are nonspecific are commensal in poultry. The objective of this study was to determine whether host specificity was exhibited by bacterial abilities to invade epithelial cells or resist leukocyte killing. In this study, leukocytes isolated from humans and chickens were used to kill Salmonella in vitro. Both Salmonella pullorum, an avian-specific serotype, and Salmonella typhimurium, a broad-host-range serotype, were sensitive to killing by polymorphonuclear leukocytes isolated from both species. Both serotypes replicated in cells of the MQ-NCSU avian-macrophage cell line. In contrast, S. pullorum was noninvasive for cultured epithelial Henle 407, chick kidney, chick ovary, and budgerigar abdominal tumor cells. In the bird challenge, however, S. typhimurium rapidly caused inflammation of the intestinal mucosa, but S. pullorum preferentially targeted the bursa of Fabricius prior to eliciting intestinal inflammation. Salmonella serotypes which cause typhoid fever in mice have been shown to target the gut-associated lymphoid tissue. Observations from this study show that S. pullorum initiated a route of infection in chicks comparable to the route it takes in cases of enteric fever. PMID:10377142

  1. Temperature variability and early clustering of record-breaking events

    NASA Astrophysics Data System (ADS)

    Anderson, Amalia; Kostinski, Alex

    2015-04-01

    As the number of climatological studies using record-breaking statistics is growing rapidly, understanding the sensitivity of the chosen time period becomes essential. To that end, here we examine the evolving variability of monthly mean temperatures and its dependence on beginning and final year. Specifically, we use an index, ?, based on record-breaking statistics and employing reversibility such that =0 indicates no trend in variability. Generally, has decreased between 1900 and 2013, indicating decreasing variability relative to early decades for stations from the contiguous USA (United States Historical Climatology Network, version 2.5). We find, somewhat surprisingly, that the observed decrease is due to an early excess of records beginning in 1917 (record low value) and 1921 (record high value). While detailed results depend on whether the data is gridded, detrended, etc., the general finding appears remarkably robust and holds globally as well.

  2. The Structure of The Extended Psychosis Phenotype in Early Adolescence—A Cross-sample Replication

    PubMed Central

    Wigman, Johanna T. W.; Vollebergh, Wilma A. M.; Raaijmakers, Quinten A. W.; Iedema, Jurjen; van Dorsselaer, Saskia; Ormel, Johan; Verhulst, Frank C.; van Os, Jim

    2011-01-01

    The extended psychosis phenotype, or the expression of nonclinical positive psychotic experiences, is already prevalent in adolescence and has a dose-response risk relationship with later psychotic disorder. In 2 large adolescent general population samples (n = 5422 and n = 2230), prevalence and structure of the extended psychosis phenotype was investigated. Positive psychotic experiences, broadly defined, were reported by the majority of adolescents. Exploratory analysis with Structural Equation Modelling (Exploratory Factor Analysis followed by Confirmatory Factor Analysis [CFA]) in sample 1 suggested that psychotic experiences were best represented by 5 underlying dimensions; CFA in sample 2 provided a replication of this model. Dimensions were labeled Hallucinations, Delusions, Paranoia, Grandiosity, and Paranormal beliefs. Prevalences differed strongly, Hallucinations having the lowest and Paranoia having the highest rates. Girls reported more experiences on all dimensions, except Grandiosity, and from age 12 to 16 years rates increased. Hallucinations, Delusions, and Paranoia, but not Grandiosity and Paranormal beliefs, were associated with distress and general measures of psychopathology. Thus, only some of the dimensions of the extended psychosis phenotype in young people may represent a continuum with more severe psychopathology and predict later psychiatric disorder. PMID:20044595

  3. The structure of the extended psychosis phenotype in early adolescence--a cross-sample replication.

    PubMed

    Wigman, Johanna T W; Vollebergh, Wilma A M; Raaijmakers, Quinten A W; Iedema, Jurjen; van Dorsselaer, Saskia; Ormel, Johan; Verhulst, Frank C; van Os, Jim

    2011-07-01

    The extended psychosis phenotype, or the expression of nonclinical positive psychotic experiences, is already prevalent in adolescence and has a dose-response risk relationship with later psychotic disorder. In 2 large adolescent general population samples (n = 5422 and n = 2230), prevalence and structure of the extended psychosis phenotype was investigated. Positive psychotic experiences, broadly defined, were reported by the majority of adolescents. Exploratory analysis with Structural Equation Modelling (Exploratory Factor Analysis followed by Confirmatory Factor Analysis [CFA]) in sample 1 suggested that psychotic experiences were best represented by 5 underlying dimensions; CFA in sample 2 provided a replication of this model. Dimensions were labeled Hallucinations, Delusions, Paranoia, Grandiosity, and Paranormal beliefs. Prevalences differed strongly, Hallucinations having the lowest and Paranoia having the highest rates. Girls reported more experiences on all dimensions, except Grandiosity, and from age 12 to 16 years rates increased. Hallucinations, Delusions, and Paranoia, but not Grandiosity and Paranormal beliefs, were associated with distress and general measures of psychopathology. Thus, only some of the dimensions of the extended psychosis phenotype in young people may represent a continuum with more severe psychopathology and predict later psychiatric disorder. PMID:20044595

  4. Early Events During Neoplastic Progression in Barrett’s Esophagus

    PubMed Central

    Reid, Brian J.

    2014-01-01

    SUMMARY Advances in genomic analysis and sequencing, transcriptomics and proteomics are rapidly increasing our understanding of the complexity, redundancies and heterogeneity among cancers. Challenges to risk stratification, prevention and early detection will become great if, as expected, EA has similar complexity compared to other cancers. Discovery of very large possible combinations of biomarkers for BE risk assessment for progression to EA may overwhelm the translational research process for biomarker validation. One approach for risk stratification and early detection would be to search for fundamental biomarkers of progression, such as mutation rate, generation of diversity and clonal expansions. However, our previous studies and others have reported that low density STR biomarkers combined with DNA content flow cytometry could stratify patients into clinically relevant risk groups to manage the cancer risk for five years into the future reasonably well.117 With new SNP based technology and larger cohort studies with greater sample sizes, there is promise to achieve better biomarkers for EA risk stratification and early detection for clinical use because genome-wide measures of chromosome instability and 17pLOH have shown promise in all prospective studies. Such a platform could be readily adapted to risk stratification and evolutionary biomarkers of progression, including measures of clonal diversity and expansions. PMID:22112482

  5. Early dissociation of nuclear factor I from the origin during initiation of adenovirus DNA replication studied by origin immobilization.

    PubMed Central

    Coenjaerts, F E; van der Vliet, P C

    1994-01-01

    The DNA-binding domain of Nuclear Factor I (NFIBD) enhances initiation of adenovirus DNA replication up to 50-fold by binding to the auxiliary region of the origin and positioning the viral DNA polymerase. To study if and when NFIBD dissociates from the template, we immobilized origin DNA to glutathione-agarose beads by means of a GST-NFIBD fusion protein. This immobilized template is active in replication. By analyzing the release of prelabeled templates from the beads under different conditions, we show that NFIBD dissociates already early during initiation. During preinitiation NFIBD remains bound, but as soon as dCTP, dATP or dTTP are added, efficient dissociation occurs. A much lower dissociation level was induced by addition of dGTP. Since dCTP, dATP and dTTP are required for formation of a pTP-CAT initiation intermediate, we explain our results by conformational changes occurring in the polymerase during initiation leading to disruption of both the interaction between the polymerase and NFI as well as the interaction between NFI and the DNA. Images PMID:7816611

  6. 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

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

    PubMed Central

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

    2015-01-01

    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

  8. Marek's disease virus influences the core gut microbiome of the chicken during the early and late phases of viral replication.

    PubMed

    Perumbakkam, Sudeep; Hunt, Henry D; Cheng, Hans H

    2014-10-01

    Marek's disease (MD) is an important neoplastic disease of chickens caused by the Marek's disease virus (MDV), an oncogenic alphaherpesvirus. In this study, dysbiosis induced by MDV on the core gut flora of chicken was assessed using next generation sequence (NGS) analysis. Total fecal and cecum-derived samples from individual birds were used to estimate the influence of MDV infection on the gut microbiome of chicken. Our analysis shows that MDV infection alters the core gut flora in the total fecal samples relatively early after infection (2-7 days) and in the late phase of viral infection (28-35 days) in cecal samples, corresponding well with the life cycle of MDV. Principle component analyses of total fecal and cecal samples showed clustering at the early and late time points, respectively. The genus Lactobacillus was exclusively present in the infected samples in both total fecal and cecal bird samples. The community colonization of core gut flora was altered by viral infection, which manifested in the enrichment of several genera during the early and late phases of MDV replication. The results suggest a relationship between viral infection and microbial composition of the intestinal tract that may influence inflammation and immunosuppression of T and B cells in the host. PMID:25065611

  9. Genetic moderation of stability in attachment security from early childhood to age 18 years: A replication study.

    PubMed

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

    2015-11-01

    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 receptor (OXTR) genetic variants. Using longitudinal data from over 550 individuals, there was no evidence that OXTR rs53576 moderated the association between attachment security during early childhood and overall coherence of mind ("security") during the Adult Attachment Interview at age 18 years. Additional analyses involving a second commonly investigated OXTR variant (rs2254298) and indices of individuals' dismissing and preoccupied attachment states of mind also failed to provide robust evidence for oxytonergic moderation of the stability in attachment security across development. The discussion focuses on research strategies for investigating genetic contributions to attachment security across the life span. PMID:26389606

  10. Early molecular events in the induction phase of contact sensitivity.

    PubMed Central

    Enk, A H; Katz, S I

    1992-01-01

    To assess changes in epidermis-derived cytokine mRNA levels early in the afferent phase of allergic contact sensitivity, total epidermal mRNA was analyzed at various times after painting skin with haptens. We used a sensitive reverse transcriptase-polymerase chain reaction technique to quantitatively compare the regulation patterns of the following mRNAs: class II major histocompatibility complex I-A alpha, tumor necrosis factor alpha (TNF-alpha), interleukin (IL) 1 alpha, IL-1 beta, interferon (IFN) gamma, granulocyte/macrophage colony-stimulating factor, IFN-induced protein 10, and macrophage inflammatory protein 2. Enhanced Langerhans cell-derived IL-1 beta mRNA signals were detected as early as 15 min after skin painting with allergens. TNF-alpha, IFN-gamma, and granulocyte/macrophage colony-stimulating factor mRNAs were found to be upregulated after application of allergens, irritant, and tolerogens, but class II major histocompatibility complex I-A alpha, IL-1 alpha, IL-1 beta, IFN-induced protein 10, and macrophage inflammatory protein 2 mRNAs were upregulated only after allergen painting. Depletion of specific cell populations demonstrated that Langerhans cells were the primary source of the IL-1 beta and class II major histocompatibility complex I-A alpha mRNAs, keratinocytes were the primary source of TNF-alpha, IL-1 alpha, IFN-induced protein 10, and macrophage inflammatory protein 2, and infiltrating T lymphocytes were the source of IFN-gamma. Relevance of the molecular findings was demonstrated by the identification of biologically active IL-1 alpha and immunoreactive TNF-alpha in culture supernatants. These studies demonstrate that Langerhans cell-derived and certain keratinocyte-derived cytokine mRNAs are selectively upregulated by allergens in the very early afferent phase of contact sensitivity. Images PMID:1741395

  11. Roles of polypyrimidine tract binding proteins in major immediate-early gene expression and viral replication of human cytomegalovirus.

    PubMed

    Cosme, Ruth S Cruz; Yamamura, Yasuhiro; Tang, Qiyi

    2009-04-01

    Human cytomegalovirus (HCMV), a member of the beta subgroup of the family Herpesviridae, causes serious health problems worldwide. HCMV gene expression in host cells is a well-defined sequential process: immediate-early (IE) gene expression, early-gene expression, DNA replication, and late-gene expression. The most abundant IE gene, major IE (MIE) gene pre-mRNA, needs to be spliced before being exported to the cytoplasm for translation. In this study, the regulation of MIE gene splicing was investigated; in so doing, we found that polypyrimidine tract binding proteins (PTBs) strongly repressed MIE gene production in cotransfection assays. In addition, we discovered that the repressive effects of PTB could be rescued by splicing factor U2AF. Taken together, the results suggest that PTBs inhibit MIE gene splicing by competing with U2AF65 for binding to the polypyrimidine tract in pre-mRNA. In intron deletion mutation assays and RNA detection experiments (reverse transcription [RT]-PCR and real-time RT-PCR), we further observed that PTBs target all the introns of the MIE gene, especially intron 2, and affect gene splicing, which was reflected in the variation in the ratio of pre-mRNA to mRNA. Using transfection assays, we demonstrated that PTB knockdown cells induce a higher degree of MIE gene splicing/expression. Consistently, HCMV can produce more viral proteins and viral particles in PTB knockdown cells after infection. We conclude that PTB inhibits HCMV replication by interfering with MIE gene splicing through competition with U2AF for binding to the polypyrimidine tract in MIE gene introns. PMID:19144709

  12. Cardiovascular events, early discontinuation of trastuzumab, and their impact on survival.

    PubMed

    Wang, Shi-Yi; Long, Jessica B; Hurria, Arti; Owusu, Cynthia; Steingart, Richard M; Gross, Cary P; Chen, Jersey

    2014-07-01

    To evaluate how often trastuzumab therapy is ended early (i.e., early discontinuation) and how cardiovascular events and early discontinuation affect survival among older women with breast cancer. A population-based cohort of female Medicare beneficiaries with stage I-III breast cancer in 2005-2009 who received trastuzumab was assembled and followed through 2011. Completed trastuzumab treatment was defined as ≥11 months of continuous trastuzumab treatments with no delay between trastuzumab treatments >45 days. We identified trastuzumab-associated cardiovascular events as those occurring within 45 days before or after the last trastuzumab treatment. Using Cox proportional hazard models, we examined the association between early discontinuation of trastuzumab and cardiovascular events on all-cause mortality. Our cohort consisted of 585 women (mean age: 71.6 years). Approximately 41 % of women discontinued trastuzumab therapy early. Patients with early discontinuation of trastuzumab were more likely to have heart failure /cardiomyopathy, atrial fibrillation, and other cardiovascular events than women who completed trastuzumab. Cardiovascular events were strongly associated with an increased risk of all-cause mortality [adjusted hazard ratio (AHR) 3.54; 95 % confidence interval (CI) 1.87 to 6.68]. Women with early discontinuation of trastuzumab had a non-significant increase in risk of all-cause mortality (AHR: 1.74; 95 % CI 0.94 to 3.23), compared to women who completed trastuzumab. Early trastuzumab discontinuation was common among older patients, and often associated with adverse cardiovascular events. Development of cardiovascular events was associated with a higher mortality risk than early trastuzumab discontinuation, implying that reducing cardiovascular complications from trastuzumab therapy could likely have a substantive impact on overall survival in this population. PMID:24951268

  13. Early embryonic-like cells are induced by downregulating replication-dependent chromatin assembly.

    PubMed

    Ishiuchi, Takashi; Enriquez-Gasca, Rocio; Mizutani, Eiji; Bokovi?, Ana; Ziegler-Birling, Celine; Rodriguez-Terrones, Diego; Wakayama, Teruhiko; Vaquerizas, Juan M; Torres-Padilla, Maria-Elena

    2015-09-01

    Cellular plasticity is essential for early embryonic cells. Unlike pluripotent cells, which form embryonic tissues, totipotent cells can generate a complete organism including embryonic and extraembryonic tissues. Cells resembling 2-cell-stage embryos (2C-like cells) arise at very low frequency in embryonic stem (ES) cell cultures. Although induced reprogramming to pluripotency is well established, totipotent cells remain poorly characterized, and whether reprogramming to totipotency is possible is unknown. We show that mouse 2C-like cells can be induced in vitro through downregulation of the chromatin-assembly activity of CAF-1. Endogenous retroviruses and genes specific to 2-cell embryos are the highest-upregulated genes upon CAF-1 knockdown. Emerging 2C-like cells exhibit molecular characteristics of 2-cell embryos and higher reprogrammability than ES cells upon nuclear transfer. Our results suggest that early embryonic-like cells can be induced by modulating chromatin assembly and that atypical histone deposition may trigger the emergence of totipotent cells. PMID:26237512

  14. Anaemia and early phase cardiovascular events on haemodialysis.

    PubMed

    Hayashi, Toshihide; Joki, Nobuhiko; Tanaka, Yuri; Hase, Hiroki

    2015-12-01

    Although the mechanism of the cardio-renal anaemia syndrome (CRAS) has been elucidated in considerable detail over the past decade, cardiovascular disease (CVD) remains a leading cause of death among patients with end-stage kidney disease (ESKD) undergoing haemodialysis, and these patients' cardiovascular mortality is greater than that of the general population. Recent studies have reported that the CVD risk increases with advancing chronic kidney disease (CKD) stage. Furthermore, the incidence of cardiovascular events is highest during the first week after dialysis initiation, with increased risk in incident haemodialysis patients. This accumulated evidence demonstrates that how patients are managed during the pre-dialysis phase may have important implications on long-term outcomes in ESKD. Anaemia, a non-traditional risk factor for CVD, advances exponentially along with declining kidney function due to insufficient erythropoietin production. Anaemia causes functional abnormalities of the heart, as represented by cardiac hypertrophy, which results from increased cardiac workload induced by an increased preload. Left ventricular hypertrophy (LVH), a traditional risk factor for CVD, is especially associated with advanced CKD stage and could be a major risk factor for cardiovascular complications such as ischaemic heart disease, heart failure, and sudden cardiac death. In ESKD, anaemia develops more severely and requires a higher amount of erythropoiesis-stimulating agent (ESA) therapy before dialysis initiation. This suggests that improvement in anaemia management during the pre-dialysis phase may have a beneficial effect on cardiac hypertrophy and contribute to reducing the CVD risk after initiating haemodialysis. PMID:26456311

  15. 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.

  16. Timing the early events during sea urchin fertilization.

    PubMed

    Schatten, G; Hlser, D

    1983-11-01

    To determine precisely the timing, duration, and sequences of the earliest events during sea urchin (Lytechinus variegatus) fertilization, the bioelectric recordings of microelectrode-impaled eggs were electronically superimposed, by video mixing, over the microscopic differential interference contrast image of the same egg at insemination. Videotape analysis, utilizing a slow-motion analyzer, demonstrates that the successful sperm triggers the bioelectric membrane potential reversal within 3.36 +/- 3.02 sec (0.72-9.76 sec range; sigma = 23 eggs) of sperm-egg attachment. This sperm, actively gyrating about its attachment site, is indistinguishable from the other, unsuccessful sperm until 12.66 +/- 2.72 sec (6.72-16.60 sec range; sigma = 15) later when the sperm tail ceases its beating and sperm incorporation ensues. The cortical granules begin to discharge, and the fertilization coat starts to elevate at the fusion site at 20.79 +/- 3.18 sec (13.62-26.08 sec range; sigma = 12) after the onset of the fertilization potential, i.e., an average of about 8 sec after the cessation of sperm-tail motility during incorporation. In most cases, the bioelectric responses starts within 7 sec of sperm adhesions; if the data are analyzed excluding the few slow cases, the fertilization potential is found to start 1.93 sec (+/- 1.28 sec) after sperm attachment. These results indicate that the first successful sperm triggers the fast block to polyspermy within 3.4 sec, perhaps as quickly as 1.9 sec, of sperm-egg adhesion, about 13 sec before the first morphological indication of fertilization, and about 21 sec before the characteristic elevation of the fertilization coat responsible for the late block to polyspermy. PMID:6688595

  17. Prp40 and early events in splice site definition.

    PubMed

    Becerra, Soraya; Andrs-Len, Eduardo; Prieto-Snchez, Silvia; Hernndez-Munain, Cristina; Su, Carlos

    2016-01-01

    The alternative splicing (AS) of precursor messenger RNA (pre-mRNA) is a tightly regulated process through which introns are removed to leave the resulting exons in the mRNA appropriately aligned and ligated. The AS of pre-mRNA is a key mechanism for increasing the complexity of proteins encoded in the genome. In humans, more than 90% of genes undergo AS, underscoring the importance of this process in RNA biogenesis. As such, AS misregulation underlies multiple human diseases. The splicing reaction is catalyzed by the spliceosome, a highly dynamic complex that assembles at or near the intron/exon boundaries and undergoes sequential conformational and compositional changes during splicing. The initial recognition of splice sites defines the exons that are going to be removed, which is a critical step in the highly regulated splicing process. Although the available lines of evidence are increasing, the molecular mechanisms governing AS, including the initial interactions occurring at intron/exon boundaries, and the factors that modulate these critical connections by functioning as a scaffold for active-site RNAs or proteins, remain poorly understood. In this review, we summarize the major hallmarks of the initial steps in the splicing process and the role of auxiliary factors that contribute to the assembly of the spliceosomal complex. We also discuss the role of the essential yeast Prp40 protein and its mammalian homologs in the specificity of this pre-mRNA processing event. In addition, we provide the first exhaustive phylogenetic analysis of the molecular evolution of Prp40 family members. WIREs RNA 2016, 7:17-32. doi: 10.1002/wrna.1312 For further resources related to this article, please visit the WIREs website. PMID:26494226

  18. 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.

  19. Phosphoproteome Dynamics Upon Changes in Plant Water Status Reveal Early Events Associated With Rapid Growth Adjustment in Maize Leaves*

    PubMed Central

    Bonhomme, Ludovic; Valot, Benot; Tardieu, Franois; Zivy, Michel

    2012-01-01

    Plant growth adjustment during water deficit is a crucial adaptive response. The rapid fine-tuned control achieved at the post-translational level is believed to be of considerable importance for regulating early changes in plant growth reprogramming. Aiming at a better understanding of early responses to contrasting plant water statuses, we carried out a survey of the protein phosphorylation events in the growing zone of maize leaves upon a range of water regimes. In this study, the impact of mild and severe water deficits were evaluated in comparison with constant optimal watering and with recovery periods lasting 5, 10, 20, 30, 45, and 60 min. Using four biological replicates per treatment and a robust quantitative phosphoproteomic methodology based on stable-isotope labeling, we identified 3664 unique phosphorylation sites on 2496 proteins. The abundance of nearly 1250 phosphorylated peptides was reproducibly quantified and profiled with high confidence among treatments. A total of 138 phosphopeptides displayed highly significant changes according to water regimes and enabled to identify specific patterns of response to changing plant water statuses. Further quantification of protein amounts emphasized that most phosphorylation changes did not reflect protein abundance variation. During water deficit and recovery, extensive changes in phosphorylation status occurred in critical regulators directly or indirectly involved in plant growth and development. These included proteins influencing epigenetic control, gene expression, cell cycle-dependent processes and phytohormone-mediated responses. Some of the changes depended on stress intensity whereas others depended on rehydration duration, including rapid recoveries that occurred as early as 5 or 10 mins after rewatering. By combining a physiological approach and a quantitative phosphoproteomic analysis, this work provides new insights into the in vivo early phosphorylation events triggered by rapid changes in plant water status, and their possible involvement in plant growth-related processes. PMID:22787273

  20. H1PVAT is a novel and potent early-stage inhibitor of poliovirus replication that targets VP1.

    PubMed

    Tijsma, Aloys; Thibaut, Hendrik Jan; Spieser, Stphane A H; De Palma, Armando; Koukni, Mohamed; Rhoden, Eric; Oberste, Steve; Prstinger, Gerhard; Volny-Luraghi, Antonia; Martin, Javier; Marchand, Arnaud; Chaltin, Patrick; Neyts, Johan; Leyssen, Pieter

    2014-10-01

    A novel small molecule, H1PVAT, was identified as a potent and selective inhibitor of the in vitro replication of all three poliovirus serotypes, whereas no activity was observed against other enteroviruses. Time-of-drug-addition studies revealed that the compound interfered with an early stage of virus replication. Four independently-selected H1PVAT-resistant virus variants uniformly carried the single amino acid substitution I194F in the VP1 capsid protein. Poliovirus type 1 strain Sabin, reverse-engineered to contain this substitution, proved to be completely insensitive to the antiviral effect of H1PVAT and was cross-resistant to the capsid-binding inhibitors V-073 and pirodavir. The VP1 I194F mutant had a smaller plaque phenotype than wild-type virus, and the amino acid substitution rendered the virus more susceptible to heat inactivation. Both for the wild-type and VP1 I194F mutant virus, the presence of H1PVAT increased the temperature at which the virus was inactivated, providing evidence that the compound interacts with the viral capsid, and that capsid stabilization and antiviral activity are not necessarily correlated. Molecular modeling suggested that H1PVAT binds with high affinity in the pocket underneath the floor of the canyon that is involved in receptor binding. Introduction of the I194F substitution in the model of VP1 induced a slight concerted rearrangement of the core ?-barrel in this pocket, which disfavors binding of the compound. Taken together, the compound scaffold, to which H1PVAT belongs, may represent another promising class of poliovirus capsid-binding inhibitors next to V-073 and pirodavir. Potent antivirals against poliovirus will be essential in the poliovirus eradication end-game. PMID:25043639

  1. A Herpes Simplex Virus Scaffold Peptide That Binds the Portal Vertex Inhibits Early Steps in Viral Replication

    PubMed Central

    Yang, Kui; Wills, Elizabeth

    2013-01-01

    Previous experiments identified a 12-amino-acid (aa) peptide that was sufficient to interact with the herpes simplex virus 1 (HSV-1) portal protein and was necessary to incorporate the portal into capsids. In the present study, cells were treated at various times postinfection with peptides consisting of a portion of the Drosophila antennapedia protein, previously shown to enter cells efficiently, fused to either wild-type HSV-1 scaffold peptide (YPYYPGEARGAP) or a control peptide that contained changes at positions 4 and 5. These 4-tyrosine and 5-proline residues are highly conserved in herpesvirus scaffold proteins and were previously shown to be critical for the portal interaction. Treatment early in infection with subtoxic levels of wild-type peptide reduced viral infectivity by over 1,000-fold, while the mutant peptide had little effect on viral yields. In cells infected for 3 h in the presence of wild-type peptide, capsids were observed to transit to the nuclear rim normally, as viewed by fluorescence microscopy. However, observation by electron microscopy in thin sections revealed an aberrant and significant increase of DNA-containing capsids compared to infected cells treated with the mutant peptide. Early treatment with peptide also prevented formation of viral DNA replication compartments. These data suggest that the antiviral peptide stabilizes capsids early in infection, causing retention of DNA within them, and that this activity correlates with peptide binding to the portal protein. The data are consistent with the hypothesis that the portal vertex is the conduit through which DNA is ejected to initiate infection. PMID:23576509

  2. A herpes simplex virus scaffold peptide that binds the portal vertex inhibits early steps in viral replication.

    PubMed

    Yang, Kui; Wills, Elizabeth; Baines, Joel D

    2013-06-01

    Previous experiments identified a 12-amino-acid (aa) peptide that was sufficient to interact with the herpes simplex virus 1 (HSV-1) portal protein and was necessary to incorporate the portal into capsids. In the present study, cells were treated at various times postinfection with peptides consisting of a portion of the Drosophila antennapedia protein, previously shown to enter cells efficiently, fused to either wild-type HSV-1 scaffold peptide (YPYYPGEARGAP) or a control peptide that contained changes at positions 4 and 5. These 4-tyrosine and 5-proline residues are highly conserved in herpesvirus scaffold proteins and were previously shown to be critical for the portal interaction. Treatment early in infection with subtoxic levels of wild-type peptide reduced viral infectivity by over 1,000-fold, while the mutant peptide had little effect on viral yields. In cells infected for 3 h in the presence of wild-type peptide, capsids were observed to transit to the nuclear rim normally, as viewed by fluorescence microscopy. However, observation by electron microscopy in thin sections revealed an aberrant and significant increase of DNA-containing capsids compared to infected cells treated with the mutant peptide. Early treatment with peptide also prevented formation of viral DNA replication compartments. These data suggest that the antiviral peptide stabilizes capsids early in infection, causing retention of DNA within them, and that this activity correlates with peptide binding to the portal protein. The data are consistent with the hypothesis that the portal vertex is the conduit through which DNA is ejected to initiate infection. PMID:23576509

  3. Sambucus nigra extracts inhibit infectious bronchitis virus at an early point during replication

    PubMed Central

    2014-01-01

    Background Infectious bronchitis virus (IBV) is a pathogenic chicken coronavirus. Currently, vaccination against IBV is only partially protective; therefore, better preventions and treatments are needed. Plants produce antimicrobial secondary compounds, which may be a source for novel anti-viral drugs. Non-cytotoxic, crude ethanol extracts of Rhodiola rosea roots, Nigella sativa seeds, and Sambucus nigra fruit were tested for anti-IBV activity, since these safe, widely used plant tissues contain polyphenol derivatives that inhibit other viruses. Results Dose–response cytotoxicity curves on Vero cells using trypan blue staining determined the highest non-cytotoxic concentrations of each plant extract. To screen for IBV inhibition, cells and virus were pretreated with extracts, followed by infection in the presence of extract. Viral cytopathic effect was assessed visually following an additional 24 h incubation with extract. Cells and supernatants were harvested separately and virus titers were quantified by plaque assay. Variations of this screening protocol determined the effects of a number of shortened S. nigra extract treatments. Finally, S. nigra extract-treated virions were visualized by transmission electron microscopy with negative staining. Virus titers from infected cells treated with R. rosea and N. sativa extracts were not substantially different from infected cells treated with solvent alone. However, treatment with S. nigra extracts reduced virus titers by four orders of magnitude at a multiplicity of infection (MOI) of 1 in a dose-responsive manner. Infection at a low MOI reduced viral titers by six orders of magnitude and pretreatment of virus was necessary, but not sufficient, for full virus inhibition. Electron microscopy of virions treated with S. nigra extract showed compromised envelopes and the presence of membrane vesicles, which suggested a mechanism of action. Conclusions These results demonstrate that S. nigra extract can inhibit IBV at an early point in infection, probably by rendering the virus non-infectious. They also suggest that future studies using S. nigra extract to treat or prevent IBV or other coronaviruses are warranted. PMID:24433341

  4. Compartmentalized Replication of R5 T Cell-Tropic HIV-1 in the Central Nervous System Early in the Course of Infection

    PubMed Central

    Sturdevant, Christa Buckheit; Joseph, Sarah B.; Schnell, Gretja; Price, Richard W.; Swanstrom, Ronald; Spudich, Serena

    2015-01-01

    Compartmentalized HIV-1 replication within the central nervous system (CNS) likely provides a foundation for neurocognitive impairment and a potentially important tissue reservoir. The timing of emergence and character of this local CNS replication has not been defined in a population of subjects. We examined the frequency of elevated cerebrospinal fluid (CSF) HIV-1 RNA concentration, the nature of CSF viral populations compared to the blood, and the presence of a cellular inflammatory response (with the potential to bring infected cells into the CNS) using paired CSF and blood samples obtained over the first two years of infection from 72 ART-nave subjects. Using single genome amplification (SGA) and phylodynamics analysis of full-length env sequences, we compared CSF and blood viral populations in 33 of the 72 subjects. Independent HIV-1 replication in the CNS (compartmentalization) was detected in 20% of sample pairs analyzed by SGA, or 7% of all sample pairs, and was exclusively observed after four months of infection. In subjects with longitudinal sampling, 30% showed evidence of CNS viral replication or pleocytosis/inflammation in at least one time point, and in approximately 16% of subjects we observed evolving CSF/CNS compartmentalized viral replication and/or a marked CSF inflammatory response at multiple time points suggesting an ongoing or recurrent impact of the infection in the CNS. Two subjects had one of two transmitted lineages (or their recombinant) largely sequestered within the CNS shortly after transmission, indicating an additional mechanism for establishing early CNS replication. Transmitted variants were R5 T cell-tropic. Overall, examination of the relationships between CSF viral populations, blood and CSF HIV-1 RNA concentrations, and inflammatory responses suggested four distinct states of viral population dynamics, with associated mechanisms of local viral replication and the early influx of virus into the CNS. This study considerably enhances the generalizability of our results and greatly expands our knowledge of the early interactions of HIV-1 in the CNS. PMID:25811757

  5. ABA Inhibits Embryo Cell Expansion and Early Cell Division Events During Coffee (Coffea arabica ‘Rubi’) Seed Germination

    PubMed Central

    Da Silva, E. A. Amaral; Toorop, Peter E.; Van Lammeren, André A. M.; Hilhorst, Henk W. M.

    2008-01-01

    Background and Aims Coffee seed germination represents an interplay between the embryo and the surrounding endosperm. A sequence of events in both parts of the seed determines whether germination will be successful or not. Following previous studies, the aim here was to further characterize the morphology of endosperm degradation and embryo growth with respect to morphology and cell cycle, and the influence of abscisic acid on these processes. Methods Growth of cells in a fixed region of the axis was quantified from light micrographs. Cell cycle events were measured by flow cytometry and by immunocytochemistry, using antibodies against β-tubulin. Aspects of the endosperm were visualized by light and scanning electron microscopy. Key Results The embryonic axis cells grew initially by isodiametric expansion. This event coincided with reorientation and increase in abundance of microtubules and with accumulation of β-tubulin. Radicle protrusion was characterized by a shift from isodiametric expansion to elongation of radicle cells and further accumulation of β-tubulin. Early cell division events started prior to radicle protrusion. Abscisic acid decreased the abundance of microtubules and inhibited the growth of the embryo cells, the reorganization of the microtubules, DNA replication in the embryonic axis, the formation of a protuberance and the completion of germination. The endosperm cap cells had smaller and thinner cell walls than the rest of the endosperm. Cells in the endosperm cap displayed compression followed by loss of cell integrity and the appearance of a protuberance prior to radicle protrusion. Conclusions Coffee seed germination is the result of isodiametric growth of the embryo followed by elongation, at the expense of integrity of endosperm cap cells. The cell cycle, including cell division, is initiated prior to radicle protrusion. ABA inhibits expansion of the embryo, and hence subsequent events, including germination. PMID:18617534

  6. An early Eocene transient warming ( 53 Ma): Implications for astronomically-paced early Eocene hyperthermal events.

    NASA Astrophysics Data System (ADS)

    Sluijs, A.; Lourens, L. J.; Kroon, D.; Zachos, J. C.; Thomas, E.; Rhl, U.

    2004-12-01

    Here we report on a pronounced hyperthermal event approximately 2 Myrs after the Paleocene-Eocene thermal maximum (PETM) and place both events in a new orbitally-tuned framework. This previously unrecognized transient event and the underlying PETM were both recovered at five sites along a 2km depth transect on the Walvis Ridge (southeast Atlantic) during Ocean Drilling Program Leg 208. Similar to the PETM, this event, \\textit{Elmo}, is marked by a red clay layer, associated with severe drop in CaCO3 concentrations, suggesting a 2 km rise in the lysocline. High-resolution (1cm) bulk carbonate ? 13C measurements of the shallowest, and hence most complete Site 1263 revealed a 1.5% drop in ? 13C and ? 18O. The negative ? 13C excursion is composed of three steep steps of which the last one corresponds to the base of the red clay layer. The post-\\textit{Elmo} interval mirrors the typical PETM signature with an exponential recovery to pre-excursion ? 13C values. The planktonic foraminiferal ? 13C record (measured on single specimens of the surface dweller \\textit{Acaranina soldadoensis}) confirms the bulk pattern, although the amplitude of the excursion, -2.5, is larger. The planktonic foraminiferal ? 18O record shows the same -1% excursion as the bulk, suggesting a fast increase in sea surface temperature of 4 degrees C. The case of conditions similar to the PETM during the ELMO event is further strengthened by the occurrence of low diversity, diminutive benthic foraminifer assemblages, and a decrease in planktonic foraminifer diversity. Examination of published isotope, X-ray fluorescence and magnetic susceptibility records further indicates that this event is global in nature and recorded in other marine and terrestrial basins. Orbital tuning of the deepest Sites 1262 magnetic susceptibility and Sites 1262 and 1267 color reflectance records to the La2004 and R7 astronomical solutions shows that the \\textit{Elmo} is five 400-kyr eccentricity cycles younger than the PETM and that both events are linked to eccentricity-maxima. This, and the subtle resemblance between the \\textit{Elmo} and PETM mentioned above, suggests that similar, astronomically modulated, mechanisms are at the root of them. The leading hypothesis to explain the PETM climatic event and its ? 13C excursion is the dissociation of submarine methane hydrates. If the \\textit{Elmo} shares a similar origin, its less extreme appearance may be associated with the ability of the methane hydrate reservoir to recharge after the PETM, especially under the warm conditions that prevailed in the interval spanning the two events.

  7. 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, Frdric

    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

  8. Identification of frequent La Nia 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 Nio events occurred regularly during the late 1700s. During the early 1800s, El Nio events occurred less often, and La Nia 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.

  9. 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.

  10. Early snowmelt events: detection, distribution, and significance in a major sub-arctic watershed

    NASA Astrophysics Data System (ADS)

    Alese Semmens, Kathryn; Ramage, Joan; Bartsch, Annett; Liston, Glen E.

    2013-03-01

    High latitude drainage basins are experiencing higher average temperatures, earlier snowmelt onset in spring, and an increase in rain on snow (ROS) events in winter, trends that climate models project into the future. Snowmelt-dominated basins are most sensitive to winter temperature increases that influence the frequency of ROS events and the timing and duration of snowmelt, resulting in changes to spring runoff. Of specific interest in this study are early melt events that occur in late winter preceding melt onset in the spring. The study focuses on satellite determination and characterization of these early melt events using the Yukon River Basin (Canada/USA) as a test domain. The timing of these events was estimated using data from passive (Advanced Microwave Scanning RadiometerEOS (AMSR-E)) and active (SeaWinds on Quick Scatterometer (QuikSCAT)) microwave remote sensors, employing detection algorithms for brightness temperature (AMSR-E) and radar backscatter (QuikSCAT). The satellite detected events were validated with ground station meteorological and hydrological data, and the spatial and temporal variability of the events across the entire river basin was characterized. Possible causative factors for the detected events, including ROS, fog, and positive air temperatures, were determined by comparing the timing of the events to parameters from SnowModel and National Centers for Environmental Prediction North American Regional Reanalysis (NARR) outputs, and weather station data. All melt events coincided with above freezing temperatures, while a limited number corresponded to ROS (determined from SnowModel and ground data) and a majority to fog occurrence (determined from NARR). The results underscore the significant influence that warm air intrusions have on melt in some areas and demonstrate the large temporal and spatial variability over years and regions. The study provides a method for melt detection and a baseline from which to assess future change.

  11. Early Folding Events, Local Interactions, and Conservation of Protein Backbone Rigidity.

    PubMed

    Pancsa, Rita; Raimondi, Daniele; Cilia, Elisa; Vranken, Wim F

    2016-02-01

    Protein folding is in its early stages largely determined by the protein sequence and complex local interactions between amino acids, resulting in lower energy conformations that provide the context for further folding into the native state. We compiled a comprehensive data set of early folding residues based on pulsed labeling hydrogen deuterium exchange experiments. These early folding residues have corresponding higher backbone rigidity as predicted by DynaMine from sequence, an effect also present when accounting for the secondary structures in the folded protein. We then show that the amino acids involved in early folding events are not more conserved than others, but rather, early folding fragments and the secondary structure elements they are part of show a clear trend toward conserving a rigid backbone. We therefore propose that backbone rigidity is a fundamental physical feature conserved by proteins that can provide important insights into their folding mechanisms and stability. PMID:26840723

  12. How Early Events Affect Growing Brains. An Interview with Neuroscientist Pat Levitt

    ERIC Educational Resources Information Center

    National Scientific Council on the Developing Child, 2006

    2006-01-01

    Recent advances in neuroscience show clearly how experience can change brain neurochemicals, and how this in turn affects the way the brain functions. As a result, early negative events actually get built into the growing brain's neurochemistry, altering the brain's architecture. Research is continuing to investigate how children with genetic…

  13. How Early Events Affect Growing Brains. An Interview with Neuroscientist Pat Levitt

    ERIC Educational Resources Information Center

    National Scientific Council on the Developing Child, 2006

    2006-01-01

    Recent advances in neuroscience show clearly how experience can change brain neurochemicals, and how this in turn affects the way the brain functions. As a result, early negative events actually get built into the growing brain's neurochemistry, altering the brain's architecture. Research is continuing to investigate how children with genetic

  14. 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,

  15. 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

  16. Nup153 and Nup98 bind the HIV-1 core and contribute to the early steps of HIV-1 replication

    SciTech Connect

    Di Nunzio, Francesca; Fricke, Thomas; Miccio, Annarita; Valle-Casuso, Jose Carlos; Perez, Patricio; Souque, Philippe; Rizzi, Ermanno; Severgnini, Marco; Mavilio, Fulvio; Charneau, Pierre; Diaz-Griffero, Felipe

    2013-05-25

    The early steps of HIV-1 replication involve the entry of HIV-1 into the nucleus, which is characterized by viral interactions with nuclear pore components. HIV-1 developed an evolutionary strategy to usurp the nuclear pore machinery and chromatin in order to integrate and efficiently express viral genes. In the current work, we studied the role of nucleoporins 153 and 98 (Nup153 and Nup98) in infection of human Jurkat lymphocytes by HIV-1. We showed that Nup153-depleted cells exhibited a defect in nuclear import, while depletion of Nup 98 caused a slight defect in HIV integration. To explore the biochemical viral determinants for the requirement of Nup153 and Nup98 during HIV-1 infection, we tested the ability of these nucleoporins to interact with HIV-1 cores. Our findings showed that both nucleoporins bind HIV-1 cores suggesting that this interaction is important for HIV-1 nuclear import and/or integration. Distribution analysis of integration sites in Nup153-depleted cells revealed a reduced tendency of HIV-1 to integrate in intragenic sites, which in part could account for the large infectivity defect observed in Nup153-depleted cells. Our work strongly supports a role for Nup153 in HIV-1 nuclear import and integration. - Highlights: ► We studied the role of Nup98 and Nup153 in HIV-1 infection. ► Nup98 binds the HIV-1 core and is involved in HIV-1 integration. ► Nup153 binds the HIV-1 core and is involved in HIV-1 nuclear import. ► Depletion of Nup153 decreased the integration of HIV-1 in transcriptionally active sites.

  17. 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

  18. Chromosomal replication initiates and terminates at random sequences but at regular intervals in the ribosomal DNA of Xenopus early embryos.

    PubMed Central

    Hyrien, O; Méchali, M

    1993-01-01

    We have analysed the replication of the chromosomal ribosomal DNA (rDNA) cluster in Xenopus embryos before the midblastula transition. Two-dimensional gel analysis showed that replication forks are associated with the nuclear matrix, as in differentiated cells, and gave no evidence for single-stranded replication intermediates (RIs). Bubbles, simple forks and double Ys were found in each restriction fragment analysed, showing that replication initiates and terminates without detectable sequence specificity. Quantification of the results and mathematical analysis showed that the average rDNA replicon replicates in 7.5 min and is 9-12 kbp in length. This time is close to the total S phase duration, and this replicon size is close to the maximum length of DNA which can be replicated from a single origin within this short S phase. We therefore infer that (i) most rDNA origins must be synchronously activated soon in S phase and (ii) origins must be evenly spaced, in order that no stretch of chromosomal DNA is left unreplicated at the end of S phase. Since origins are not specific sequences, it is suggested that this spatially and temporally concerted pattern of initiation matches some periodic chromatin folding, which itself need not rely on DNA sequence. Images PMID:8223461

  19. Chromatin signatures of the Drosophila replication program

    PubMed Central

    Eaton, Matthew L.; Prinz, Joseph A.; MacAlpine, Heather K.; Tretyakov, George; Kharchenko, Peter V.; MacAlpine, David M.

    2011-01-01

    DNA replication initiates from thousands of start sites throughout the Drosophila genome and must be coordinated with other ongoing nuclear processes such as transcription to ensure genetic and epigenetic inheritance. Considerable progress has been made toward understanding how chromatin modifications regulate the transcription program; in contrast, we know relatively little about the role of the chromatin landscape in defining how start sites of DNA replication are selected and regulated. Here, we describe the Drosophila replication program in the context of the chromatin and transcription landscape for multiple cell lines using data generated by the modENCODE consortium. We find that while the cell lines exhibit similar replication programs, there are numerous cell line-specific differences that correlate with changes in the chromatin architecture. We identify chromatin features that are associated with replication timing, early origin usage, and ORC binding. Primary sequence, activating chromatin marks, and DNA-binding proteins (including chromatin remodelers) contribute in an additive manner to specify ORC-binding sites. We also generate accurate and predictive models from the chromatin data to describe origin usage and strength between cell lines. Multiple activating chromatin modifications contribute to the function and relative strength of replication origins, suggesting that the chromatin environment does not regulate origins of replication as a simple binary switch, but rather acts as a tunable rheostat to regulate replication initiation events. PMID:21177973

  20. Environmental change during the Late Berriasian - Early Valanginian: a prelude to the late Early Valanginian carbon-isotope event?

    NASA Astrophysics Data System (ADS)

    Morales, Chlo; Schnyder, Johann; Spangenberg, Jorge; Adatte, Thierry; Westermann, Stephane; Fllmi, Karl

    2010-05-01

    The Valanginian period is well known for a positive excursion in marine and terrestrial ?13C records, which has been interpreted as the consequence of a major perturbation in the global carbon cycle (Lini et al., 1992; Erba et al., 2004). In contrast to the positive ?13C excursions of the Early Aptian and latest Cenomanian, marine organic-rich sediments have only been recognized from a few localities (van de Schootbrugge et al., 2003; Reboulet et al., 2003; Grcke et al., 2005; Westermann et al., in press). The ?13C excursion began in the late Early Valanginian (campylotoxus ammonite zone) and gradually ended during the Late Valanginian. It is associated with a phase of widespread carbonate-platform drowning on the shelf (Fllmi et al., 1994) and a decline in calcareous nannofossils in the pelagic realm (Erba et al., 2004). As a triggering mechanism, numerous authors invoke the formation of the Para-Etendeka flood basalt. The correlation of this episode with the Valanginian ?13C event depends, however, on the absolute ages attributed to the Valanginian stage. The recent geological timescale by Ogg et al. (2008) shows that the major eruptional phase occurred during the Late Valanginian. This may imply that the late Early Valanginian ?13C event resulted from a combination of different factors. Important paleoenvironmental change occurred already in the latest Berriasian and earliest Valanginian, prior to the positive ?13C excursion. An increase in nutrient input near the onset of the ?13C excursion (campylotoxus ammonite zone), which may be considered as a trigger of the carbon cycle perturbation, has been identified in different studies, (Hennig, 2003; Duchamp-Alphonse et al., 2007; Bornemann & Mutterlose, 2008). Heterozoan faunal associations became dominant since the Early Valanginian on the northern Tethyan Helvetic platform and may indicate the beginning of sea-water eutrophication (Fllmi et al., 2007). Clay assemblages in the Tethys and Western European basins show that the climate became more humid during the Late Berriasian (Hallam et al., 1991, Schnyder et al., 2009). The aim of this project is to precisely characterize and date paleoenvironmental and paleoclimatic change during the latest Berriasian-Early Valanginian time interval in order to decipher if they can be viewed as precursor events, linked with the late Early Valanginian ?13C event. Three key sections have been studied: Capriolo (N Italy), Montclus (SE France) and Musfallen (E Switzerland) located in the Lombardian and Vocontian basins and on the Helvetic platform, respectively. Phosphorus and stable-isotope analyses have been performed, in addition to clay-mineralogy and facies determinations. The three sections show similar and comparable trends: The phosphorus content (in ppm) is higher in Late Berriasian sediments (compared to Early Berriasian and Valanginian deposits) and this period is also characterised by a decrease in ?13C values. This is interpreted as the result of enhanced continental weathering, which would be coeval with a change to a more humid climate during the Late Berriasian (Schnyder et al., 2009). References: Bornemann, A. and Mutterlose, J. (2008). "Calcareous nannofossil and d13C records from the Early Cretaceous of the Western Atlantic ocean: evidence of enhanced fertilization accross the Berriasian-Valanginian transition." palaios 23: 821-832. Duchamp-Alphonse, S., Gardin, S., Fiet, N., Bartolini, A., Blamart, D. and Pagel, M. (2007). "Fertilization of the northwestern Tethys (Vocontian basin, SE France) during the Valanginian carbon isotope perturbation: Evidence from calcareous nannofossils and trace element data." Palaeogeography, Palaeoclimatology, Palaeoecology 243(1-2): 132-151. Fllmi, K.B., Weissert, H., Bisping, M. & Funk, H. 1994: Phosphogenesis, carbon-isotope stratigraphy, and carbonate-platform evolution along the Lower Cretaceous northern tethyan margin. Geological Society of America, Bulletin 106, 729-746. F^llmi, K.B., Bodin, S., Godet, A., Linder, P. and Van de Scho

  1. 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.

  2. 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.

  3. Early Events in Kaposi's Sarcoma-Associated Herpesvirus Infection of Target Cells ?

    PubMed Central

    Chandran, Bala

    2010-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV), the most recently identified member of the herpesvirus family, infects a variety of target cells in vitro and in vivo. This minireview surveys current information on the early events of KSHV infection, including virus-receptor interactions, involved envelope glycoproteins, mode of entry, intracellular trafficking, and initial viral and host gene expression programs. We describe data supporting the hypothesis that KSHV manipulates preexisting host cell signaling pathways to allow successful infection. The various signaling events triggered by infection, and their potential roles in the different stages of infection and disease pathogenesis, are summarized. PMID:19923183

  4. A temperature sensitive mutant of heat shock protein 70 reveals an essential role during the early steps of tombusvirus replication.

    PubMed

    Wang, Robert Yung-Liang; Stork, Jozsef; Pogany, Judit; Nagy, Peter D

    2009-11-10

    By co-opting host proteins for their replication, plus-stranded RNA viruses can support robust replication and suppress host anti-viral responses. Tomato bushy stunt virus (TBSV) recruit the cellular heat shock protein 70 (Hsp70), an abundant cytosolic chaperone, into the replicase complex. By taking advantage of yeast model host, we demonstrate that the four-member SSA subfamily of HSP70 genes is essential for TBSV replication. The constitutively expressed SSA1 and SSA2, which are resident proteins in the viral replicase, can be complemented by the heat-inducible SSA3 and/or SSA4 for TBSV replication. Using a yeast strain carrying a temperature sensitive ssa1(ts), but lacking functional SSA2/3/4, we show that inactivation of Ssa1p(ts) led to a defect in membrane localization of the viral replication proteins, resulting in cytosolic distribution of the viral proteins and lack of replicase activity. An in vitro replicase assembly assay with Ssa1p(ts) revealed that functional Ssa1p is required during the replicase assembly process, but not during minus- or plus-strand synthesis. Temperature shift experiments from nonpermissive to permissive in ssa1(ts) yeast revealed that the re-activated Ssa1p(ts) could promote efficient TBSV replication in the absence of other SSA genes. We also demonstrate that the purified recombinant Ssa3p can facilitate the in vitro assembly of the TBSV replicase on yeast membranes, demonstrating that Ssa3p can fully complement the function of Ssa1p. Taken together, the cytosolic SSA subfamily of Hsp70 proteins play essential and multiple roles in TBSV replication. PMID:19748649

  5. Controls of event-based pesticide leaching in natural soils: A systematic study based on replicated field scale irrigation experiments

    NASA Astrophysics Data System (ADS)

    Klaus, Julian; Zehe, Erwin; Elsner, Martin; Palm, Juliane; Schneider, Dorothee; Schröder, Boris; Steinbeiss, Sibylle; van Schaik, Loes; West, Stephanie

    2014-05-01

    Tile drains strongly influence the water cycle in agricultural catchment in terms of water quantity and quality. The connectivity of preferential flow to tile drains can create shortcuts for rapid transport of solutes into surface waters. The leaching of pesticides can be linked to a set of main factors including, rainfall characteristics, soil moisture, chemical properties of the pesticides, soil properties, and preferential flow paths. The connectivity of the macropore system to the tile drain is crucial for pesticide leaching. Concurring influences of the main factors, threshold responses and the role of flow paths are still poorly understood. The objective of this study is to investigate these influences by a replica series of three irrigation experiments on a tile drain field site using natural and artificial tracers together with applied pesticides. We found a clear threshold behavior in the initialization of pesticide transport that was different between the replica experiments. Pre-event soil water contributed significantly to the tile drain flow, and creates a flow path for stored pesticides from the soil matrix to the tile drain. This threshold is controlled by antecedent soil moisture and precipitation characteristics, and the interaction between the soil matrix and preferential flow system. Fast transport of pesticides without retardation and the remobilization could be attributed to this threshold and the interaction between the soil matrix and the preferential flow system. Thus, understanding of the detailed preferential flow processes clearly enhances the understanding of pesticide leaching on event and long term scale, and can further improve risk assessment and modeling approaches.

  6. Chlamydia trachomatis Infection of Endocervical Epithelial Cells Enhances Early HIV Transmission Events

    PubMed Central

    Buckner, Lyndsey R.; Amedee, Angela M.; Albritton, Hannah L.; Kozlowski, Pamela A.; Lacour, Nedra; McGowin, Chris L.; Schust, Danny J.; Quayle, Alison J.

    2016-01-01

    Chlamydia trachomatis causes a predominantly asymptomatic, but generally inflammatory, genital infection that is associated with an increased risk for HIV acquisition. Endocervical epithelial cells provide the major niche for this obligate intracellular bacterium in women, and the endocervix is also a tissue in which HIV transmission can occur. The mechanism by which CT infection enhances HIV susceptibility at this site, however, is not well understood. Utilizing the A2EN immortalized endocervical epithelial cell line grown on cell culture inserts, we evaluated the direct role that CT-infected epithelial cells play in facilitating HIV transmission events. We determined that CT infection significantly enhanced the apical-to-basolateral migration of cell-associated, but not cell-free, HIVBaL, a CCR5-tropic strain of virus, across the endocervical epithelial barrier. We also established that basolateral supernatants from CT-infected A2EN cells significantly enhanced HIV replication in peripheral mononuclear cells and a CCR5+ T cell line. These results suggest that CT infection of endocervical epithelial cells could facilitate both HIV crossing the mucosal barrier and subsequent infection or replication in underlying target cells. Our studies provide a mechanism by which this common STI could potentially promote the establishment of founder virus populations and the maintenance of local HIV reservoirs in the endocervix. Development of an HIV/STI co-infection model also provides a tool to further explore the role of other sexually transmitted infections in enhancing HIV acquisition. PMID:26730599

  7. 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

  8. Dissemination of a Highly Virulent Pathogen: Tracking The Early Events That Define Infection

    PubMed Central

    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

  9. Observations of Early/Fast VLF Events on Vieques Island, Puerto Rico

    NASA Astrophysics Data System (ADS)

    Pasko, V. P.; Inan, U. S.; Wood, T. G.; Stanley, M. A.; Mathews, J. D.; George, J. J.; Fong, N. T.

    2002-12-01

    Early/Fast VLF events are registered as sudden (i.e., "fast" < 20 ms) subionospheric VLF signal changes, occurring simultaneously (i.e., "early", <20 ms) with lightning discharges [e.g., Inan et al., GRL, 20, 2355, 1993]. These events constitute evidence of the direct energetic coupling between tropospheric thunderstorms and the overlying mesospheric and lower ionospheric regions. In August-September 2001 Penn State University organized an experimental campaign in Puerto Rico to perform correlative studies of lightning and lightning-induced ionospheric effects. A set of instruments employed for these studies included Arecibo Observatory 430 MHz UHF radar, New Mexico Tech Interferometer, and a video system. As part of this campaign Stanford University deployed broadband and narrowband VLF receivers at Casa Cielo, Vieques Island, Puerto Rico (18.12 deg N, 65.50 deg W), which were operated continuously during the time period August 21- September 15, 2001. The narrowband measurements of the NAU (Aguadilla, Puerto Rico), NLK (Jim Creek, Washington) and NAA (Cutler, Maine) signals were performed every day from 1500UT to 1400UT while broadband recordings were made 1 minute out of every 5 minutes from 1630UT to 1000UT. In this talk we report observations of spectacular early/fast VLF events, which were detected on the 40.75 kHz NAU signal on multiple occasions during August 31, September 1, 2 and 13, 2001. The observed signal amplitude changes ranged from a fraction of a dB up to 19 dB, with both positive and negative field changes. The unusually large events were superposed on top of a very high degree of variability of signal amplitude, caused by the fact that the magnetic loop antenna was aligned to null the ground signal and was thus disposed to only detect the sky wave signal. Some of the observed events exhibited recovery signatures with duration on the order of several tens of seconds, while a subset of events did not exhibit clear recovery signatures, possibly masked by the high variability of the NAU signal. The majority of reported events exhibit very sharp onsets (<20 ms) clearly associated with strong radio atmospheric signatures observed in multiple VLF channels. In all observed cases the thunderstorm cells possibly responsible for these events were located at distances ranging from approximately 150 to 400 km from the observational site.

  10. 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.

  11. Early Events in Helix Unfolding Under External Forces: A Milestoning Analysis

    PubMed Central

    Kreuzer, Steven M; Elber, Ron; Moon, Tess J

    2012-01-01

    Initial events of helix breakage as a function of load are considered using Molecular Dynamics simulations and Milestoning analysis. A helix length of ~100 amino acids is considered as a model for typical helices found in molecular machines and as a model that minimizes end effects for early events of unfolding. Transitions of individual amino acids (averaged over the helixs interior residues) are examined and its surrounding hydrogen bonds are considered. Dense kinetic networks are constructed that, with Milestoning analysis, provide the overall kinetics of early breakage events. Network analysis and selection of MaxFlux pathways illustrate that load impacts unfolding mechanisms in addition to time scales. At relatively high (100pN) load levels, the principal intermediate is the 310-helix, while at relatively low (10pN) levels the ?-helix is significantly populated, albeit not as an unfolding intermediate. Coarse variables are examined at different levels of resolution; the rate of unfolding illustrates remarkable stability under changes in the coarsening. Consistent prediction of about ~5ns for the time of a single amino-acid unfolding event are obtained. Hydrogen bonds are much faster coarse variables (by about 2 orders of magnitude) compared to backbone torsional transition, which gates unfolding and thereby provides the appropriate coarse variable for the initiation of unfolding. PMID:22471347

  12. 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...

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

    ERIC Educational Resources Information Center

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

    2014-01-01

    Cunningham and Stanovich reported a longitudinal investigation over 10years 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

  14. 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

  15. 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.

  16. 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; WactawskiWende, 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 2fold 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 wholebody protein breakdown is an early event in development of PDAC. PMID:25261994

  17. 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

  18. Notch pathway regulates female germ cell meiosis progression and early oogenesis events in fetal mouse.

    PubMed

    Feng, Yan-Min; Liang, Gui-Jin; Pan, Bo; Qin, Xun-Si; Zhang, Xi-Feng; Chen, Chun-Lei; Li, Lan; Cheng, Shun-Feng; De Felici, Massimo; Shen, Wei

    2014-01-01

    A critical process of early oogenesis is the entry of mitotic oogonia into meiosis, a cell cycle switch regulated by a complex gene regulatory network. Although Notch pathway is involved in numerous important aspects of oogenesis in invertebrate species, whether it plays roles in early oogenesis events in mammals is unknown. Therefore, the rationale of the present study was to investigate the roles of Notch signaling in crucial processes of early oogenesis, such as meiosis entry and early oocyte growth. Notch receptors and ligands were localized in mouse embryonic female gonads and 2 Notch inhibitors, namely DAPT and L-685,458, were used to attenuate its signaling in an in vitro culture system of ovarian tissues from 12.5 days post coitum (dpc) fetus. The results demonstrated that the expression of Stra8, a master gene for germ cell meiosis, and its stimulation by retinoic acid (RA) were reduced after suppression of Notch signaling, and the other meiotic genes, Dazl, Dmc1, and Rec8, were abolished or markedly decreased. Furthermore, RNAi of Notch1 also markedly inhibited the expression of Stra8 and SCP3 in cultured female germ cells. The increased methylation status of CpG islands within the Stra8 promoter of the oocytes was observed in the presence of DAPT, indicating that Notch signaling is probably necessary for maintaining the epigenetic state of this gene in a way suitable for RA stimulation. Furthermore, in the presence of Notch inhibitors, progression of oocytes through meiosis I was markedly delayed. At later culture periods, the rate of oocyte growth was decreased, which impaired subsequent primordial follicle assembly in cultured ovarian tissues. Taken together, these results suggested new roles of the Notch signaling pathway in female germ cell meiosis progression and early oogenesis events in mammals. PMID:24398584

  19. 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

  20. Replication and Control of Circular Bacterial Plasmids

    PubMed Central

    del Solar, Gloria; Giraldo, Rafael; Ruiz-Echevarra, Mara Jess; Espinosa, Manuel; Daz-Orejas, Ramn

    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. 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

  2. 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.

  3. 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, Cte dIvoire 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

  4. 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 δ13C and δ18O 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 δ13C and δ18O 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 δ18O 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.

  5. Rearranged JC virus noncoding control regions found in progressive multifocal leukoencephalopathy patient samples increase virus early gene expression and replication rate.

    PubMed

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

    2010-10-01

    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

  6. 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

  7. Preserving the Past: An Early Interview Improves Delayed Event Memory in Children With Intellectual Disabilities

    PubMed Central

    Brown, Deirdre A; Lewis, Charlie N; Lamb, Michael E

    2015-01-01

    The influence of an early interview on children's (N = 194) later recall of an experienced event was examined in children with mild and moderate intellectual disabilities (CWID; 7–12 years) and typically developing (TD) children matched for chronological (7–12 years) or mental (4–9 years) age. Children previously interviewed were more informative, more accurate, and less suggestible. CWID (mild) recalled as much information as TD mental age matches, and were as accurate as TD chronological age matches. CWID (moderate) recalled less than TD mental age matches but were as accurate. Interviewers should elicit CWID's recall as early as possible and consider developmental level and severity of impairments when evaluating eyewitness testimony. PMID:25876042

  8. 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.

  9. The glutathione transferase of Nicotiana benthamiana NbGSTU4 plays a role in regulating the early replication of Bamboo mosaic virus

    PubMed Central

    Chen, I-Hsuan; Chiu, Meng-Hsuen; Cheng, Shun-Fang; Hsu, Yau-Heiu; Tsai, Ching-Hsiu

    2013-01-01

    Bamboo mosaic virus (BaMV) is a single-stranded positive-sense RNA virus. One of the plant glutathione S-transferase (GST) genes, NbGSTU4, responds as an upregulated gene in Nicotiana benthamiana post BaMV infection. In order to identify the role of NbGSTU4 in BaMV infection, the expression of NbGSTU4 was knocked down using a virus-induced gene silencing technique or was transiently expressed in N. benthamiana in BaMV inoculation. The results show a significant decrease in BaMV RNA accumulation when the expression level of NbGSTU4 is reduced; whereas the viral RNA accumulation increases when NbGSTU4 is transiently expressed. Furthermore, this study identified that the involvement of NbGSTU4 in viral RNA accumulation occurs by its participation in the viral early replication step. The findings show that the NbGSTU4 protein expressed from Escherichia coli can interact with the 3? untranslated region (UTR) of the BaMV RNA in vitro in the presence of glutathione (GSH). The addition of GSH in the in vitro replication assay shows an enhancement of minus-strand but not plus-strand RNA synthesis. The results suggest that the plant GST protein plays a role in binding viral RNA and delivering GSH to the replication complex to create a reduced condition for BaMV minus-strand RNA synthesis. PMID:23701112

  10. Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology

    PubMed Central

    Rissman, Robert A.; Poon, Wayne W.; Blurton-Jones, Mathew; Oddo, Salvatore; Torp, Reidun; Vitek, Michael P.; LaFerla, Frank M.; Rohn, Troy T.; Cotman, Carl W.

    2004-01-01

    Neurofibrillary tangles (NFTs) are composed of abnormal aggregates of the cytoskeletal protein tau. Together with amyloid β (Aβ) plaques and neuronal and synaptic loss, NFTs constitute the primary pathological hallmarks of Alzheimer disease (AD). Recent evidence also suggests that caspases are activated early in the progression of AD and may play a role in neuronal loss and NFT pathology. Here we demonstrate that tau is cleaved at D421 (ΔTau) by executioner caspases. Following caspase-cleavage, ΔTau facilitates nucleation-dependent filament formation and readily adopts a conformational change recognized by the early pathological tau marker MC1. ΔTau can be phosphorylated by glycogen synthase kinase-3β and subsequently recognized by the NFT antibody PHF-1. In transgenic mice and AD brains, ΔTau associates with both early and late markers of NFTs and is correlated with cognitive decline. Additionally, ΔTau colocalizes with Aβ1–42 and is induced by Aβ1–42 in vitro. Collectively, our data imply that Aβ accumulation triggers caspase activation, leading to caspase-cleavage of tau, and that this is an early event that may precede hyperphosphorylation in the evolution of AD tangle pathology. These results suggest that therapeutics aimed at inhibiting tau caspase-cleavage may prove beneficial not only in preventing NFT formation, but also in slowing cognitive decline. PMID:15232619

  11. 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.

  12. 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

  13. 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.

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

    PubMed

    Davies, M S

    1996-01-01

    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(2+) (B(H) = 78.3 mu T, B(HAC) = 40 mu T peak-peak at 60 Hz, B(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. PMID:8860733

  15. Two New Early Bacteriophage T4 Genes, repEA and repEB, That Are Important for DNA Replication Initiated from Origin E

    PubMed Central

    Vaiskunaite, Rita; Miller, Andrew; Davenport, Laura; Mosig, Gisela

    1999-01-01

    Two new, small, early bacteriophage T4 genes, repEA and repEB, located within the origin E (oriE) region of T4 DNA replication, affect functioning of this origin. An important and unusual property of the oriE region is that it is transcribed at early and late periods after infection, but in opposite directions (from complementary DNA strands). The early transcripts are mRNAs for RepEA and RepEB proteins, and they can serve as primers for leading-strand DNA synthesis. The late transcripts, which are genuine antisense RNAs for the early transcripts, direct synthesis of virion components. Because the T4 genome contains several origins, and because recombination can bypass a primase requirement for retrograde synthesis, neither defects in a single origin nor primase deficiencies are lethal in T4 (Mosig et al., FEMS Microbiol. Rev. 17:8398, 1995). Therefore, repEA and repEB were expected and found to be important for T4 DNA replication only when activities of other origins were reduced. To investigate the in vivo roles of the two repE genes, we constructed nonsense mutations in each of them and combined them with the motA mutation sip1 that greatly reduces initiation from other origins. As expected, T4 DNA synthesis and progeny production were severely reduced in the double mutants as compared with the single motA mutant, but early transcription of oriE was reduced neither in the motA nor in the repE mutants. Moreover, residual DNA replication and growth of the double mutants were different at different temperatures, suggesting different functions for repEA and repEB. We surmise that the different structures and protein requirements for functioning of the different origins enhance the flexibility of T4 to adapt to varied growth conditions, and we expect that different origins in other organisms with multiorigin chromosomes might differ in structure and function for similar reasons. PMID:10559179

  16. 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.

  17. 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.

  18. The 6-Aminoquinolone WC5 Inhibits Different Functions of the Immediate-Early 2 (IE2) Protein of Human Cytomegalovirus That Are Essential for Viral Replication

    PubMed Central

    Mercorelli, Beatrice; Luganini, Anna; Muratore, Giulia; Massari, Serena; Terlizzi, Maria Elena; Tabarrini, Oriana

    2014-01-01

    The human cytomegalovirus (HCMV) immediate-early 2 (IE2) protein is a multifunctional factor essential for viral replication. IE2 modulates both viral and host gene expression, deregulates cell cycle progression, acts as an immunomodulator, and antagonizes cellular antiviral responses. Based on these facts, IE2 has been proposed as an important target for the development of innovative antiviral approaches. We previously identified the 6-aminoquinolone WC5 as a promising inhibitor of HCMV replication, and here, we report the dissection of its mechanism of action against the viral IE2 protein. Using glutathione S-transferase (GST) pulldown assays, mutagenesis, cell-based assays, and electrophoretic mobility shift assays, we demonstrated that WC5 does not interfere with IE2 dimerization, its interaction with TATA-binding protein (TBP), and the expression of a set of cellular genes that are stimulated by IE2. On the contrary, WC5 targets the regulatory activity exerted by IE2 on different responsive viral promoters. Indeed, WC5 blocked the IE2-dependent negative regulation of the major immediate-early promoter by preventing IE2 binding to the crs element. Moreover, WC5 reduced the IE2-dependent transactivation of a series of indicator constructs driven by different portions of the early UL54 gene promoter, and it also inhibited the transactivation of the murine CMV early E1 promoter by the IE3 protein, the murine cytomegalovirus (MCMV) IE2 homolog. In conclusion, our results indicate that the overall anti-HCMV activity of WC5 depends on its ability to specifically interfere with the IE2-dependent regulation of viral promoters. Importantly, our results suggest that this mechanism is conserved in murine CMV, thus paving the way for further preclinical evaluation in an animal model. PMID:25155603

  19. The early Toarcian anoxic event: what the beginning and the end of the story are?

    NASA Astrophysics Data System (ADS)

    Mattioli, Emanuela; Plancq, Julien; Raucsik, Bla

    2010-05-01

    The early Toarcian anoxic event: what the beginning and the end of the story are? E. Mattioli (1), J. Plancq (1), and B. Rauksik (2) (1) UMR 5125 PEPS, CNRS, France; Universit Lyon 1, Campus de la DOUA, Btiment Gode, 69622 Villeurbanne Cedex, France (emanuela.mattioli@univ-lyon1.fr) (2) Department of Earth and Environmental Sciences, University of Pannonia, Veszprm, Hungary The early Toarcian anoxic event (T-OAE) and the associated biotic crisis have received much attention in the last decade. However, the events forewarning the crisis as well as its aftermath are still poorly known. The T-OAE coincides with a prominent carbon isotope negative excursion (T-CIE) that is preceded by an excursion of similar intensity at the Pliensbachian-Toarcian boundary (Hesselbo et al., 2007). The onset of T-CIE occurred some 700 kyr later than the end of the Boundary-CIE (Suan et al., 2008a). This succession of events demonstrates that the T-OAE was a complex suite of environmental perturbations. In this work, we focused on calcareous nannofossil assemblages occurring in the Peniche section (Portugal) during the Boundary-CIE with the aim to understand if calcifying plankton reacted in a similar/different way to the two CIEs. Also, two sections and one borehole located along a W-E transect, along the NW-Tethyan shelf (in the Yorkshire coast, in the E Paris Basin, and in Mecsek Basin, respectively), were investigated to assess which way calcareous nannoplankton recovered after the crisis, and if the recovery was a synchronous event. The production by nannoplankton collapsed during the T-CIE, as demonstrated by the lowest absolute abundance of nannofossils measured in Peniche and other studied sites (Mattioli et al., 2008). Besides this nannofossil abundance decrease, also the size of the incertae sedis Schizosphaerella test was drastically reduced (Suan et al., 2008b). If a similar size decrease is also recorded during the Boundary-CIE, calcareous nannofossil abundances are very high, and assemblages seem not to record an environmental stress. The study of the calcareous nannofossil assemblages along a W-E transect in the NW-Tethyan shelf shows a progressive, but significant decrease in abundance fluxes from W to E, and the lowest fluxes are recorded in the Mecsek Basin that was closer to the oceanic Tethys. A progressive re-colonization of the lower photic zone by deep-dweller nannofossil taxa, mainly Crepidolithus crassus, is observed in the aftermath of the anoxic event, but this re-colonization occurred earlier in the Mecsek Basin, probably because of more effective marine connections with the open-ocean. This set of data indicates that: (1) environmental deterioration was recurrent until it reached its acme during the T-OAE; (2) post-crisis recovery of surface water environments was not synchronous, depending on palaeoceanographic conditions occurring within the western Tethys. Our scenario implies an intrinsically long-lasting suite of events and argues in favour of long-lasting CO2 degassing, most likely related to the emplacement of the large igneous province of Karoo-Ferrar as the main cause of the Toarcian environmental perturbations. Acknowledgements. We would like to thank John McArthur for kindly providing us the Toarcian samples from the Yorkshire coast. Hesselbo et al. (2007). Carbon-isotope record of the Early Jurassic (Toarcian) oceanic anoxic event from fossil wood and marine carbonate (Lusitanian Basin, Portugal), Earth Planet. Sci. Lett. 253, 455- 470. Mattioli et al. (2008). Calcareous nannoplankton changes across the early Toarcian oceanic anoxic event in the western Tethys. Paleoceanography 23, PA3208, doi:10.1029/2007PA001435, 2008. Suan et al. (2008a). Duration of the Early Toarcian carbon isotope excursion deduced from spectral analysis: Consequence for its possible causes. Earth Planet. Sci. Lett. 267, 666-679. Suan et al. (2008b). Evidence for major environmental perturbation prior to and during the Toarcian (Early Jurassic) oceanic anoxic event from the Lusitanian Basin, Portugal. Paleoceanography 23,

  20. 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

  1. Heterologous microarray experiments allow the identification of the early events associated with potato tuber cold sweetening

    PubMed Central

    Bagnaresi, Paolo; Moschella, Anna; Beretta, Ottavio; Vitulli, Federico; Ranalli, Paolo; Perata, Pierdomenico

    2008-01-01

    Background Since its discovery more than 100 years ago, potato (Solanum tuberosum) tuber cold-induced sweetening (CIS) has been extensively investigated. Several carbohydrate-associated genes would seem to be involved in the process. However, many uncertainties still exist, as the relative contribution of each gene to the process is often unclear, possibly as the consequence of the heterogeneity of experimental systems. Some enzymes associated with CIS, such as β-amylases and invertases, have still to be identified at a sequence level. In addition, little is known about the early events that trigger CIS and on the involvement/association with CIS of genes different from carbohydrate-associated genes. Many of these uncertainties could be resolved by profiling experiments, but no GeneChip is available for the potato, and the production of the potato cDNA spotted array (TIGR) has recently been discontinued. In order to obtain an overall picture of early transcriptional events associated with CIS, we investigated whether the commercially-available tomato Affymetrix GeneChip could be used to identify which potato cold-responsive gene family members should be further studied in detail by Real-Time (RT)-PCR (qPCR). Results A tomato-potato Global Match File was generated for the interpretation of various aspects of the heterologous dataset, including the retrieval of best matching potato counterparts and annotation, and the establishment of a core set of highly homologous genes. Several cold-responsive genes were identified, and their expression pattern was studied in detail by qPCR over 26 days. We detected biphasic behaviour of mRNA accumulation for carbohydrate-associated genes and our combined GeneChip-qPCR data identified, at a sequence level, enzymatic activities such as β-amylases and invertases previously reported as being involved in CIS. The GeneChip data also unveiled important processes accompanying CIS, such as the induction of redox- and ethylene-associated genes. Conclusion Our Global Match File strategy proved critical for accurately interpretating heterologous datasets, and suggests that similar approaches may be fruitful for other species. Transcript profiling of early events associated with CIS revealed a complex network of events involving sugars, redox and hormone signalling which may be either linked serially or act in parallel. The identification, at a sequence level, of various enzymes long known as having a role in CIS provides molecular tools for further understanding the phenomenon. PMID:18416834

  2. Events during Early Triassic recovery from the end-Permian extinction

    NASA Astrophysics Data System (ADS)

    Tong, Jinnan; Zhang, Suxin; Zuo, Jingxun; Xiong, Xinqi

    2007-01-01

    The Palaeozoic-Mesozoic transition is characterized not only by the biggest Phanerozoic mass extinction, at the end of Permian, but also a prolonged period of recovery of the biota during the succeeding Early Triassic. The delayed recovery is generally attributed to the effects of extreme environmental conditions on the Early Triassic ecosystem. However, there has been very little study of the cause and mechanism of the environmental conditions that prevailed during the period of extinction and subsequent recovery. Research on the Permian-Triassic boundary and Lower Triassic, especially that on environmental events at the beginning of the Triassic in South China, indicates that the slowness of the recovery may be the result of three factors: (1) extreme environmental conditions that persisted through the transitional period and which were maintained by, for example, intermittent contemporary volcanism; (2) a passive evolutionary and ecologic strategy of the biota, in which r-selection taxa were dominant and K-selection forms insignificant; (3) an immature, poorly functioning ecosystem, which had difficulty in responding to and withstanding extreme environmental changes. According to data from South China, environmental changes were frequent during the Late Permian, and especially serious at the Permian-Triassic boundary. The Late Permian ecosystem was well structured and fully functioning as a result of a long period of steady development during the late Palaeozoic, and was capable of resisting general environmental changes. However, increasingly frequent and probably more extreme environmental events in the latest Permian may have led to a general collapse of this ecosystem and to the mass extinction at the end of the Permian. The Early Triassic ecosystem was immature, functioned poorly, and was unable to respond effectively to environmental changes, so that persisting extreme environmental conditions slowed ecosystem reconstruction considerably, and the recovery of the biota therefore took a relatively long time. The environmental events at the Permian-Triassic boundary might not be significantly different from those at other Phanerozoic transitions, but they consisted of a series of events that occurred at intervals during the transitional period.

  3. 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

  4. 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 δ7Li values is expected to characterize OAEs. The studied sections illustrate this phenomenon: δ7Li values decrease to a minimum coincident with the negative carbon-isotope excursion that effectively records the onset of OAE 1a. A second negative δ7Li 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.

  5. 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

  6. Assemblage level and intraspecific response of calcareous nannofossils during early Eocene hyperthermal events.

    NASA Astrophysics Data System (ADS)

    Joachim, C.; Mutterlose, J.

    2012-04-01

    The composition of calcareous nannofossils across the early Eocene has been investigated at the equatorial Atlantic (Demerara Rise; ODP Site 1260A, 277.17 - 227.04 mbsf & 1260B, 256.16 - 235.10 mbsf), including the Paleocene - Eocene Thermal Maximum (PETM), Eocene thermal maximum 2 (ETM2) = Eocene layer of mysterious origin (Elmo) and ETM3 ("X"-event). These hyperthermal events are marked by a substantial input of isotopically light carbon into the oceans, related to a general warming trend, which led to ocean acidification. Perturbations of the carbon system are thought to have caused significant changes in the composition of marine biota. The PETM interval of Site 1260, defined by the onset and the termination of a negative carbon isotope anomaly with a value of ~ - 2 , is 1.39 m thick (1260A, 276.87 - 275.48 mbsf). The lowermost 65 cm thick interval (1260A, 276.87 - 276.22 mbsf) with a carbonate content lower than 20 % includes a distinctive basal clay layer of approximately 40 cm thickness. The ETM2 is 78 cm thick (1260B, 238.93 - 238.15 mbsf) and marked by a negative carbon isotope excursion of ~ - 1 . The final ETM3 is 17cm thick (1260A, 227.06 - 226.89 mbsf) and shows a negative shift of the carbon isotopes of - 1.2 . The PETM is preceded by two short eutrophic events, where the nannofossil-based productivity index shows very high values, with concomitant low temperatures, the latter eutrophic event is directly preceding the onset of the carbon isotope excursion. The PETM excursion flora can be divided in three groups: 1) Small taxa - or taxa with a big aperture, like Coccolithus minimus, Coccolithus latus and Coccolithus foraminis, which are regarded as stress forms of Coccolithus pelagicus, reacting to possible surface water acidification during the initial phase of the PETM. 2) The large sized Coccolithus bownii, which appears as an acme during the body and early recovery, may profit from increasing pH and decreasing DIC conditions. 3) Teratoid ("malformed") discoasters are not restricted to the PETM and are therefore rather related to higher temperatures then to changes of the oceans carbonate system. Size measurements in the common species of C. pelagicus, including several ecophenotypes like C. minimus and C. latus, show marked changes during the events.

  7. 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.

  8. Temporal sequence and spatial distribution of early events of fertilization in single sea urchin eggs

    SciTech Connect

    Eisen, A.; Kiehart, D.P.; Wieland, S.J.; Reynolds, G.T.

    1984-11-01

    Measurements and observations of five early events of fertilization, singly and in pairs, from single sea urchin eggs have revealed the precise temporal sequence and spatial distribution of these events. In the Arbacia punctulata egg, a wave of surface contraction occurs coincident with membrane depolarization (t = 0). These two earliest events are followed by the onset of a rapid, propagated increase in cytoplasmic-free calcium at approx.23 s as measured by calcium-aequorin luminescence. The luminescence reaches its peak value by 40 s after the membrane depolarization. The luminescence remains uniformly elevated for some time before its decay over several minutes. The onset of an increase in the pyridin nucleotide (NAD(P)H) fluorescence follows the membrane depolarization at approx.51 s. The fertilization membrane begins its elevation in a wave-like fashion coincidentally with the increase in NAD(P)H fluorescence. Similar results are observed in the Lytechinus variegatus egg. The results suggest that while the increase in cytoplasmic-free calcium may be important for many changes occurring in the egg, the elevated-free calcium is not directly responsible for the propagated wave of cortical granule exocytosis. 32 references, 10 figures.

  9. Temporal sequence and spatial distribution of early events of fertilization in single sea urchin eggs.

    PubMed

    Eisen, A; Kiehart, D P; Wieland, S J; Reynolds, G T

    1984-11-01

    Measurements and observations of five early events of fertilization, singly and in pairs, from single sea urchin eggs have revealed the precise temporal sequence and spatial distribution of these events. In the Arbacia punctulata egg, a wave of surface contraction occurs coincident with membrane depolarization (t = 0). These two earliest events are followed by the onset of a rapid, propagated increase in cytoplasmic-free calcium at approximately 23 s as measured by calcium-aequorin luminescence. The luminescence reaches its peak value by 40 s after the membrane depolarization. The luminescence remains uniformly elevated for some time before its decay over several minutes. The onset of an increase in the pyridine nucleotide (NAD(P)H) fluorescence follows the membrane depolarization at approximately 51 s. The fertilization membrane begins its elevation in a wave-like fashion coincidentally with the increase in NAD(P)H fluorescence. Similar results are observed in the Lytechinus variegatus egg. The results suggest that while the increase in cytoplasmic-free calcium may be important for many changes occurring in the egg, the elevated-free calcium is not directly responsible for the propagated wave of cortical granule exocytosis. PMID:6490715

  10. Early events of citrus greening (Huanglongbing) disease development at the ultrastructural level.

    PubMed

    Folimonova, Svetlana Y; Achor, Diann S

    2010-09-01

    Citrus greening (Huanglongbing [HLB]) is one of the most destructive diseases of citrus worldwide. The causal agent of HLB in Florida is thought to be 'Candidatus Liberibacter asiaticus'. Understanding of the early events in HLB infection is critical for the development of effective measures to control the disease. In this work, we conducted cytopathological studies by following the development of the disease in citrus trees graft inoculated with 'Ca. L. asiaticus'-containing material under greenhouse conditions to examine the correlation between ultrastructural changes and symptom production, with the main objective of characterizing the early events of infection. Based on our observations, one of the first degenerative changes induced upon invasion of the pathogen appears to be swelling of middle lamella between cell walls surrounding sieve elements. This anatomical aberration was often observed in samples from newly growing flushes in inoculated sweet orange and grapefruit trees at the early "presymptomatic" stage of HLB infection. Development of symptoms and their progression correlated with an increasing degree of microscopic aberrations. Remarkably, the ability to observe the bacterium in the infected tissue also correlated with the degree of the disease progression. Large numbers of bacterial cells were found in phloem sieve tubes in tissue samples from presymptomatic young flushes. In contrast, we did not observe the bacteria in highly symptomatic leaf samples, suggesting a possibility that, at more advanced stages of the disease, a major proportion of 'Ca. L. asiaticus' is present in a nonviable state. We trust that observations reported here advance our understanding of how 'Ca. L. asiaticus' causes disease. Furthermore, they may be an important aid in answering a question: when and where within an infected tree the tissue serves as a better inoculum source for acquisition and transmission of the bacterium by its psyllid vector. PMID:20701493

  11. Dose and Effect Thresholds for Early Key Events in a PPAR?-Mediated Mode of Action.

    PubMed

    Lake, April D; Wood, Charles E; Bhat, Virunya S; Chorley, Brian N; Carswell, Gleta K; Sey, Yusupha M; Kenyon, Elaina M; Padnos, Beth; Moore, Tanya M; Tennant, Alan H; Schmid, Judith E; George, Barbara Jane; Ross, David G; Hughes, Michael F; Corton, J Christopher; Simmons, Jane Ellen; McQueen, Charlene A; Hester, Susan D

    2016-02-01

    Current strategies for predicting adverse health outcomes of environmental chemicals are centered on early key events in toxicity pathways. However, quantitative relationships between early molecular changes in a given pathway and later health effects are often poorly defined. The goal of this study was to evaluate short-term key event indicators using qualitative and quantitative methods in an established pathway of mouse liver tumorigenesis mediated by peroxisome proliferator-activated receptor alpha (PPAR?). Male B6C3F1 mice were exposed for 7 days to di (2-ethylhexyl) phthalate (DEHP), di-n-octyl phthalate (DNOP), and n-butyl benzyl phthalate (BBP), which vary in PPAR? activity and liver tumorigenicity. Each phthalate increased expression of select PPAR? target genes at 7 days, while only DEHP significantly increased liver cell proliferation labeling index (LI). Transcriptional benchmark dose (BMDT) estimates for dose-related genomic markers stratified phthalates according to hypothetical tumorigenic potencies, unlike BMDs for non-genomic endpoints (relative liver weights or proliferation). The 7-day BMDT values for Acot1 as a surrogate measure for PPAR? activation were 29, 370, and 676?mg/kg/day for DEHP, DNOP, and BBP, respectively, distinguishing DEHP (liver tumor BMD of 35?mg/kg/day) from non-tumorigenic DNOP and BBP. Effect thresholds were generated using linear regression of DEHP effects at 7 days and 2-year tumor incidence values to anchor early response molecular indicators and a later phenotypic outcome. Thresholds varied widely by marker, from 2-fold (Pdk4 and proliferation LI) to 30-fold (Acot1) induction to reach hypothetical tumorigenic expression levels. These findings highlight key issues in defining thresholds for biological adversity based on molecular changes. PMID:26519955

  12. Human neocortical development: the importance of embryonic and early fetal events.

    PubMed

    Meyer, G

    2001-08-01

    The identification of numerous genes involved in the development of the cerebral cortex has led to an increased interest in the early stages of corticogenesis, when the first postmitotic neurons migrate into the cortical plate to form the foundation of the adult cortex. However, the cellular substrate of gene expression in early human cortical development is widely unknown. This article analyzes the complex sequence of events in the differentiation of the preplate, the predecessor of the neocortex, and discusses the possible origin and migratory routes of the neuronal populations involved in the transition from preplate to cortical plate. The neuronal classes present in embryonic and early fetal stages are redefined in terms of their relationship with the Reelin-Dab1 signaling pathway whose integrity is essential for successful migration into the cortex. A timetable of developmental steps is provided, and the peculiarities of the preplate derivatives in the human brain, marginal zone, and subplate are discussed. The results presented here may contribute to a deeper understanding of the pathogenesis of migration disorders. PMID:11488396

  13. 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

  14. 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…

  15. Universal Sequence Replication, Reversible Polymerization and Early Functional Biopolymers: A Model for the Initiation of Prebiotic Sequence Evolution

    PubMed Central

    Walker, Sara Imari; Grover, Martha A.; Hud, Nicholas V.

    2012-01-01

    Many models for the origin of life have focused on understanding how evolution can drive the refinement of a preexisting enzyme, such as the evolution of efficient replicase activity. Here we present a model for what was, arguably, an even earlier stage of chemical evolution, when polymer sequence diversity was generated and sustained before, and during, the onset of functional selection. The model includes regular environmental cycles (e.g. hydration-dehydration cycles) that drive polymers between times of replication and functional activity, which coincide with times of different monomer and polymer diffusivity. Template-directed replication of informational polymers, which takes place during the dehydration stage of each cycle, is considered to be sequence-independent. New sequences are generated by spontaneous polymer formation, and all sequences compete for a finite monomer resource that is recycled via reversible polymerization. Kinetic Monte Carlo simulations demonstrate that this proposed prebiotic scenario provides a robust mechanism for the exploration of sequence space. Introduction of a polymer sequence with monomer synthetase activity illustrates that functional sequences can become established in a preexisting pool of otherwise non-functional sequences. Functional selection does not dominate system dynamics and sequence diversity remains high, permitting the emergence and spread of more than one functional sequence. It is also observed that polymers spontaneously form clusters in simulations where polymers diffuse more slowly than monomers, a feature that is reminiscent of a previous proposal that the earliest stages of life could have been defined by the collective evolution of a system-wide cooperation of polymer aggregates. Overall, the results presented demonstrate the merits of considering plausible prebiotic polymer chemistries and environments that would have allowed for the rapid turnover of monomer resources and for regularly varying monomer/polymer diffusivities. PMID:22493682

  16. Slip-Related Changes in Plantar Pressure Distribution, and Parameters for Early Detection of Slip Events

    PubMed Central

    Choi, Seungyoung; Cho, Hyungpil; Kang, Boram; Lee, Dong Hun; Kim, Mi Jung

    2015-01-01

    Objective To investigate differences in plantar pressure distribution between a normal gait and unpredictable slip events to predict the initiation of the slipping process. Methods Eleven male participants were enrolled. Subjects walked onto a wooden tile, and two layers of oily vinyl sheet were placed on the expected spot of the 4th step to induce a slip. An insole pressure-measuring system was used to monitor plantar pressure distribution. This system measured plantar pressure in four regions (the toes, metatarsal head, arch, and heel) for three events: the step during normal gait; the recovered step, when the subject recovered from a slip; and the uncorrected, harmful slipped step. Four variables were analyzed: peak pressure (PP), contact time (CT), the pressure-time integral (PTI), and the instant of peak pressure (IPP). Results The plantar pressure pattern in the heel was unique, as compared with other parts of the sole. In the heel, PP, CT, and PTI values were high in slipped and recovered steps compared with normal steps. The IPP differed markedly among the three steps. The IPPs in the heel for the three events were, in descending order (from latest to earliest), slipped, recovered, and normal steps, whereas in the other regions the order was normal, recovered, and slipped steps. Finally, the metatarsal head-to-heel IPP ratios for the normal, recovered, and slipped steps were 6.1±2.9, 3.1±3.0, and 2.2±2.5, respectively. Conclusion A distinctive plantar pressure pattern in the heel might be useful for early detection of a slip event to prevent slip-related injuries. PMID:26798603

  17. 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

  18. Project Dakota Outreach: Replicating Family Centered, Community Based Early Intervention Policy and Practice, 1991-1994. Final Report.

    ERIC Educational Resources Information Center

    Kjerland, Linda; And Others

    This project worked to help community programs and interagency groups develop fluid organizational structures and better assist staff and parents in the provision of family-centered, community-based early intervention services for young children with disabilities and their families. Highlights of the service model include transdisciplinary…

  19. 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,

  20. Actomyosin mediates gravisensing and early transduction events in reoriented cut snapdragon spikes.

    PubMed

    Zhang, Zhaoqi; Friedman, Haya; Meir, Shimon; Belausov, Eduard; Philosoph-Hadas, Sonia

    2011-07-15

    We investigated the involvement of the actomyosin network in the early events of the gravitropic response of cut snapdragon (Antirrhinum majus L.) spikes. The effects of the actin-modulating drug, cytochalasin D (CD) and/or the myosin inhibitor, 2,3-butanedione-2-monoxime (BDM) on amyloplast displacement, lateral auxin transport and consequently on stem bending were examined. The inhibitory effect on cytoskeleton integrity was studied by using indirect immunofluorescence double-labeling of actin and myosin. Our results demonstrate that no organizational changes in actin filaments occurred in cortical and endodermal cells of the stem bending zone during reorientation. These results suggest that actin depolymerization is not required for amyloplast sedimentation. Unlike the chloroplasts in the cortex, the amyloplasts in the endodermis were surrounded by actin and myosin, indicating that amyloplasts may be attached to the actin filaments via the motor protein, myosin. This suggests the involvement of myosin as part of the actomyosin complex in amyloplast movement in vertical as well as in reoriented stems. This suggestion was supported by the findings showing that: (a) BDM or CD disrupted the normal organization of actin either by altering characteristic distribution patterns of myosin-like protein in the cortex (BDM), or by causing actin fragmentation (CD); (b) both compounds inhibited the gravity-induced amyloplast displacement in the endodermis. Additionally, these compounds also inhibited lateral auxin transport across the stem and stem gravitropic bending. Our study suggests that during stem reorientation amyloplasts possibly remain attached to the actin filaments, using myosin as a motor protein. Thus, gravisensing and early transduction events in the gravitropic response of snapdragon spikes, manifested by amyloplast displacement and lateral auxin transport, are mediated by the actomyosin complex. PMID:21388706

  1. 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.

  2. 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.

  3. 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 35) at autism diagnosis. PMID:25878901

  4. 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

  5. Association of Early Age at Establishment of Chronic Hepatitis B Infection with Persistent Viral Replication, Liver Cirrhosis and Hepatocellular Carcinoma: A Systematic Review

    PubMed Central

    Shimakawa, Yusuke; Yan, Hong-Jing; Tsuchiya, Naho; Bottomley, Christian; Hall, Andrew J.

    2013-01-01

    Age at infection with hepatitis B virus (HBV) is a known risk factor for chronic HBV infection. However, in addition, there is some evidence that early age at infection further increases the risk of primary liver cancer beyond its association with increased risk of chronic infection. This systematic review of observational studies assesses the association between age at initiation of chronic HBV infection and liver cirrhosis, hepatocellular carcinoma, and their predictors including indicators of ongoing viral replication and hepatic damage. The review includes birth order and maternal HBV serology as proxies for age at infection. Electronic searches in two English-language (Medline and Embase, until Jan 2012) and two Chinese-language (CNKI and SinoMed, until Sep 2012) databases without language restriction and manual search through reference lists identified 7,077 papers, of which 19 studies of 21 outcomes (8 primary liver cancer, 1 liver cirrhosis, 10 viral replication and 2 liver inflammation) are included. One study directly examined the age at infection in a longitudinal cohort, 12 assessed maternal sero-status and 6 investigated birth order. The direction of associations in all studies was in accordance with our hypothesis that earlier age at infection is associated with worse outcomes in addition to its effect of increasing the probability of chronic HBV infection. This has implications for the control of hepatitis B. PMID:23894479

  6. 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

    Silva, Louisa M T; Schalock, Mark; 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

  7. 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

  8. 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.

  9. 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

  10. Early Maternal Deprivation Enhances Voluntary Alcohol Intake Induced by Exposure to Stressful Events Later in Life

    PubMed Central

    Peñasco, Sara; Mela, Virginia; López-Moreno, Jose Antonio; Viveros, María-Paz; Marco, Eva M.

    2015-01-01

    In the present study, we aimed to assess the impact of early life stress, in the form of early maternal deprivation (MD, 24 h on postnatal day, pnd, 9), on voluntary alcohol intake in adolescent male and female Wistar rats. During adolescence, from pnd 28 to pnd 50, voluntary ethanol intake (20%, v/v) was investigated using the two-bottle free choice paradigm. To better understand the relationship between stress and alcohol consumption, voluntary alcohol intake was also evaluated following additional stressful events later in life, that is, a week of alcohol cessation and a week of alcohol cessation combined with exposure to restraint stress. Female animals consumed more alcohol than males only after a second episode of alcohol cessation combined with restraint stress. MD did not affect baseline voluntary alcohol intake but increased voluntary alcohol intake after stress exposure, indicating that MD may render animals more vulnerable to the effects of stress on alcohol intake. During adolescence, when animals had free access to alcohol, MD animals showed lower body weight gain but a higher growth rate than control animals. Moreover, the higher growth rate was accompanied by a decrease in food intake, suggesting an altered metabolic regulation in MD animals that may interact with alcohol intake. PMID:25821601

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

    PubMed Central

    Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, KevinW.; Barrett, EugeneJ.; 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 3days to 4weeks 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 1week, blunted vasodilatory response in small resistance vessel in 4weeks and microvascular recruitment in as early as 3days. Insulin-stimulated whole body glucose disposal did not begin to progressively decrease until after 1week. 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

  12. Airway PI3K pathway activation is an early and reversible event in lung cancer development.

    PubMed

    Gustafson, Adam M; Soldi, Raffaella; Anderlind, Christina; Scholand, Mary Beth; Qian, Jun; Zhang, Xiaohui; Cooper, Kendal; Walker, Darren; McWilliams, Annette; Liu, Gang; Szabo, Eva; Brody, Jerome; Massion, Pierre P; Lenburg, Marc E; Lam, Stephen; Bild, Andrea H; Spira, Avrum

    2010-04-01

    Although only a subset of smokers develop lung cancer, we cannot determine which smokers are at highest risk for cancer development, nor do we know the signaling pathways altered early in the process of tumorigenesis in these individuals. On the basis of the concept that cigarette smoke creates a molecular field of injury throughout the respiratory tract, this study explores oncogenic pathway deregulation in cytologically normal proximal airway epithelial cells of smokers at risk for lung cancer. We observed a significant increase in a genomic signature of phosphatidylinositol 3-kinase (PI3K) pathway activation in the cytologically normal bronchial airway of smokers with lung cancer and smokers with dysplastic lesions, suggesting that PI3K is activated in the proximal airway before tumorigenesis. Further, PI3K activity is decreased in the airway of high-risk smokers who had significant regression of dysplasia after treatment with the chemopreventive agent myo-inositol, and myo-inositol inhibits the PI3K pathway in vitro. These results suggest that deregulation of the PI3K pathway in the bronchial airway epithelium of smokers is an early, measurable, and reversible event in the development of lung cancer and that genomic profiling of these relatively accessible airway cells may enable personalized approaches to chemoprevention and therapy. Our work further suggests that additional lung cancer chemoprevention trials either targeting the PI3K pathway or measuring airway PI3K activation as an intermediate endpoint are warranted. PMID:20375364

  13. Differential network analyses of Alzheimer's disease identify early events in Alzheimer's disease pathology.

    PubMed

    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 low 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. PMID:25147748

  14. 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

  15. Differential Network Analyses of Alzheimer's Disease Identify Early Events in Alzheimer's Disease Pathology

    PubMed Central

    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 low 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. PMID:25147748

  16. 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

  17. 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

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

    PubMed

    Siles, Laura; Alegre, Leonor; Tijero, Vernica; Munn-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

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

    NASA Astrophysics Data System (ADS)

    Kremer, Katrina; Yrro, Bl; Marillier, Franois; Hilbe, Michael; Corboud, Pierre; Rachoud-Schneider, Anne-Marie; Girardclos, Stphanie

    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.

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

    PubMed

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

    2015-03-01

    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 30min/day for 5days. 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

  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 30min/day for 5days. 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. Early and Strong Immune Responses Are Associated with Control of Viral Replication and Recovery in Lassa Virus-Infected Cynomolgus Monkeys?

    PubMed Central

    Baize, Sylvain; Marianneau, Philippe; Loth, Philippe; Reynard, Stphanie; Journeaux, Alexandra; Chevallier, Michle; Tordo, Nol; Deubel, Vincent; Contamin, Hugues

    2009-01-01

    Lassa virus causes a hemorrhagic fever endemic in West Africa. The pathogenesis and the immune responses associated with the disease are poorly understood, and no vaccine is available. We followed virological, pathological, and immunological markers associated with fatal and nonfatal Lassa virus infection of cynomolgus monkeys. The clinical picture was characterized by fever, weight loss, depression, and acute respiratory syndrome. Transient thrombocytopenia and lymphopenia, lymphadenopathy, splenomegaly, infiltration of mononuclear cells, and alterations of the liver, lungs, and endothelia were observed. Survivors exhibited fewer lesions and a lower viral load than nonsurvivors. Although all animals developed strong humoral responses, antibodies appeared more rapidly in survivors and were directed against GP1, GP2, and NP. Type I interferons were detected early after infection in survivors but only during the terminal stages in fatalities. The mRNAs for CXCL10 (IP-10) and CXCL11 (I-TAC) were abundant in peripheral blood mononuclear cells and lymph nodes from infected animals, but plasma interleukin-6 was detected only in fatalities. In survivors, high activated-monocyte counts were followed by a rise in the total number of circulating monocytes. Activated T lymphocytes circulated in survivors, whereas T-cell activation was low and delayed in fatalities. In vitro stimulation with inactivated Lassa virus induced activation of T lymphocytes from all infected monkeys, but only lymphocytes from survivors proliferated. Thus, early and strong immune responses and control of viral replication were associated with recovery, whereas fatal infection was characterized by major alterations of the blood formula and, in organs, weak immune responses and uncontrolled viral replication. PMID:19297492

  3. Extracellular matrix disruption is an early event in the pathogenesis of skeletal disease in mucopolysaccharidosis I.

    PubMed

    Heppner, Jonathan M; Zaucke, Frank; Clarke, Lorne A

    2015-02-01

    Progressive skeletal and connective tissue disease represents a significant clinical burden in all of the mucopolysaccharidoses. Despite the introduction of enzyme replacement strategies for many of the mucopolysaccharidoses, symptomatology related to bone and joint disease appears to be recalcitrant to current therapies. In order to address these unmet medical needs a clearer understanding of skeletal and connective tissue disease pathogenesis is required. Historically the pathogenesis of the mucopolysaccharidoses has been assumed to directly relate to progressive storage of glycosaminoglycans. It is now apparent for many lysosomal storage disorders that more complex pathogenic mechanisms underlie patients' clinical symptoms. We have used proteomic and genome wide expression studies in the murine mucopolysaccharidosis I model to identify early pathogenic events occurring in micro-dissected growth plate tissue. Studies were conducted using 3 and 5-week-old mice thus representing a time at which no obvious morphological changes of bone or joints have taken place. An unbiased iTRAQ differential proteomic approach was used to identify candidates followed by validation with multiple reaction monitoring mass spectrometry and immunohistochemistry. These studies reveal significant decreases in six key structural and signaling extracellular matrix proteins; biglycan, fibromodulin, PRELP, type I collagen, lactotransferrin, and SERPINF1. Genome-wide expression studies in embryonic day 13.5 limb cartilage and 5 week growth plate cartilage followed by specific gene candidate qPCR studies in the 5week growth plate identified fourteen significantly deregulated mRNAs (Adamts12, Aspn, Chad, Col2a1, Col9a1, Hapln4, Lum, Matn1, Mmp3, Ogn, Omd, P4ha2, Prelp, and Rab32). The involvement of biglycan, PRELP and fibromodulin; all members of the small leucine repeat proteoglycan family is intriguing, as this protein family is implicated in the pathogenesis of late onset osteoarthritis. Taken as a whole, our data indicates that alteration of the extracellular matrix represents a very early event in the pathogenesis of the mucopolysaccharidoses and implies that biomechanical failure of chondro-osseous tissue may underlie progressive bone and joint disease symptoms. These findings have important therapeutic implications. PMID:25410057

  4. 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 audiovisual 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 audiovisual 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 facevoice pair appeared amongst a train of neutral facevoice 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

  5. Reflections on some early events related to behavior analysis of child development.

    PubMed

    Bijou, S W

    1996-01-01

    A series of events related to the early application of behavioral principles to child behavior and development is described. The events began in the 1930s at Columbia University with a solicited letter from John B. Watson suggesting a master's degree thesis problem, and continued through the 1950s and 1960s at the University of Washington. Specifically, these happenings resulted in (a) research demonstrating that Skinner's laboratory method for studying nonhuman organisms could be profitably applied to the laboratory study of young normal children; (b) a demonstration that by successive approximations, a normal child can be operantly conditioned to respond to an arbitrary situation; (c) research showing that the effects of simple schedules of reinforcement obtained with nonhuman organisms could be duplicated in young normal and retarded children; (d) the demonstration that Skinner's operant laboratory method could be adapted to study young children in field situations; (e) research showing that operant principles can be successfully applied to the treatment of a young autistic boy with a serious visual handicap; (f) laboratory studies showing that mothers can be trained to treat their own young children who have behavior problems; (g) an in-home study demonstrating that a mother can treat her own child who has behavior problems; (h) a demonstration that operant principles can be applied effectively to teaching reading, writing, and arithmetic to children with retardation; and (i) publication of a book, Child Development: A Systematic and Empirical Theory, in collaboration with Donald M. Baer, by Prentice Hall in their Century Psychological Series. PMID:22478239

  6. Reflections on some early events related to behavior analysis of child development

    PubMed Central

    Bijou, Sidney W.

    1996-01-01

    A series of events related to the early application of behavioral principles to child behavior and development is described. The events began in the 1930s at Columbia University with a solicited letter from John B. Watson suggesting a master's degree thesis problem, and continued through the 1950s and 1960s at the University of Washington. Specifically, these happenings resulted in (a) research demonstrating that Skinner's laboratory method for studying nonhuman organisms could be profitably applied to the laboratory study of young normal children; (b) a demonstration that by successive approximations, a normal child can be operantly conditioned to respond to an arbitrary situation; (c) research showing that the effects of simple schedules of reinforcement obtained with nonhuman organisms could be duplicated in young normal and retarded children; (d) the demonstration that Skinner's operant laboratory method could be adapted to study young children in field situations; (e) research showing that operant principles can be successfully applied to the treatment of a young autistic boy with a serious visual handicap; (f) laboratory studies showing that mothers can be trained to treat their own young children who have behavior problems; (g) an in-home study demonstrating that a mother can treat her own child who has behavior problems; (h) a demonstration that operant principles can be applied effectively to teaching reading, writing, and arithmetic to children with retardation; and (i) publication of a book, Child Development: A Systematic and Empirical Theory, in collaboration with Donald M. Baer, by Prentice Hall in their Century Psychological Series. PMID:22478239

  7. 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 (1418 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

  8. Early virological and immunological events in asymptomatic Epstein-Barr virus infection in African children.

    PubMed

    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

    2015-03-01

    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

  9. Trastuzumab-related cardiac events in the treatment of early breast cancer.

    PubMed

    Fried, Georgeta; Regev, Tslil; Moskovitz, Mor

    2013-11-01

    Trastuzumab is considered a cornerstone in the treatment of human epidermal growth factor receptor-2 (HER2)-positive breast cancer. Cardiac toxicity is an important side effect of treatment and can limit the use of this drug known to act synergistically with cardiotoxicity from anthracyclines. A retrospective study was performed on breast cancer patients with early breast cancer, and HER2 overexpression treated with adjuvant/neoadjuvant chemotherapy and trastuzumab between 2005 and 2010. Cardiac events (CE) were recorded if left ventricular ejection fraction (LVEF) reduction was more than 10 % from baseline echocardiography. Treatment-related potential risk and protective factors were recorded. Median age of the 124 patients included in this analysis was 51 years (range 29-70 years). Treatment regimens were anthracycline-cyclophosphamide (AC)-Taxol (105 patients), TCH (12 patients), and CAF/Taxol combination (7 patients). CE were observed in 26 (21 %) patients. Trastuzumab was stopped in 9 (7 %) patients and rechallenged in five after periods ranging from 19 to 120 days. There was a significant decrease in LVEF between baseline/post-AC and during trastuzumab treatment (mean LVEF 64.29 vs. 61.97 %, p < 0.001). Treatment-related risk factors were age and interval since last AC. Trastuzumab loading dose (8 vs. 4 mg) did not influence CE rate. 56 (45 %) patients received left chest wall irradiation with significantly increased CE rates, 16 (31.4 %) versus 10 (15.4 %), in patients without radiotherapy (p < 0.05). The presence of any cardiac risk factor caused a trend toward increased risk, not statistically significant. No connection was found between possible cardioprotective drugs and reduced rates of toxicity. The incidence of cardiac toxicity with trastuzumab adjuvant treatment in our study is similar to other reports. Only radiotherapy to the left chest wall increased the risk for CE. Further prospective studies are needed, including echocardiographic measurement and biochemical data (troponin I), for early recognition and monitoring of high-risk patients. PMID:24154507

  10. Early events of fertilization in sea urchin eggs are sensitive to actin-binding organic molecules.

    PubMed

    Chun, Jong T; Limatola, Nunzia; Vasilev, Filip; Santella, Luigia

    2014-08-01

    We previously demonstrated that many aspects of the intracellular Ca(2+) increase in fertilized eggs of starfish are significantly influenced by the state of the actin cytoskeleton. In addition, the actin cytoskeleton appeared to play comprehensive roles in modulating cortical granules exocytosis and sperm entry during the early phase of fertilization. In the present communication, we have extended our work to sea urchin which is believed to have bifurcated from the common ancestor in the phylogenetic tree some 500 million years ago. To corroborate our earlier findings in starfish, we have tested how the early events of fertilization in sea urchin eggs are influenced by four different actin-binding drugs that promote either depolymerization or stabilization of actin filaments. We found that all the actin drugs commonly blocked sperm entry in high doses and significantly reduced the speed of the Ca(2+) wave. At low doses, however, cytochalasin B and phalloidin increased the rate of polyspermy. Overall, certain aspects of Ca(2+) signaling in these eggs were in line with the morphological changes induced by the actin drugs. That is, the time interval between the cortical flash and the first Ca(2+) spot at the sperm interaction site (the latent period) was significantly prolonged in the eggs pretreated with cytochalasin B or latrunculin A, whereas the Ca(2+) decay kinetics after the peak was specifically attenuated in the eggs pretreated with jasplakinolide or phalloidin. In addition, the sperm interacting with the eggs pretreated with actin drugs often generated multiple Ca(2+) waves, but tended to fail to enter the egg. Thus, our results indicated that generation of massive Ca(2+) waves is neither indicative of sperm entry nor sufficient for cortical granules exocytosis in the inseminated sea urchin eggs, whereas the structure and functionality of the actin cytoskeleton are the major determining factors in the two processes. PMID:24960199

  11. Timing and evolution of ocean anoxic event during Early Cambrian in south China

    NASA Astrophysics Data System (ADS)

    Yang, J.; Jiang, S.; Pi, D.; Ling, H.

    2008-12-01

    The Precambrian/Cambrian (PC-C) interval is one of the most interesting intervals in the evolution of life because of the sudden diversification of animals with mineralized skeletons, known as "Cambrian Explosion". The Yangtze Platform in south China is one of the best occurrences that can provide excellent insights into the palaeo-environmental and biological changes across the PC-C boundary. Our study show that the ocean anoxia were widespread during the Early Cambrian period, however, the start of this anoxic event was not from the PC-C boundary (i.e., 542 Ma), but some 7 Ma later (~535 Ma) when the Niutitang Formation black rock series (black phosphorite, chert, and black shale) deposited along a thousand kilometer long NEE zone in the transitional facies in the Yangtze Platform, while the major Cambrian radiation (Changjiang fauna) took place during 521-511 Ma. During the Niutitang period, the depositional environment of the Early Cambrian sedimentary sequence in south China have evolved from an initial oxic/dysoxic to a major anoxic/euxinic environment, and then back to dysoxic/oxic environment. A Ni-Mo sulfide layer occurred in the lower part of the Niutitang black shales which contains extremely enrichments of many metals, and can serve as a marker layer in south China when the depositional environment turned into euxinic condition. Re-Os isotope study of the sulfide ores and host black shales show an age of 535 Ma. Initial Os isotopic compositions, Mo isotopic compositions, and rare earth elements and Pt group element geochemistry suggest involvement of submarine hydrothermal fluids during the metal enrichments in black shale.

  12. Early Eocene changes in the frequency and spatial distribution of extreme precipitation events

    NASA Astrophysics Data System (ADS)

    Carmichael, Matthew; Lunt, Daniel; Pancost, Richard

    2015-04-01

    Global warming over the next 100 years is likely to result not only in changes to the spatial distribution of mean annual precipitation, but also to the seasonality of precipitation and the frequency of hydrological extremes, with far-reaching socio-economic and ecological impacts. The study of the sensitivity of the hydrological cycle to episodes of global warmth in the geologic past is receiving increased attention from the paleoclimate community, but our understanding of the occurrence of hydrological extremes remains limited. The warming associated with the Paleocene-Eocene Thermal Maximum (PETM) hyperthermal (~56 Ma) has received widespread attention given its global nature, rapid onset and transient nature. A range of geomorphological, microfossil and biomarker proxies suggest significant hydrological changes occurred at the PETM which have traditionally been interpreted in terms of changes in mean annual precipitation; recently changes in the frequency of hydrological extremes at the PETM have also been suggested. In this work, we seek to better understand whether numerical climate models run with boundary conditions appropriate for the early Eocene (56 - 49 Ma) are capable of simulating changes in the frequency of intense precipitation ('storm') events by analysing GCM-simulated precipitation rates at an hourly frequency. Our Eocene simulations are performed at x2 and x4 preindustrial CO2 using a coupled atmosphere-ocean GCM, HadCM3L. Differences in climatology between high and low CO2 may be considered analogous to the changes which occurred at the PETM. Our results indicate significant changes occur in the precipitation intensity-frequency relationships at locations which correspond to sites from which PETM proxies exist. The percentage of time during which precipitation occurs and the overall number of events lasting longer than an hour declines in the high-CO2 model. These changes tend to occur with an associated increase in mean storm precipitation rate, such that hydrological extremes occur with a reduced return-period. We explore how these relationships vary spatially and show relative changes vary between sites in close geographic proximity. Our results suggest that the interpretation of existing paleoclimatic proxies for hydrological change must consider both changes in mean annual precipitation rate, but also changes in the frequency of intense, high impact events.

  13. Global correlations of mid Early Triassic events: The Induan/Olenekian boundary in the Dolomites (Italy)

    NASA Astrophysics Data System (ADS)

    Posenato, Renato

    2008-12-01

    The Dolomites (Southern Alps, Italy) are a reference-area for research on the end-Permian mass extinction and its Early Triassic aftermath. The effects on shallow marine benthic biota are recorded in the Werfen Formation, a thick mixed carbonate-siliciclastic sedimentary succession. Only in its lower (Griesbachian) and upper (Spathian) parts, this formation is bio-chronologically constrained by means of conodonts and ammonoids, whilst no significant bioevent occurs in its middle part. This represents an impediment to the biochronologic recognition of the Induan/Olenekian boundary (IOB). The Bulla/Pufels (Val Gardena) succession is a key-section for the P/T boundary and Early Triassic for global correlation due to the abundance of studies on biostratigraphy (mostly on conodonts), magnetostratigraphy and chemostratigraphy carried out there by stratigraphers of various nationalities. Recent chemostratigraphic studies have permitted the recognition of some carbon isotope positive peaks, the strongest of which is considered to approximate the IOB. However, various authors have reached different conclusions on the position of the maximum peak and thus on the IOB location. This leads to important stratigraphic consequences for the calibration of conodont biostratigraphy. The critical revision of the traditional stratigraphic units (litho- and biostratigraphy), under-evaluated in most of the recent literature, and magneto-, chemo- and sequence stratigraphic units allowed herein an integrated stratigraphic scale for the Bulla/Pufels section to be proposed. This contribution highlights the mid Early Triassic Dolomites record for regional and global correlations. The most significant results attained herein regard the different lithostratigraphic subdivisions of the middle Werfen Formation and its consequences on the position of the IOB with respect to the conodont and bivalve biostratigraphy and sequence stratigraphic units. The upper part of the section is attributed herein to the Gastropod Oolite Member, which is represented by the lithozone A, a predominant supratidal episode, and the lower part of the subtidal lithozone B. Between the lithozones A and B, a sequence boundary of 3th order (Sc2/Sc3) is located. The maximum carbon isotope excursion is near this boundary, which therefore approximates the IOB in the Dolomites. This proposal suggests a Dienerian age for the FO of the conodont Pachycladina obliqua, which occurs about 60 m below the stage boundary. No significant biotic event, either for molluscs or conodonts, occurred across this stage boundary.

  14. 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.

  15. 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.

  16. 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

  17. Modeling early haematologic adverse events in conformal and intensity-modulated pelvic radiotherapy in anal cancer

    PubMed Central

    Robinson, Maxwell; Sabbagh, Ahmed; Muirhead, Rebecca; Durrant, Lisa; Van den Heuvel, Frank; Hawkins, Maria

    2015-01-01

    Background and purpose To determine if there are differences between dose to pelvic bone marrow (PBM) using intensity modulated radiotherapy (IMRT) under UK guidance versus conformal radiotherapy (CRT) per ACT II protocol and if differences translate to rates of early haematological adverse events grade 3 or greater (HT3+). Methods and materials Two groups of 20+ patients, treated under IMRT and CRT regimes respectively, were identified. All patients underwent weekly blood cell count: haemoglobin (HgB), white cell count (WCC), absolute neutrophil count (ANC) and platelets (plats). Percent volume of PBM and sub structures receiving 525Gy were tested for statistical significance. Regression models were used to test for correlation to blood counts. NTCP modeling was also performed. Results PMB dose metrics showed a significant increase in the IMRT group. Regression analysis showed iliac and lumbosacral PBM dose metrics to associate with reduced nadir ANC and WCC. NTCP at HT3+ was 0.13 using IMRT relative to 0.07 using CRT (p<0.05). Conclusion Whilst this is a relatively small retrospective study and lacks information on the distribution of active PBM, IMRT treatment has been shown to significantly increase PMB irradiation. PBM dose metrics have been shown to be predictive of WCC and ANC suppression. NTCP modeling predicts much high risk of HT3+. Paradoxically, actual rates of HT3+ were comparable suggesting that differences in the distributions of dose metrics maybe a significant factor and/or that there are insufficiency in the NTCP modeling. PMID:26409831

  18. 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-μs conformational diffusion dynamics of the unfolded chains. A fractional population of the unfolded chains collapses on the 1 – 100 μs 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

  19. 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

  20. 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

  1. Impact of early and late winter icing events on sub-arctic dwarf shrubs.

    PubMed

    Preece, C; Phoenix, G K

    2014-01-01

    Polar regions are predicted to undergo large increases in winter temperature and an increased frequency of freeze-thaw cycles, which can cause ice layers in the snow pack and ice encasement of vegetation. Early or late winter timing of ice encasement could, however, modify the extent of damage caused to plants. To determine impacts of the date of ice encasement, a novel field experiment was established in sub-arctic Sweden, with icing events simulated in January and March 2008 and 2009. In the subsequent summers, reproduction, phenology, growth and mortality, as well as physiological indicators of leaf damage were measured in the three dominant dwarf shrubs: Vaccinium uliginosum, Vaccinium vitis-idaea and Empetrum nigrum. It was hypothesised that January icing would be more damaging compared to March icing due to the longer duration of ice encasement. Following 2 years of icing, E. nigrum berry production was 83% lower in January-iced plots compared to controls, and V. vitis-idaea electrolyte leakage was increased by 69%. Conversely, electrolyte leakage of E. nigrum was 25% lower and leaf emergence of V. vitis-idaea commenced 11 days earlier in March-iced plots compared to control plots in 2009. There was no effect of icing on any of the other parameters measured, indicating that overall these study species have moderate to high tolerance to ice encasement. Even much longer exposure under the January icing treatment does not clearly increase damage. PMID:23574610

  2. 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.

  3. Expression homeostasis during DNA replication.

    PubMed

    Voichek, Yoav; Bar-Ziv, Raz; Barkai, Naama

    2016-03-01

    Genome replication introduces a stepwise increase in the DNA template available for transcription. Genes replicated early in S phase experience this increase before late-replicating genes, raising the question of how expression levels are affected by DNA replication. We show that in budding yeast, messenger RNA (mRNA) synthesis rate is buffered against changes in gene dosage during S phase. This expression homeostasis depends on acetylation of H3 on its internal K56 site by Rtt109/Asf1. Deleting these factors, mutating H3K56 or up-regulating its deacetylation, increases gene expression in S phase in proportion to gene replication timing. Therefore, H3K56 acetylation on newly deposited histones reduces transcription efficiency from replicated DNA, complementing its role in guarding genome stability. Our study provides molecular insight into the mechanism maintaining expression homeostasis during DNA replication. PMID:26941319

  4. 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...

  5. Epigenetic silencing of miR-137 is an early event in colorectal carcinogenesis

    PubMed Central

    Balaguer, Francesc; Link, Alexander; Lozano, Juan Jose; Cuatrecasas, Miriam; Nagasaka, Takeshi; Boland, C. Richard; Goel, Ajay

    2010-01-01

    Global downregulation of microRNAs is a common feature in colorectal cancer (CRC). Whereas CpG island hypermethylation constitutes a mechanism for miRNA silencing, this field largely remains unexplored. Herein, we describe the epigenetic regulation of miR-137 and its contribution to colorectal carcinogenesis. We determined the methylation status of miR-137 CpG island in a panel of six CRC cell lines and 409 colorectal tissues (21 normal colonic mucosa from healthy individuals (N-N), 160 primary CRC tissues and their corresponding normal mucosa (N-C) and 68 adenomas). TaqMan RT-PCR and in situ hybridization were used to analyze miR-137 expression. In vitro functional analysis of miR-137 was performed. Gene targets of miR-137 were identified using a combination of bio-informatic and transcriptomic approaches. We experimentally validated the miRNA:mRNA interactions. Methylation of the miR-137 CpG island was a cancer-specific event, and was frequently observed in CRC cell lines (100%), adenomas (82.3%) and CRC (81.4%) but not in N-C (14.4%, p<0.0001 for CRC) and N-N (4.7%, p<0.0001 for CRC). Expression of miR-137 was restricted to the colonocytes in normal mucosa, and inversely correlated with the level of methylation. Transfection of miR-137 precursor in CRC cells significantly inhibited cell proliferation. Gene expression profiling after miR-137 transfection discovered novel potential mRNA targets. We validated the interaction between miR-137 and LSD-1. Our data firstly indicate that miR-137 acts as a tumor suppressor in the colon and is frequently silenced by promoter hypermethylation. Methylation-silencing of miR-137 in colorectal adenomas suggests it to be an early event, which has prognostic and therapeutic implications. PMID:20682795

  6. 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

  7. 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.

  8. Shorter Exposures to Harder X-Rays Trigger Early Apoptotic Events in Xenopus laevis Embryos

    PubMed Central

    Dong, JiaJia; Mury, Sean P.; Drahos, Karen E.; Moscovitch, Marko

    2010-01-01

    Background A long-standing conventional view of radiation-induced apoptosis is that increased exposure results in augmented apoptosis in a biological system, with a threshold below which radiation doses do not cause any significant increase in cell death. The consequences of this belief impact the extent to which malignant diseases and non-malignant conditions are therapeutically treated and how radiation is used in combination with other therapies. Our research challenges the current dogma of dose-dependent induction of apoptosis and establishes a new parallel paradigm to the photoelectric effect in biological systems. Methodology/Principal Findings We explored how the energy of individual X-ray photons and exposure time, both factors that determine the total dose, influence the occurrence of cell death in early Xenopus embryo. Three different experimental scenarios were analyzed and morphological and biochemical hallmarks of apoptosis were evaluated. Initially, we examined cell death events in embryos exposed to increasing incident energies when the exposure time was preset. Then, we evaluated the embryo's response when the exposure time was augmented while the energy value remained constant. Lastly, we studied the incidence of apoptosis in embryos exposed to an equal total dose of radiation that resulted from increasing the incoming energy while lowering the exposure time. Conclusions/Significance Overall, our data establish that the energy of the incident photon is a major contributor to the outcome of the biological system. In particular, for embryos exposed under identical conditions and delivered the same absorbed dose of radiation, the response is significantly increased when shorter bursts of more energetic photons are used. These results suggest that biological organisms display properties similar to the photoelectric effect in physical systems and provide new insights into how radiation-mediated apoptosis should be understood and utilized for therapeutic purposes. PMID:20126466

  9. 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

  10. 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

  11. 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 δ13C 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.

  12. 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, Jrg; 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) invitro, and following subcutaneous administration invivo, 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

  13. 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

  14. 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.

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

    PubMed

    Leyhe, Thomas; Mller, 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, Mller, 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

  16. Demyelinating events in early multiple sclerosis have inherent severity and recovery

    PubMed Central

    Mowry, E M.; Pesic, M; Grimes, B; Deen, S; Bacchetti, P; Waubant, E

    2009-01-01

    Background: It is unclear whether the severity of and recovery from the initial demyelinating event (IDE) are recapitulated in subsequent multiple sclerosis (MS) relapses. We sought to identify the factors associated with relapse severity and recovery and to evaluate whether events have inherent severity or recovery. Methods: Patients seen at the UCSF MS Clinic within 1 year of disease onset were identified from a prospective database. Ordinal logistic regression was used to analyze predictors of three-level categorizations of event severity and recovery. Results: We identified 330 patients with MS or clinically isolated syndrome; 152 had a second event and 63 had a third event. Nonwhite and younger patients were at an increased risk of more severe demyelinating events. A severe prior event predicted a substantial increase in the odds of being above any given severity cutoff for a severe subsequent event (for second event severity, odds ratio [OR] = 5.62, 95% confidence interval [CI] [2.39, 13.26], p < 0.0001; for third event severity, OR = 6.74, 95% CI [1.67, 27.18], p = 0.007). Similarly, poor recovery of the IDE predicted poor second event recovery (OR = 5.28, 95% CI [1.95, 14.25], p = 0.001), while fair or poor second event recovery predicted about a 5- or 13-fold increase in the odds of poor third event recovery. A more severe event also predicted a substantial increase in the odds of poor recovery. Conclusions: Patients with severe presentation and poor recovery at disease onset continue on a similar trajectory with subsequent demyelinating events. Whether genetic or other biologic factors are responsible for this pattern remains to be determined. GLOSSARY BS/CE = brainstem/cerebellum; CI = confidence interval; CIS = clinically isolated syndrome; DMT = disease-modifying therapy; EDSS = Expanded Disability Status Scale; FS = Functional Systems; IDE = initial demyelinating event; MS = multiple sclerosis; N/A = not applicable; OR = odds ratio; RRMS = relapsing-remitting multiple sclerosis; VA = visual acuity. PMID:19221292

  17. Targeted Deletion of FGL2 Leads to Increased Early Viral Replication and Enhanced Adaptive Immunity in a Murine Model of Acute Viral Hepatitis Caused by LCMV WE

    PubMed Central

    Khattar, Ramzi; Luft, Olga; Yavorska, Nataliya; Shalev, Itay; Phillips, M. James; Adeyi, Oyedele; Gao, Darrin; Bartczak, Agata; Urbanellis, Peter; Shyu, Wendy; Zhang, Jianhua; Manuel, Justin; Levy, Gary A.; Selzner, Nazia

    2013-01-01

    Mounting effective innate and adaptive immune responses are critical for viral clearance and the generation of long lasting immunity. It is known that production of inhibitory factors may result in the inability of the host to clear viruses, resulting in chronic viral persistence. Fibrinogen-like protein 2 (FGL2) has been identified as a novel effector molecule of CD4+CD25+ Foxp3+ regulatory T (Treg) cells that inhibits immune activity by binding to FC?RIIB expressed primarily on antigen presenting cells (APC). In this study, we show that infection of mice with Lymphocytic Choriomeningitis Virus WE (LCMV WE) leads to increased plasma levels of FGL2, which were detected as early as 2 days post-infection (pi) and persisted until day 50 pi. Mice deficient in FGL2 (fgl2?/?) had increased viral titers of LCMV WE in the liver early p.i but cleared the virus by day 12 similar to wild type mice. Dendritic cells (DC) isolated from the spleens of LCMV WE infected fgl2?/? had increased expression of the DC maturation markers CD80 and MHC Class II compared to wild type (fgl2+/+). Frequencies of CD8+ and CD4+ T cells producing IFN? in response to ex vivo peptide re-stimulation isolated from the spleen and lymph nodes were also increased in LCMV WE infected fgl2 ?/? mice. Increased frequencies of CD8+ T cells specific for LCMV tetramers GP33 and NP396 were detected within the liver of fgl2?/? mice. Plasma from fgl2?/? mice contained higher titers of total and neutralizing anti-LCMV antibody. Enhanced anti-viral immunity in fgl2?/? mice was associated with increased levels of serum alanine transaminase (ALT), hepatic necrosis and inflammation following LCMV WE infection. These data demonstrate that targeting FGL2 leads to early increased viral replication but enhanced anti-viral adaptive T & B cell responses. Targeting FGL2 may enhance the efficacy of current anti-viral therapies for hepatotropic viruses. PMID:24146739

  18. Organic geochemistry of the early Toarcian oceanic anoxic event in Hawsker Bottoms, Yorkshire, England

    NASA Astrophysics Data System (ADS)

    French, K. L.; Seplveda, J.; Trabucho-Alexandre, J.; Grcke, D. R.; Summons, R. E.

    2014-03-01

    A comprehensive organic geochemical investigation of the Hawsker Bottoms outcrop section in Yorkshire, England has provided new insights about environmental conditions leading into and during the Toarcian oceanic anoxic event (T-OAE; ?183 Ma). Rock-Eval and molecular analyses demonstrate that the section is uniformly within the early oil window. Hydrogen index (HI), organic petrography, polycyclic aromatic hydrocarbon (PAH) distributions, and tricyclic terpane ratios mark a shift to a lower relative abundance of terrigenous organic matter supplied to the sampling locality during the onset of the T-OAE and across a lithological transition. Unlike other ancient intervals of anoxia and extinction, biomarker indices of planktonic community structure do not display major changes or anomalous values. Depositional environment and redox indicators support a shift towards more reducing conditions in the sediment porewaters and the development of a seasonally stratified water column during the T-OAE. In addition to carotenoid biomarkers for green sulfur bacteria (GSB), we report the first occurrence of okenane, a marker of purple sulfur bacteria (PSB), in marine samples younger than ?1.64 Ga. Based on modern observations, a planktonic source of okenane's precursor, okenone, would require extremely shallow photic zone euxinia (PZE) and a highly restricted depositional environment. However, due to coastal vertical mixing, the lack of planktonic okenone production in modern marine sulfidic environments, and building evidence of okenone production in mat-dwelling Chromatiaceae, we propose a sedimentary source of okenone as an alternative. Lastly, we report the first parallel compound-specific ?C13 record in marine- and terrestrial-derived biomarkers across the T-OAE. The ?C13 records of short-chain n-alkanes, acyclic isoprenoids, and long-chain n-alkanes all encode negative carbon isotope excursions (CIEs), and together, they support an injection of isotopically light carbon that impacted both the atmospheric and marine carbon reservoirs. To date, molecular ?C13 records of the T-OAE display a negative CIE that is smaller in magnitude compared to the bulk organic ?C13 excursion. Although multiple mechanisms could explain this observation, our molecular, petrographic, and Rock-Eval data suggest that variable mixing of terrigenous and marine organic matter is an important factor affecting the bulk organic ?C13 records of the T-OAE.

  19. 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.

  20. Early Verb Learning: How Do Children Learn How to Compare Events?

    ERIC Educational Resources Information Center

    Childers, Jane B.; Parrish, Rebecca; Olson, Christina V.; Burch, Clare; Fung, Gavin; McIntyre, Kevin P.

    2016-01-01

    An important problem verb learners must solve is how to extend verbs. Children could use cross-situational information to guide their extensions; however, comparing events is difficult. In 2 studies, researchers tested whether children benefit from initially seeing a pair of similar events ("progressive alignment") while learning new…

  1. 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).

  2. 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".

  3. 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.

  4. 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...

  5. 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.

  6. 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

  7. 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.

  8. 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…

  9. 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

  10. Early and late event-related potentials are modulated by infant and adult faces of high and low attractiveness.

    PubMed

    Hahn, Amanda C; Symons, Lawrence A; Kredel, Taylor; Hanson, Kevin; Hodgson, Lianne; Schiavone, Lori; Jantzen, K J

    2016-04-01

    The processing of infant faces may be somewhat distinct from that of adult faces. Indeed, recent neuroimaging studies have provided evidence of an early, "baby-specific" neural response whereby infant faces are perceived more rapidly than adult faces. Using event-related potentials, the present study aimed to determine whether the preferential response to infant faces is present at both early and late stages of face processing, and to investigate the effects of esthetic appearance on the processing of adult and infant faces by directly manipulating the perceived attractiveness or cuteness within a given face identity. Here, we find evidence for enhanced processing of infant faces, relative to adult faces, at both early (N170, P2) and late (LPC) stages of face processing. We also find that the esthetic appearance of both infant and adult faces modulates early neural responses, with enhanced responses to less attractive/cute faces as compared to more attractive/cute faces. Overall, our results provide additional evidence for a preferential response to infant faces at early stages of processing, and provide new evidence that this preferential response occurs at later stages of face processing as well, independent of the esthetic quality of the face or observer sex. PMID:26160142

  11. A Critical Role for CD63 in HIV Replication and Infection of Macrophages and Cell Lines

    PubMed Central

    Chen, Hui; Dziuba, Natallia; Friedrich, Brian; von Lindern, Jana; Murray, James L.; Rojo, Daniel R.; Hodge, Thomas W.; OBrien, William A.; Ferguson, Monique R.

    2009-01-01

    HIV infection typically involves interaction of Env with CD4 and a chemokine coreceptor, either CCR5 or CXCR4. Other cellular factors supporting HIV replication have also been characterized. We previously demonstrated a role for CD63 in early HIV infection events in macrophages via inhibition by anti-CD63 antibody pretreatment. To confirm the requirement for CD63 in HIV replication, we decreased CD63 expression using CD63-specific short interfering RNAs (siRNA), and showed inhibition of HIV replication in macrophages. Surprisingly, pretreatment with CD63 siRNA not only silenced CD63 expression by 90%, but also inhibited HIV-1 replication in a cultured cell line (U373-MAGI) which had been previously shown to be insensitive to CD63 monoclonal antibody inhibition. Although the anti-CD63 antibody was previously shown to inhibit early HIV infection events only in macrophages, we now show a potential role for CD63 in later HIV replication events in macrophages and cell lines. Further delineation of the role of CD63 in HIV replication may lead to development of novel therapeutic compounds. PMID:18682304

  12. Early Perception of Written Syllables in French: An Event-Related Potential Study

    ERIC Educational Resources Information Center

    Doignon-Camus, Nadege; Bonnefond, Anne; Touzalin-Chretien, Pascale; Dufour, Andre

    2009-01-01

    The present study examined whether written syllable units are perceived in first steps of letter string processing. An illusory conjunction experiment was conducted while event-related potentials were recorded. Colored pseudowords were presented such that there was a match or mismatch between the syllable boundaries and the color boundaries. The

  13. 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).

  14. 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

  15. Exposure to Potentially Traumatic Events in Early Childhood: Differential Links to Emergent Psychopathology

    ERIC Educational Resources Information Center

    Briggs-Gowan, Margaret J.; Carter, Alice S.; Clark, Roseanne; Augustyn, Marilyn; McCarthy, Kimberly J.; Ford, Julian D.

    2010-01-01

    Research NeedsObjective: To examine associations between exposure to potentially traumatic events (PTEs) and clinical patterns of symptoms and disorders in preschool children. Method: Two hundred and thirteen referred and non-referred children, ages 24 to 48 months (MN = 34.9, SD = 6.7 months) were studied. Lifetime exposure to PTEs (family

  16. 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

  17. 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

  18. Seismology-based early identification of dam-formation landquake events.

    PubMed

    Chao, Wei-An; Zhao, Li; Chen, Su-Chin; Wu, Yih-Min; Chen, Chi-Hsuan; Huang, Hsin-Hua

    2016-01-01

    Flooding resulting from the bursting of dams formed by landquake events such as rock avalanches, landslides and debris flows can lead to serious bank erosion and inundation of populated areas near rivers. Seismic waves can be generated by landquake events which can be described as time-dependent forces (unloading/reloading cycles) acting on the Earth. In this study, we conduct inversions of long-period (LP, period ≥20 s) waveforms for the landquake force histories (LFHs) of ten events, which provide quantitative characterization of the initiation, propagation and termination stages of the slope failures. When the results obtained from LP waveforms are analyzed together with high-frequency (HF, 1-3 Hz) seismic signals, we find a relatively strong late-arriving seismic phase (dubbed Dam-forming phase or D-phase) recorded clearly in the HF waveforms at the closest stations, which potentially marks the time when the collapsed masses sliding into river and perhaps even impacting the topographic barrier on the opposite bank. Consequently, our approach to analyzing the LP and HF waveforms developed in this study has a high potential for identifying five dam-forming landquake events (DFLEs) in near real-time using broadband seismic records, which can provide timely warnings of the impending floods to downstream residents. PMID:26753931

  19. Seismology-based early identification of dam-formation landquake events

    PubMed Central

    Chao, Wei-An; Zhao, Li; Chen, Su-Chin; Wu, Yih-Min; Chen, Chi-Hsuan; Huang, Hsin-Hua

    2016-01-01

    Flooding resulting from the bursting of dams formed by landquake events such as rock avalanches, landslides and debris flows can lead to serious bank erosion and inundation of populated areas near rivers. Seismic waves can be generated by landquake events which can be described as time-dependent forces (unloading/reloading cycles) acting on the Earth. In this study, we conduct inversions of long-period (LP, period ≥20 s) waveforms for the landquake force histories (LFHs) of ten events, which provide quantitative characterization of the initiation, propagation and termination stages of the slope failures. When the results obtained from LP waveforms are analyzed together with high-frequency (HF, 1–3 Hz) seismic signals, we find a relatively strong late-arriving seismic phase (dubbed Dam-forming phase or D-phase) recorded clearly in the HF waveforms at the closest stations, which potentially marks the time when the collapsed masses sliding into river and perhaps even impacting the topographic barrier on the opposite bank. Consequently, our approach to analyzing the LP and HF waveforms developed in this study has a high potential for identifying five dam-forming landquake events (DFLEs) in near real-time using broadband seismic records, which can provide timely warnings of the impending floods to downstream residents. PMID:26753931

  20. Seismology-based early identification of dam-formation landquake events

    NASA Astrophysics Data System (ADS)

    Chao, Wei-An; Zhao, Li; Chen, Su-Chin; Wu, Yih-Min; Chen, Chi-Hsuan; Huang, Hsin-Hua

    2016-01-01

    Flooding resulting from the bursting of dams formed by landquake events such as rock avalanches, landslides and debris flows can lead to serious bank erosion and inundation of populated areas near rivers. Seismic waves can be generated by landquake events which can be described as time-dependent forces (unloading/reloading cycles) acting on the Earth. In this study, we conduct inversions of long-period (LP, period ≥20 s) waveforms for the landquake force histories (LFHs) of ten events, which provide quantitative characterization of the initiation, propagation and termination stages of the slope failures. When the results obtained from LP waveforms are analyzed together with high-frequency (HF, 1–3 Hz) seismic signals, we find a relatively strong late-arriving seismic phase (dubbed Dam-forming phase or D-phase) recorded clearly in the HF waveforms at the closest stations, which potentially marks the time when the collapsed masses sliding into river and perhaps even impacting the topographic barrier on the opposite bank. Consequently, our approach to analyzing the LP and HF waveforms developed in this study has a high potential for identifying five dam-forming landquake events (DFLEs) in near real-time using broadband seismic records, which can provide timely warnings of the impending floods to downstream residents.

  1. 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…

  2. 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

  3. 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…

  4. Astronomical pacing of late Palaeocene to early Eocene global warming events.

    PubMed

    Lourens, Lucas J; Sluijs, Appy; Kroon, Dick; Zachos, James C; Thomas, Ellen; Rhl, Ursula; Bowles, Julie; Raffi, Isabella

    2005-06-23

    At the boundary between the Palaeocene and Eocene epochs, about 55 million years ago, the Earth experienced a strong global warming event, the Palaeocene-Eocene thermal maximum. The leading hypothesis to explain the extreme greenhouse conditions prevalent during this period is the dissociation of 1,400 to 2,800 gigatonnes of methane from ocean clathrates, resulting in a large negative carbon isotope excursion and severe carbonate dissolution in marine sediments. Possible triggering mechanisms for this event include crossing a threshold temperature as the Earth warmed gradually, comet impact, explosive volcanism or ocean current reorganization and erosion at continental slopes, whereas orbital forcing has been excluded. Here we report a distinct carbonate-poor red clay layer in deep-sea cores from Walvis ridge, which we term the Elmo horizon. Using orbital tuning, we estimate deposition of the Elmo horizon at about 2 million years after the Palaeocene-Eocene thermal maximum. The Elmo horizon has similar geochemical and biotic characteristics as the Palaeocene-Eocene thermal maximum, but of smaller magnitude. It is coincident with carbon isotope depletion events in other ocean basins, suggesting that it represents a second global thermal maximum. We show that both events correspond to maxima in the approximately 405-kyr and approximately 100-kyr eccentricity cycles that post-date prolonged minima in the 2.25-Myr eccentricity cycle, implying that they are indeed astronomically paced. PMID:15944716

  5. 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…

  6. High-affinity RNA Aptamers Against the HIV-1 Protease Inhibit Both In Vitro Protease Activity and Late Events of Viral Replication

    PubMed Central

    Duclair, Sonald; Gautam, Archana; Ellington, Andrew; Prasad, Vinayaka R

    2015-01-01

    HIV-1 aspartyl protease (PR) plays a key role in virion morphogenesis, underscoring the effectiveness of protease inhibitors (PI). Despite their utility, side effects and drug-resistance remains a problem. We report the development of RNA aptamers as inhibitors of HIV-1 PR for potential use in anti-HIV gene therapy. Employing Systematic Evolution of Ligands by Exponential Enrichment (SELEX), we isolated four unique families of anti-HIV-1 PR RNA aptamers displaying moderate binding affinities (Kd = 92–140 nmol/l) and anti-PR inhibitory activity (Kis = 138–647 nmol/l). Second-generation RNA aptamers selected from partially randomized pools based on two of the aptamer sequences displayed striking enhancements in binding (Kds = 2–22 nmol/l) and inhibition (Kis = 31–49 nmol/l). The aptamers were specific in that they did not bind either the related HIV-2 protease, or the cellular aspartyl protease, Cathepsin D. Site-directed mutagenesis of a second-generation aptamer to probe the predicted secondary structure indicated that the stem-loops SL2 and SL3 and the stem P1 were essential for binding and that only the 3'-most 17 nucleotides were dispensable. Anti-PR aptamers inhibited HIV replication in vitro and the degree of inhibition was higher for second-generation aptamers with greater affinity and the inhibition was abrogated for a nonbinding aptamer variant. PMID:25689224

  7. 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...

  8. Early Top-Down Influences on Bistable Perception Revealed by Event-Related Potentials

    ERIC Educational Resources Information Center

    Pitts, Michael A.; Gavin, William J.; Nerger, Janice L.

    2008-01-01

    A longstanding debate exists in the literature concerning bottom-up vs. top-down influences on bistable perception. Recently, a technique has been developed to measure early changes in brain activity (via ERPs) related to perceptual reversals (Kornmeier & Bach, 2004). An ERP component, the reversal negativity (RN) has been identified, and is

  9. 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.

  10. Modeling evidences for global warming, Arctic seawater freshening, and sluggish oceanic circulation during the Early Toarcian anoxic event

    NASA Astrophysics Data System (ADS)

    Dera, Guillaume; Donnadieu, Yannick

    2012-06-01

    The paleoecological disturbances recorded during the Early Toarcian warming event (183 Myr ago), including marine anoxia, sea level rise, seawater acidification, carbonate production crisis, and species extinctions, are often regarded as past examples of Earth's possible responses to the rapid emergence of super greenhouse conditions. However, physical mechanisms explaining both the global and local expressions of paleoenvironmental events are still highly debated. Here we analyze the paleoclimatic and paleoceanographic consequences of increases in atmospheric pCO2 levels at a multiscale resolution using a fully coupled ocean-atmosphere model (FOAM). We show that, in association with stronger high-latitude precipitation rates and enhanced continental runoff, the demise of polar sea ice due to the global warming event involved a regional freshening of Arctic surface seawaters. These disturbances lead to progressive slowdowns of the global oceanic circulation accountable for widespread ocean stratification and bottom anoxia processes in deep oceanic settings and epicontinental basins. In agreement with very negative oxygen isotope values measured on fossil shells from the NW Tethys, our simulations also show that recurrent discharges of brackish and nutrient-rich Arctic surface waters through the Viking Corridor could have led to both vertical and geographical gradients in salinity and seawater ?18O in the NW Tethyan seas. Locally contrasted conditions in water mass density and rises in productivity rates due to strong nutrient supplies could partly explain the regional severity of the anoxic event in the restricted Euro-boreal domains, as it has been previously suggested and modeled regionally.

  11. 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.

  12. Early childhood behavior trajectories and the likelihood of experiencing a traumatic event and PTSD by young adulthood

    PubMed Central

    Schaeffer, Cindy M.; Petras, Hanno; Ialongo, Nicholas S.; Breslau, Naomi

    2015-01-01

    This study modeled children's trajectories of teacher rated aggressive-disruptive behavior problems assessed at six time points between the ages of 6 and 11 and explored the likelihood of being exposed to DSM-IV qualifying traumatic events and posttraumatic stress disorder (PTSD) in 837 urban first graders (71% African American) followed-up for 15 years. Childhood trajectories of chronic high or increasing aggressive-disruptive behavior distinguished males more likely to be exposed to an assaultive violence event as compared to males with a constant course of low behavior problems (ORchronic high = 2.8, 95% CI = 1.3, 6.1 and ORincreasing = 4.5, 95% CI = 2.3, 9.1, respectively). Among females, exposure to traumatic events and vulnerability to PTSD did not vary by behavioral trajectory. The findings illustrate that repeated assessments of disruptive classroom behavior during early school years identifies more fully males at increased risk for PTSD-level traumatic events, than a single measure at school entry does. PMID:19139797

  13. The Canonical Immediate Early 3 Gene Product pIE611 of Mouse Cytomegalovirus Is Dispensable for Viral Replication but Mediates Transcriptional and Posttranscriptional Regulation of Viral Gene Products

    PubMed Central

    Rattay, Stephanie; Trilling, Mirko; Megger, Dominik A.; Sitek, Barbara; Meyer, Helmut E.; Hengel, Hartmut

    2015-01-01

    ABSTRACT Transcription of mouse cytomegalovirus (MCMV) immediate early ie1 and ie3 is controlled by the major immediate early promoter/enhancer (MIEP) and requires differential splicing. Based on complete loss of genome replication of an MCMV mutant carrying a deletion of the ie3-specific exon 5, the multifunctional IE3 protein (611 amino acids; pIE611) is considered essential for viral replication. Our analysis of ie3 transcription resulted in the identification of novel ie3 isoforms derived from alternatively spliced ie3 transcripts. Construction of an IE3-hemagglutinin (IE3-HA) virus by insertion of an in-frame HA epitope sequence allowed detection of the IE3 isoforms in infected cells, verifying that the newly identified transcripts code for proteins. This prompted the construction of an MCMV mutant lacking ie611 but retaining the coding capacity for the newly identified isoforms ie453 and ie310. Using Δie611 MCMV, we demonstrated the dispensability of the canonical ie3 gene product pIE611 for viral replication. To determine the role of pIE611 for viral gene expression during MCMV infection in an unbiased global approach, we used label-free quantitative mass spectrometry to delineate pIE611-dependent changes of the MCMV proteome. Interestingly, further analysis revealed transcriptional as well as posttranscriptional regulation of MCMV gene products by pIE611. IMPORTANCE Cytomegaloviruses are pathogenic betaherpesviruses persisting in a lifelong latency from which reactivation can occur under conditions of immunosuppression, immunoimmaturity, or inflammation. The switch from latency to reactivation requires expression of immediate early genes. Therefore, understanding of immediate early gene regulation might add insights into viral pathogenesis. The mouse cytomegalovirus (MCMV) immediate early 3 protein (611 amino acids; pIE611) is considered essential for viral replication. The identification of novel protein isoforms derived from alternatively spliced ie3 transcripts prompted the construction of an MCMV mutant lacking ie611 but retaining the coding capacity for the newly identified isoforms ie453 and ie310. Using Δie611 MCMV, we demonstrated the dispensability of the canonical ie3 gene product pIE611 for viral replication and delineated pIE611-dependent changes of the MCMV proteome. Our findings have fundamental implications for the interpretation of earlier studies on pIE3 functions and highlight the complex orchestration of MCMV gene regulation. PMID:26063418

  14. End-Binding Protein 1 (EB1) Up-regulation is an Early Event in Colorectal Carcinogenesis

    PubMed Central

    Stypula-Cyrus, Yolanda; Mutyal, Nikhil N.; Cruz, Mart Angelo Dela; Kunte, Dhananjay P.; Radosevich, Andrew J.; Wali, Ramesh; Roy, Hemant K.; Backman, Vadim

    2014-01-01

    End-binding protein (EB1) is a microtubule protein that binds to the tumor suppressor adenomatous polyposis coli (APC). While EB1 is implicated as a potential oncogene, its role in cancer progression is unknown. Therefore, we analyzed EB1/APC expression at the earliest stages of colorectal carcinogenesis and in the uninvolved mucosa ("field effect") of human and animal tissue. We also performed siRNA-knockdown in colon cancer cell lines. EB1 is up-regulated in early and field carcinogenesis in the colon, and the cellular/nano-architectural effect of EB1 knockdown depended on the genetic context. Thus, dysregulation of EB1 is an important early event in colon carcinogenesis. PMID:24492008

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

    SciTech Connect

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

    2015-03-15

    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.

  16. 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.

  17. Impaired Early Attentional Processes in Parkinson’s Disease: A High-Resolution Event-Related Potentials Study

    PubMed Central

    Bocquillon, Perrine; Bourriez, Jean-Louis; Palmero-Soler, Ernesto; Defebvre, Luc; Derambure, Philippe; Dujardin, Kathy

    2015-01-01

    Introduction The selection of task-relevant information requires both the focalization of attention on the task and resistance to interference from irrelevant stimuli. A previous study using the P3 component of the event-related potentials suggested that a reduced ability to resist interference could be responsible for attention disorders at early stages of Parkinson’s disease (PD), with a possible role of the dorsolateral prefrontal cortex (DLPFC). Methods Our objective was to better determine the origin of this impairment, by studying an earlier ERP component, the N2, and its subcomponents, as they reflect early inhibition processes and as they are known to have sources in the anterior cingulate cortex (ACC), which is involved together with the DLPFC in inhibition processes. Fifteen early-stage PD patients and 15 healthy controls (HCs) performed a three-stimulus visual oddball paradigm, consisting in detecting target inputs amongst standard stimuli, while resisting interference from distracter ones. A 128-channel electroencephalogram was recorded during this task and the generators of the N2 subcomponents were identified using standardized weighted low-resolution electromagnetic tomography (swLORETA). Results PD patients displayed fewer N2 generators than HCs in both the DLPFC and the ACC, for all types of stimuli. In contrast to controls, PD patients did not show any differences between their generators for different N2 subcomponents. Conclusion Our data suggest that impaired inhibition in PD results from dysfunction of the DLPFC and the ACC during the early stages of attentional processes. PMID:26135906

  18. The onset of childhood amnesia in childhood: A prospective investigation of the course and determinants of forgetting of early-life events

    PubMed Central

    Bauer, Patricia J.; Larkina, Marina

    2013-01-01

    The present research was an examination of the onset of childhood amnesia and how it relates to maternal narrative style, an important determinant of autobiographical memory development. Children and their mothers discussed unique events when the children were 3 years of age. Different subgroups of children were tested for recall of the events at ages 5, 6, 7, 8, and 9 years. At the later session, they were interviewed by an experimenter about the events discussed 2 to 6 years previously with their mothers (early-life events). Children ages 5, 6, and 7 remembered 60% or more of the early-life events. In contrast, children ages 8 and 9 years remembered fewer than 40% of the early-life events. Overall maternal narrative style predicted children's contributions to mother-child conversations at age 3 years; it did not have cross-lagged relations to memory for early-life events at ages 5 to 9 years. Maternal deflections of the conversational turn to the child predicted the amount of information children later reported about the early-life events. The findings have implications for our understanding of the onset of childhood amnesia and the achievement of an adult-like distribution of memories in the school years. They highlight the importance of forgetting processes in explanations of the amnesia. PMID:24236647

  19. 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.

  20. Studies on prion replication in spleen.

    PubMed

    Raeber, A J; Montrasio, F; Hegyi, I; Frigg, R; Klein, M A; Aguzzi, A; Weissmann, C

    2001-01-01

    Some of the early events following scrapie infection take place in the lymphoreticular system (LRS) and result in significant replication of prions in lymphoid organs. The identity of the cells in the LRS that produce prions and their role in neuroinvasion are still unknown. We find that in the spleen of scrapie-infected mice, prions are associated with T and B cells and to a somewhat lesser degree with the stroma, which contains the follicular dendritic cells (FDC's); curiously, no infectivity was found in lymphocytes from blood of the same mice. Thus, splenic lymphocytes either replicate prions or acquire them from another source. Studies on PrP knockout mice with ectopic expression of PrP restricted to only B or T lymphocytes suggest that neither of these by themselves are competent for prion replication. To determine whether B and T cells are able to pick up prions from other sources, irradiated wild-type mice were reconstituted with PrP-deficient lymphohaematopoietic stem cells. Following intraperitoneal inoculation of these mice, no infectivity was found on splenic lymphocytes whereas the stroma (comprising the radiation-resistant, PrP-expressing FDC's) contained prions. These results imply that splenic lymphocytes can acquire prions, possibly from FDC's, but only if they express PrP. PMID:11785678

  1. Studies on Prion Replication in Spleen

    PubMed Central

    Montrasio, Fabio; Hegyi, Ivan; Frigg, Rico; Klein, Michael A.; Aguzzi, Adriano; Weissmann, Charles

    2001-01-01

    Some of the early events following scrapie infection take place in the lymphoreticular system (LRS) and result in significant replication of prions in lymphoid organs. The identity of the cells in the LRS that produce prions and their role in neuroinvasion are still unknown. We find that in the spleen of scrapie-infected mice, prions are associated with T and B cells and to a somewhat lesser degree with the stroma, which contains the follicular dendritic cells (FDC's); curiously, no infectivity was found in lymphocytes from blood of the same mice. Thus, splenic lymphocytes either replicate prions or acquire them from another source. Studies on PrP knockout mice with ectopic expression of PrP restricted to only B or T lymphocytes suggest that neither of these by themselves are competent for prion replication. To determine whether B and T cells are able to pick up prions from other sources, irradiated wild-type mice were reconstituted with PrP-deficient lymphohaematopoietic stem cells. Following intraperitoneal inoculation of these mice, no infectivity was found on splenic lymphocytes whereas the stroma (comprising the radiation-resistant, PrP-expressing FDC's) contained prions. These results imply that splenic lymphocytes can acquire prions, possibly from FDC's, but only if they express PrP. PMID:11785678

  2. Loss of pectin is an early event during infection of cocoyam roots by Pythium myriotylum.

    PubMed

    Boudjeko, Thadde; Andme-Onzighi, Christine; Vicr, Mat; Balang, Alain-Pierre; Ndoumou, Denis Omokolo; Driouich, Azeddine

    2006-01-01

    Cocoyam (Xanthosoma sagittifolium) is an important tuber crop in most tropical zones of Africa and America. In Cameroon, its cultivation is hampered by a soil-borne fungus Pythium myriotylum which is responsible for root rot disease. The mechanism of root colonisation by the fungus has yet to be elucidated. In this study, using microscopical and immunocytochemical methods, we provide a new evidence regarding the mode of action of the fungus and we describe the reaction of the plant to the early stages of fungal invasion. We show that the fungal attack begins with the colonisation of the peripheral and epidermal cells of the root apex. These cells are rapidly lost upon infection, while cortical and stele cells are not. Labelling with the cationic gold, which binds to negatively charged wall polymers such as pectins, is absent in cortical cells and in the interfacial zone of the infected roots while it is abundant in the cell walls of stele cells. A similar pattern of labelling is also found when using the anti-pectin monoclonal antibody JIM5, but not with anti-xyloglucan antibodies. This suggests that early during infection, the fungus causes a significant loss of pectin probably via degradation by hydrolytic enzymes that diffuse and act away from the site of attack. Additional support for pectin loss is the demonstration, via sugar analysis, that a significant decrease in galacturonic acid content occurred in infected root cell walls. In addition, we demonstrate that one of the early reactions of X. sagittifolium to the fungal invasion is the formation of wall appositions that are rich in callose and cellulose. PMID:16160840

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

    PubMed

    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

  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. Dynamic Crystallography Reveals Early Signalling Events in Ultraviolet Photoreceptor UVR8

    PubMed Central

    Zeng, Xiaoli; Ren, Zhong; Wu, Qi; Fan, Jun; Peng, Pan-Pan; Tang, Kun; Zhang, Ruiqin; Zhao, Kai-Hong; Yang, Xiaojing

    2015-01-01

    Arabidopsis thaliana UVR8 (AtUVR8) is a long-sought-after photoreceptor that undergoes dimer dissociation in response to UV-B light. Crystallographic and mutational studies have identified two crucial tryptophan residues for UV-B responses in AtUVR8. However, the mechanism of UV-B perception and structural events leading up to dimer dissociation remain elusive at the molecular level. We applied dynamic crystallography to capture light-induced structural events in photoactive AtUVR8 crystals. Here we report two intermediate structures at 1.67Å resolution. At the epicenter of UV-B signaling, concerted motions associated with Trp285/Trp233 lead to ejection of a water molecule, which weakens an intricate network of hydrogen bonds and salt bridges at the dimer interface. Partial opening of the β-propeller structure due to thermal relaxation of conformational strains originating in the epicenter further disrupts the dimer interface and leads to dimer dissociation. These dynamic crystallographic observations provide structural insights into the photo-perception and signaling mechanism of UVR8. PMID:26097745

  6. 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.

  7. 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.

  8. 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

  9. Early Oligocene geomagnetic field behavior from ODP Site 1128: Complex records of short-period polarity events

    NASA Astrophysics Data System (ADS)

    Molina-Garza, R. S.; Fuller, M. D.

    2001-12-01

    At Site 1128, in the Great Australian Bight, Leg 182 of the Ocean Drilling Program recovered a thick (~350 m) section of Upper Eocene and Lower Oligocene marine calcareous clays. Shipboard measurements established a magnetostratigraphy that can unambiguously be correlated to chrons C13n to C10n of the global polarity time scale (GPTS), and a less complete record of chrons C17n to C15r (due to poor core recovery). Correlation to the GPTS is further supported by available biostratigraphic data. For the Lower Oligocene sequence, average sedimentation rate is estimated at ~4 cm/kyr. The sediments recovered thus allow to test for the completeness and reliability of the geomagnetic field polarity during the Early Oligocene. The original shipboard long-core measurements suggested the presence of additional short polarity events or geomagnetic field excursions during chrons C13n, C12r, C11r, and C11n. In order to examine the reliability of the record and the nature of possible short-polarity events, we obtained discrete samples from the entire sequence at ~1 m intervals, with a closer sample spacing in critical intervals (~10 cm). The natural remanence of these sediments is normally simple. After removing a small soft overprint, the magnetization decays towards the origin with distributed coercivities and distributed unblocking temperatures. Demagnetization behavior and other rock magnetic data indicate that the remanence resides primarily in a cubic phase such as magnetite or maghemite, with a small contribution from hematite. Discrete samples from chron C12r did not reproduce the long-core record for two of the supposed events, single samples suggest the presence of short events or cryptochrons near the base of both C13n and C12r, and multiple samples suggest the existence of short-period normal polarity events during C11r and near the top of C12r. The records of these events are, however, complex. Demagnetization results indicate that the magnetization consists of an intermediate- (10-40 mT) and a high-coercivity (40-80 mT) component. Only the intermediate coercivity magnetization records normal polarities, although transitional directions are observed in both components. Hysteresis data suggest the presence of PSD particles, and show no discernable difference between sediments recording short-period polarity events and those with uniform near univectorial behavior and single polarity, suggesting uniformity of remanence carriers. The two components of the NRM can be attributed to the presence of two carriers with different lock-in time mechanisms.

  10. 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.

  11. 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.

  12. 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

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

    PubMed

    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. PMID:23360887

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

    PubMed

    Eriksson, Anna; Lennartsson, Andreas; Lehmann, Sren

    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 beenfound 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. 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

  16. Salt stress sensing and early signalling events in plant roots: Current knowledge and hypothesis.

    PubMed

    Shabala, Sergey; Wu, Honghong; Bose, Jayakumar

    2015-12-01

    Soil salinity is a major environmental constraint to crop production. While the molecular identity and functional expression of Na(+) transport systems mediating Na(+) exclusion from the cytosol has been studied in detail, far less is known about the mechanisms by which plants sense high Na(+) levels in the soil and the rapid signalling events that optimise plant performance under saline conditions. This review aims to fill this gap. We first discuss the nature of putative salt stress sensors, candidates which include Na(+) transport systems, mechanosensory proteins, proteins with regulatory Na(+) binding sites, sensing mediated by cyclic nucleotide-gated channels, purine receptors, annexin and voltage gating. We suggest that several transport proteins may be clustered together to form a microdomain in a lipid raft, allowing rapid changes in the activity of an individual protein to be translated into stress-induced Ca(2+) and H2O2 signatures. The pathways of stress signalling to downstream targets are discussed, and the kinetics and specificity of salt stress signalling between glycophytes and halophytes is compared. We argue that these sensing mechanisms operate in parallel, providing plants with a robust system for decoding information about the specific nature and severity of the imposed salt stress. PMID:26706063

  17. 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.

  18. Repression of early lateral root initiation events by transient water deficit in barley and maize

    PubMed Central

    Bab, Aurlie; Lavigne, Tristan; Sverin, Jean-Philippe; Nagel, Kerstin A.; Walter, Achim; Chaumont, Franois; Batoko, Henri; Beeckman, Tom; Draye, Xavier

    2012-01-01

    The formation of lateral roots (LRs) is a key driver of root system architecture and developmental plasticity. The first stage of LR formation, which leads to the acquisition of founder cell identity in the pericycle, is the primary determinant of root branching patterns. The fact that initiation events occur asynchronously in a very small number of cells inside the parent root has been a major difficulty in the study of the molecular regulation of branching patterns. Inducible systems that trigger synchronous lateral formation at predictable sites have proven extremely valuable in Arabidopsis to decipher the first steps of LR formation. Here, we present a LR repression system for cereals that relies on a transient water-deficit treatment, which blocks LR initiation before the first formative divisions. Using a time-lapse approach, we analysed the dynamics of this repression along growing roots and were able to show that it targets a very narrow developmental window of the initiation process. Interestingly, the repression can be exploited to obtain negative control root samples where LR initiation is absent. This system could be instrumental in the analysis of the molecular basis of drought-responsive as well as intrinsic pathways of LR formation in cereals. PMID:22527396

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

    NASA Astrophysics Data System (ADS)

    Simões, Ana; Carneiro, Ana; Diogo, Maria Paula

    2012-03-01

    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 Diário de Notícias ( Daily News) and the Diário dos Açores ( Azores Daily). In particular, we look at how the 1900 solar eclipse, a hot topic throughout Europe, was reported by the capital newspaper, and how news on seismology were conveyed in the period 1907-1910 in the newspaper published in Azores, an archipelago with a significant seismic and volcanic activity. We argue that the importance conceded to these scientific news was related to their overwhelming features, that their dissimilar presentation stemmed from their local relevance allied to their different nature, predictable in the case of eclipses, and unpredictable in the case of earthquakes, and that behind these two instances of science journalism laid an attempt by the scientific and political communities to gain the support of the general public to such an extent that these two specific instances of science journalism transcended their usual features to become successful forms of expository science.

  20. Early Events of Virus-Cell Interaction in an Adenovirus System

    PubMed Central

    Lonberg-Holm, Karl; Philipson, Lennart

    1969-01-01

    The interaction of 32P-labeled adenovirus type 2 and HeLa or KB cells has been examined during early infection. The kinetics of virus uncoating to deoxyribonuclease-sensitive products, the partial characterization of three such products by gradient centrifugation, and the distribution of these products in the extranuclear and nuclear portions of infected cells are reported. The results are compatible with the following model. Extracellular virus attaches to a receptor on the plasma membrane. The membrane-bound virus has a half-life of less than 15 min and is transformed to a partly uncoated product which is free inside the cell and about half of which rapidly enters the cell nucleus. This is rapidly transformed, in both cytoplasm and nucleus, to a membrane-bound virion “core.” The proteins of the bound “core” are then removed from the intact virus deoxyribonucleic acid (DNA). In the nucleus, viral DNA is the main product and there the overall sequence is completed in about 2 hr. PMID:4898584

  1. Hypoinnervation is an early event in experimental myocardial remodelling induced by pressure overload

    PubMed Central

    Mhlfeld, Christian; Schipke, Julia; Schmidt, Albrecht; Post, Heiner; Pieske, Burkert; Sedej, Simon

    2013-01-01

    Structural and functional remodelling of cardiomyocytes, capillaries and cardiac innervation occurs in left ventricular hypertrophy (LVH) and heart failure (HF) in response to pressure-induced overload. However, the onset, time course and the extent of these morphological alterations remain controversial. In the present study, we tested the hypothesis that the progression from hypertrophy to HF is accompanied by changes in the innervation (hyper- or hypoinnervation). Left ventricles of wild-type murine hearts subjected to pressure overload-induced hypertrophy by transverse aortic constriction (TAC) were investigated by morphometric and design-based stereological methods at 1 and 4?weeks after TAC and compared with sham-operated mice. Mice developed compensated LVH at 1week and typical signs of HF, such as left ventricular dilation, reduced ejection fraction and increased relative lung weight at 4?weeks post-TAC. At the (sub-)cellular level, cardiomyocyte myofibrillar and mitochondrial volume increased progressively in response to mechanical overload. The total length of capillaries was not significantly increased after TAC, indicating a misrelationship between the cardiomyocyte and the capillary compartment. The myocardial innervation decreased already during the development of LVH and did not significantly decrease further during the progression to HF. In conclusion, our study suggests that early loss of myocardial innervation density and increased heterogeneity occur during pressure overload-induced hypertrophy, and that these changes appear to be independent of cardiomyocyte and capillary remodelling. PMID:23565587

  2. 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.

  3. Molybdenum Isotope Variations in the Toarcian (Early Jurassic): Constraining Paleoredox Changes During an Ocean Anoxic Event

    NASA Astrophysics Data System (ADS)

    Pearce, C. R.; Cohen, A. S.; Coe, A. L.; Burton, K. W.

    2005-12-01

    Molybdenum is a redox sensitive element that is sequestered by marine sediments and chemical precipitates, and is capable of recording changes in oceanic conditions over time. Whilst Mo concentrations have been used in conjunction with other geochemical information as an indicator of the local water conditions (e.g. Re/Mo ratios; Crusius et al., 1996), the natural isotopic variations in Mo also offer considerable potential as a global paleoredox proxy. Previous Mo isotope studies have looked at long-term changes in the oxygenation state of the oceans (e.g. Siebert et al., 2003; Arnold et al., 2005), as the long residence time of the dominant molybdate ion ensures that oceanic Mo is isotopically uniform and consequently provides a truly global record of marine conditions over intervals >1 Ma. To date little attention has been paid to the possibility of Mo isotope variations that may have occurred over timescales shorter than this. However, there is increasing evidence that sudden and substantial changes have occurred in the marine environment in the past. The geochemical behaviour of Mo is such that relatively rapid isotopic changes may now be resolvable using the latest high precision stratigraphical and analytical techniques. We have produced Mo isotope data from a suite of organic rich sedimentary rocks deposited over an interval of ~1.5 Ma spanning the Toarcian Ocean Anoxic Event (OAE) that occurred ~183 Ma ago. As with other Mesozoic OAEs, the Toarcian event is associated with a dramatic increase in the organic carbon content of the sedimentary deposits and with a mass extinction. Recent geochemical studies have also revealed a stepped ?13Corg negative excursion of ~ -7, marked excursions in the seawater 187Os/188Os and 87Sr/86Sr ratios, and evidence for a sudden temperature increase of ~10C, all of which indicate a substantial environmental change at that time (Cohen et al., 2004; Kemp et al., 2005). Our Mo isotope data were obtained using a Nu Instruments MC-ICP-MS and are presented as ?98/95Mo relative to an in-house standard. The natural and instrumental fractionation factors are determined using a 100Mo-97Mo double spike and an offline Newton-Raphson deconvolution procedure, resulting in an external reproducibility of <0.15 (2 s.d.). Preliminary results reveal at least two abrupt ?98/95Mo excursions of 0.6 and 0.8, both of which appear to be correlated with the rapid negative shifts in ?13Corg. In addition, longer term changes in ?98/95Mo can be resolved across the OAE. These findings have important implications for our understanding of the changes in the marine environment that occurred during the Toarcian OAE. Our results also show that variations in the Mo isotope composition of seawater have occurred relatively suddenly at certain times in the past, and indicate that this isotope system has the ability, under certain circumstances, to record abrupt changes in global oceanic conditions. Crusius, J. et al. (1996), EPSL 145, 65-78; Siebert, C. et al. (2003), EPSL 211, 159-171; Arnold, G.L. et al. (2005), Science 304, 87-90; Cohen, A.S. et al. (2004), Geology 32, 157-160; Kemp, D.B. et al. (2005), Nature In Press.

  4. Early hydrogen-bonding events in the folding reaction of ubiquitin.

    PubMed Central

    Briggs, M S; Roder, H

    1992-01-01

    The formation of hydrogen-bonded structure in the folding reaction of ubiquitin, a small cytoplasmic protein with an extended beta-sheet and an alpha-helix surrounding a pronounced hydrophobic core, has been investigated by hydrogen-deuterium exchange labeling in conjunction with rapid mixing methods and two-dimensional NMR analysis. The time course of protection from exchange has been measured for 26 back-bone amide protons that form stable hydrogen bonds upon refolding and exchange slowly under native conditions. Amide protons in the beta-sheet and the alpha-helix, as well as protons involved in hydrogen bonds at the helix/sheet interface, become 80% protected in an initial 8-ms folding phase, indicating that the two elements of secondary structure form and associate in a common cooperative folding event. Somewhat slower protection rates for residues 59, 61, and 69 provide evidence for the subsequent stabilization of a surface loop. Most probes also exhibit two minor phases with time constants of about 100 ms and 10 s. Only two of the observed residues, Gln-41 and Arg-42, display significant slow folding phases, with amplitudes of 37% and 22%, respectively, which can be attributed to native-like folding intermediates containing cis peptide bonds for Pro-37 and/or Pro-38. Compared with other proteins studied by pulse labeling, including cytochrome c, ribonuclease, and barnase, the initial formation of hydrogen-bonded structure in ubiquitin occurs at a more rapid rate and slow-folding species are less prominent. Images PMID:1312711

  5. Prior chronic clopidogrel therapy is associated with increased adverse events and early stent thrombosis.

    PubMed

    Asher, Elad; Fefer, Paul; Sabbag, Avi; Herscovici, Romana; Regev, Ehud; Mazin, Israel; Shlomo, Nir; Zahger, Doron; Atar, Shaul; Hammerman, Haim; Polak, Arthur; Beigel, Roy; Matetzky, Shlomi

    2016-01-27

    Despite the growing use of clopidogrel, limited data exist regarding the prognostic significance of chronic clopidogrel therapy in patients sustaining acute coronary syndrome (ACS). Our aim was to determine whether patients sustaining ACS while on chronic clopidogrel therapy have a worse prognosis than clopidogrel-nave patients. A total of 5,386 consecutive ACS patients were prospectively characterised and followed-up for 30 days. Of them, 680 (13?%) were treated with clopidogrel prior to the index ACS. Major adverse cardiovascular events (MACE) were defined as death, recurrent ACS, stroke and/or stent thrombosis. Compared with clopidogrel-nave, chronic clopidogrel-treated patients were older (66 12 vs 63 13, respectively; p

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

    PubMed Central

    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 mother-child relationship as the vehicle for child improvement, is efficacious for children who experienced multiple traumatic and stressful life events (TSEs). Methods Participants comprised 75 preschool-aged children and their mothers referred to treatment following the childs exposure to domestic violence. Dyads were randomly assigned to CPP or to a comparison group that received monthly case management plus referrals to community services and were assessed at intake, posttest, and 6-month follow-up. Treatment effectiveness was examined by level of child TSE risk exposure (<4 risks versus 4+ TSEs). Results For children in the 4+ risk group, those who received CPP showed significantly greater improvements in PTSD and depression symptoms, PTSD diagnosis, number of co-occurring diagnoses, and behavior problems compared to those in the comparison group. CPP children with <4 risks showed greater improvements in symptoms of PTSD than those in the comparison group. Mothers of children with 4+ TSEs in the CPP group showed greater reductions in symptoms of PTSD and depression than those randomized to the comparison condition. Analyses of 6-month follow-up data suggest improvements were maintained for the high risk group. Conclusions The data provide evidence that CPP is effective in improving outcomes for children who experienced four or more TSEs and had positive effects for their mothers as well. Practice Implications Numerous studies show that exposure to childhood trauma and adversity has negative consequences for later physical and mental health, but few interventions have been specifically evaluated to determine their effectiveness for children who experienced multiple TSEs. The findings suggest that including the mother as an integral participant in the childs treatment may be particularly effective in the treatment of young children exposed to multiple risks. PMID:21816474

  7. 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).

  8. 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-β), 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-β, 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

  9. 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 109cfu/kg (LD50) live E.coli by intravenous infusion were treated or not with compstatin at the time of challenge or 5hrs thereafter. Changes in the fibroproliferative response at 24hrs 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 24hrs 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

  10. Petrography and carbonate isotope stratigraphy from MIS AND-1B core, Antarctica: Evidence of the early Pliocene warming event

    NASA Astrophysics Data System (ADS)

    Scopelliti, G.; Bellanca, A.; Neri, R.

    2011-03-01

    A large portion of ANDRILL (ANtarctic geological DRILLing) core AND-1B recovered in the Western Ross Sea and spanning the early Pliocene has been investigated in order to obtain a detailed carbonate isotope record from Antarctic margin sediments through the early Pliocene warming event. Petrographic observations and mineralogical analyses reveal the authigenic nature of the carbonate and small proportions of Fe and Mg incorporated within the calcite lattice. High productivity conditions testified by ~ 80 m-thick diatomite interval (383 to 460 mbsf) well fit with the composite nature of the authigenic carbonate generally characterizing organic matter-rich sediments. As is known, sediments from the Polar Region are generally poor in carbonate. Although in the investigated portion of AND-1B core the carbonate seldom exceeds 5% in content, an automated Carbonate Preparation Device was used to obtain a high-resolution stable isotope dataset. Paleoenvironmental conditions characterized by high organic matter flux are supported by negative δ 13C values suggesting a contribution of isotopically light biogenic CO 2 during the carbonate precipitation. As to δ 18O, even if melting glaciers are thought to be responsible for depletion in 18O composition, the isotope record exhibits long- and short-term trends. Analysis of the long-term trend constrains the Pliocene warming climax in an interval between 400-450 mbsf highlighting that most of the event is not documented because of a 800 kyr hiatus. The short-term trend documents the influence of obliquity controlling the annual insolation, but also that of precession-linked cyclicity seldom documented at high latitude.

  11. Human cytomegalovirus function inhibits replication of herpes simplex virus

    SciTech Connect

    Cockley, K.D.; Shiraki, K.; Rapp, F.

    1988-01-01

    Human embryonic lung (HEL) cells infected with human cytomegalovirus (HCMV) restricted the replication of herpes simplex virus type 1 (HSV-1). A delay in HSV replication of 15 h as well as a consistent, almost 3 log inhibition of HSV replication in HCMV-infected cell cultures harvested 24 to 72 h after superinfection were observed compared with controls infected with HSV alone. Treatment of HCMV-infected HEL cells with cycloheximide (100 ..mu..g/ml) for 3 or 24 h was demonstrated effective in blocking HCMV protein synthesis, as shown by immunoprecipitation with HCMV antibody-positive polyvalent serum. Cycloheximide treatment of HCMV-infected HEL cells and removal of the cycloheximide block before superinfection inhibited HSV-1 replication more efficiently than non-drug-treated superinfected controls. HCMV DNA-negative temperature-sensitive mutants restricted HSV as efficiently as wild-type HCMV suggesting that immediate-early and/or early events which occur before viral DNA synthesis are sufficient for inhibition of HSV. Inhibition of HSV-1 in HCMV-infected HEL cells was unaffected by elevated temperature (40.5/sup 0/C). However, prior UV irradiation of HCMV removed the block to HSV replication, demonstrating the requirement for an active HCMV genome. HSV-2 replication was similarly inhibited in HCMV-infected HEL cells. Superinfection of HCMV-infected HEL cells with HSV-1 labeled with (/sup 3/H)thymidine provided evidence that the labeled virus could penetrate to the nucleus of cells after superinfection. Evidence for penetration of superinfecting HSV into HCMV-infected cells was also provided by blot hybridization of HSV DNA synthesized in cells infected with HSV alone versus superinfected cell cultures at 0 and 48 h after superinfection.

  12. 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 60-80N. During 1-5 August, negative 850 hPa temperature anomalies between -2 and -4C were found poleward of 70-75N between 90E and the Dateline over the Arctic Ocean while positive 850 hPa temperature anomalies of 8-9C were found over eastern Russia near 60N. The associated anomalously strong 850 hPa meridional temperature gradient of ~10C (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.

  13. 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 μl 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 μl 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

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

    PubMed

    Duarte, Joo V; Pereira, Joo 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

  15. Altering second-order configurations reduces the adaptation effects on early face-sensitive event-related potential components

    PubMed Central

    Vakli, Pl; Nmeth, Kornl; Zimmer, Mrta; Schweinberger, Stefan R.; Kovcs, Gyula

    2014-01-01

    The spatial distances among the features of a face are commonly referred to as second-order relations, and the coding of these properties is often regarded as a cornerstone in face recognition. Previous studies have provided mixed results regarding whether the N170, a face-sensitive component of the event-related potential, is sensitive to second-order relations. Here we investigated this issue in a gender discrimination paradigm following long-term (5 s) adaptation to normal or vertically stretched male and female faces, considering that the latter manipulation substantially alters the position of the inner facial features. Gender-ambiguous faces were more likely judged to be female following adaptation to a male face and vice versa. This aftereffect was smaller but statistically significant after being adapted to vertically stretched when compared to unstretched adapters. Event-related potential recordings revealed that adaptation effects measured on the amplitude of the N170 show strong modulations by the second-order relations of the adapter: reduced N170 amplitude was observed, however, this reduction was smaller in magnitude after being adapted to stretched when compared to unstretched faces. These findings suggest early face-processing, as reflected in the N170 component, proceeds by extracting the spatial relations of inner facial features. PMID:24971058

  16. 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.

  17. Timing of the Toarcian Ocean Anoxic Event (Early Jurassic) from correlation of astronomically forced global stratigraphic sections

    NASA Astrophysics Data System (ADS)

    Huang, C.; Hinnov, L. A.; Hesselbo, S. P.

    2012-12-01

    The Early Toarcian Oceanic Anoxic Event (OAE) in the Early Jurassic Period is associated with a major negative carbon isotope excursion (CIE), mass extinction, marine transgression and global warming. The Toarcian OAE is thought to have been caused by flood basalt magmatism, and may have been a trigger for mass extinction. However, these proposed causes of the Toarcian OAE and associated biotic crisis are not adequately resolved by a precise chronology. The duration of the Toarcian OAE has been estimated to be anywhere from ~0.12 to ~0.9 Myr, most recently 0.74 to 3.26 Myr from U-Pb dating. The CIE associated with the Toarcian OAE has a similar pattern at numerous localities, and there is evidence for astronomical forcing of marine carbon isotopes. Here we estimate a duration of ~625 kyr for the main negative CIE, ~860 kyr for the polymorphum zone and >1.58 Myr for the levisoni zone based on 405-kyr astronomical eccentricity tuning of the marine section at Peniche (Portugal). This 405-kyr tuned series provides a ~2.5 Myr continuous high-resolution chronology through the Early Toarcian. There are 6, or possibly 7 short eccentricity cycles in the main CIE interval at Peniche. To confirm this astronomically based estimate, we analyzed five other sections at Yorkshire (UK), Dotternhausen (Germany), Valdorbia (Italy), Mechowo (Poland) and Serrucho, Neuqun (Argentina), from marine and terrestrial carbon isotopic series. These six stratigraphic sections from Early Jurassic western Tethys and eastern Panthalassa record the Toarcian OAE with ~6 prominent carbon isotope cycles in the CIE that provide us a 600 100 kyr duration. The Peniche 405 kyr-tuned series indicates that the pre- and post-CIE intervals experienced strong precession-eccentricity-forced climate change, whereas the CIE interval is marked by dominant obliquity forcing. These dramatic and abrupt changes in astronomical response in the carbon isotopes point to fundamental shifting in the Early Toarcian paleoclimate system that is directly linked to the global carbon cycle.

  18. Probing early events in ferrous cytochrome c folding with time-resolved natural and magnetic circular dichroism spectroscopies.

    PubMed

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

    2009-10-01

    In a 1998 collaboration with Tony Fink, we coupled nanosecond circular dichroism methods (TRCD) with a CO-photolysis system for quickly triggering folding in cytochrome c (cyt c) in order to make the first time-resolved far-UV CD measurement of early secondary structure formation in a protein. The small signal observed in that initial study, approximately 10% of native helicity, became the seed for increasingly robust results from subsequent studies bringing additional natural and magnetic circular polarization dichroism and optical rotatory dispersion detection methods (e.g., TRORD, TRMCD, and TRMORD), coupled to fast photolysis and photoreduction triggers, to the study of early folding events. Nanosecond polarization methods are reviewed here in the context of the range of initiation methods and structure-sensitive probes currently available for fast folding studies. We also review the impact of experimental results from fast polarization studies on questions in folding dynamics such as the possibility of multiple folding pathways implied by energy landscape models, the sequence dependence of ultrafast helix formation, and the simultaneity of chain collapse and secondary structure formation implicit in molten globule models for kinetic folding intermediates. PMID:19538147

  19. 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

  20. Antiretroviral Treatment Start-Time during Primary SIVmac Infection in Macaques Exerts a Different Impact on Early Viral Replication and Dissemination

    PubMed Central

    Sellier, Pierre; Mannioui, Abdelkrim; Bourry, Olivier; Dereuddre-Bosquet, Nathalie; Delache, Benoit; Brochard, Patricia; Calvo, Julien; Prévot, Sophie; Roques, Pierre

    2010-01-01

    Background The time of infection is rarely known in human cases; thus, the effects of delaying the initiation of antiretroviral therapy (ART) on the peripheral viral load and the establishment of viral reservoirs are poorly understood. Methodology/Principal Findings Six groups of macaques, infected intravenously with SIVmac251, were given placebo or antiretroviral therapy to explore reservoir establishment; macaques were treated for 2 weeks, with treatment starting 4 hours, 7 or 14 days after infection. Viral replication and dissemination were measured in the gut (rectum), in the lung and in blood and lymphoid tissues (peripheral lymph nodes), by quantifying viral RNA, DNA and 2LTR circles. We used immunohistochemistry (CD4 and CD68) to assess the impact of these treatments on the relative amount of virus target cells in tissue. Treatment that was started 4 hours post-infection (pi) decreased viral replication and dissemination in blood and tissue samples, which were assessed on day 14 (RNA/DNA/2LTR circles). The virus remained detectable and lymphoid tissues were activated in LN and the gut in both placebo- and ART-treated animals. Viral RNA in plasma continued to be lower in macaques treated seven days after infection; however, this was not the case for viral DNA in peripheral blood mononuclear cells. There was a small but significant difference in RNA and DNA levels in tissues between placebo- and ART-treated animals on day 21. When started 14 days after infection, treatment resulted in a limited decrease in the plasma viral load. Conclusions Treatment that was started 4 hours after infection significantly reduced viral replication and dissemination. When started 7 days after infection, it was of slight virological benefit in peripheral blood and in tissues, and treatment was even less effective if started 14 days pi. These data favor starting ART no longer than one week after intravenous SIVmac251 exposure. PMID:20485497

  1. 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.

  2. Early impact event and fluid activity on H chondrite parent body registered in the Pułtusk 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 Pułtusk meteorite containing vein-like metal accumulations [6]. In the Pułtusk, 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 Pułtusk 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] Krzesińska A., 2011. Meteorites 1: 3-12.

  3. 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

  4. 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.

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

    NASA Astrophysics Data System (ADS)

    Hernndez-Almeida, Ivn; Sierro, Francisco; Cacho, Isabel; Abel Flores, Jos

    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 (Hernndez-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. Hernndez-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

  6. Outreach: Replicating Services for Young Handicapped Children.

    ERIC Educational Resources Information Center

    Gunn, Lynn, Ed.

    Presented are eight author contributed chapters dealing with the outreach and replication of federally funded early education programs for handicapped children. M. Karnes and R. Zehrbach consider decisions regarding identification and assessment of replicable products (such as curricula and audiovisual presentations). Discussed by D. Stedman are…

  7. Decoupling of carbon isotope records between organic matter and carbonate prior to the Toarcian Oceanic Anoxic Event (Early Jurassic)

    NASA Astrophysics Data System (ADS)

    Bodin, Stephane; Kothe, Tim; Krencker, Francois-Nicolas; Suan, Guillaume; Heimhofer, Ulrich; Immenhauser, Adrian

    2014-05-01

    Across the Pliensbachian-Toarcian boundary (P-To, Early Jurassic), ca. 1 Myr before the Toarcian Oceanic Anoxic Event (T-OAE), an initial negative carbon isotope excursion has been documented in western Tethys sedimentary rocks. In carbonate, its amplitude (2-3 permil) is similar to the subsequent excursion recorded at the onset of the T-OAE. Being also associated with a rapid warming event, the significance of this first carbon isotope shift, in terms of paleoenvironmental interpretation and triggering mechanism, remains however elusive. Taking advantage of expanded and rather continuous sections in the High Atlas of Morocco, several high-resolution, paired organic-inorganic carbon isotope records have been obtained across the Upper Pliensbachian - Lower Toarcian interval. At the onset of the T-OAE, an abrupt 1-2 permil negative shift is recorded in both organic and inorganic phases, succeeded by a relatively longer term 1-2 permil negative trend and a final slow return to pre-excursion conditions. In accordance with previous interpretations, this pattern indicates a perturbation of the entire exogenic carbon isotope reservoir at the onset of the T-OAE by the sudden release of isotopically light carbon into the atmosphere. By contrast, there is no negative shift in carbon isotopes for the P-To event recorded in bulk organic matter of Morocco. Given the strong dominance of terrestrial particles in the bulk organic matter fraction, this absence indicates that massive input of 12C-rich carbon into the atmosphere is not likely to have happened during the P-To event. A pronounced (2 permil) and abrupt negative shift in carbon isotope is however recorded in the bulk carbonate phase. We suggest that this decoupling between organic and inorganic phase is due to changes in the nature of the bulk carbonate phase. Indeed, the negative shift occurs at the lithological transition between Pliensbachian-lowermost Toarcian limestone-marl alternations and the Lower Toarcian marl-dominated deposits. Before the P-To event, vigorous shallow-water carbonate factories were responsible for the bulk of carbonate production and export into the basin. Being dominated by aragonite precipitation, they tend to have a more positive carbon isotope signature than carbonate produced offshore. The demise of the shallow water platforms during the P-To event has led to a drastic reduction in the amount of carbonate in the rock record (indicated by the switch from limestone-marl alternations to a marl-dominated sequence), as well as to a marked decrease in the production and export of isotopically heavy carbon, ultimately recorded by a negative shift in the isotopic signature of the bulk carbonate fraction. This study highlights the need of paired organic-inorganic carbon isotope record in order to fully distinguish regional from global perturbation in the carbon cycle.

  8. Impact of COX2 genotype, ER status and body constitution on risk of early events in different treatment groups of breast cancer patients

    PubMed Central

    Markkula, Andrea; Simonsson, Maria; Rosendahl, Ann H; Gaber, Alexander; Ingvar, Christian; Rose, Carsten; Jernstrm, Helena

    2014-01-01

    The COX2 rs5277 (306G>C) polymorphism has been associated with inflammation-associated cancers. In breast cancer, tumor COX-2 expression has been associated with increased estrogen levels in estrogen receptor (ER)-positive and activated Akt-pathway in ER-negative tumors. Our study investigated the impact of COX2 genotypes on early breast cancer events and treatment response in relation to tumor ER status and body constitution. In Sweden, between 2002 and 2008, 634 primary breast cancer patients, aged 2599 years, were included. Disease-free survival was assessed for 570 rs5277-genotyped patients. Body measurements and questionnaires were obtained preoperatively. Clinical data, patient- and tumor-characteristics were obtained from questionnaires, patients' charts, population registries and pathology reports. Minor allele(C) frequency was 16.1%. Genotype was not linked to COX-2 tumor expression. Median follow-up was 5.1 years. G/G genotype was not associated with early events in patients with ER-positive tumors, adjusted HR 0.77 (0.461.29), but conferred an over 4-fold increased risk in patients with ER-negative tumors, adjusted HR 4.41 (1.2116.02)(pinteraction = 0.015). Chemotherapy-treated G/G-carriers with a breast volume ?850 ml had an increased risk of early events irrespective of ER status, adjusted HR 8.99 (1.1470.89). Endocrine-treated C-allele carriers with ER-positive tumors and a breast volume ?850 ml had increased risk of early events, adjusted HR 2.30 (1.124.75). COX2 genotype, body constitution and ER status had a combined effect on the risk of early events and treatment response. The high risk for early events in certain subgroups of patients suggests that COX2 genotype in combination with body measurements may identify patients in need of more personalized treatment. PMID:24599585

  9. Evidence of resilience to past climate change in Southwest Asia: Early farming communities and the 9.2 and 8.2 ka events

    NASA Astrophysics Data System (ADS)

    Flohr, Pascal; Fleitmann, Dominik; Matthews, Roger; Matthews, Wendy; Black, Stuart

    2016-03-01

    Climate change is often cited as a major factor in social change. The so-called 8.2 ka event was one of the most pronounced and abrupt Holocene cold and arid events. The 9.2 ka event was similar, albeit of a smaller magnitude. Both events affected the Northern Hemisphere climate and caused cooling and aridification in Southwest Asia. Yet, the impacts of the 8.2 and 9.2 ka events on early farming communities in this region are not well understood. Current hypotheses for an effect of the 8.2 ka event vary from large-scale site abandonment and migration (including the Neolithisation of Europe) to continuation of occupation and local adaptation, while impacts of the 9.2 ka have not previously been systematically studied. In this paper, we present a thorough assessment of available, quality-checked radiocarbon (14C) dates for sites from Southwest Asia covering the time interval between 9500 and 7500 cal BP, which we interpret in combination with archaeological evidence. In this way, the synchronicity between changes observed in the archaeological record and the rapid climate events is tested. It is shown that there is no evidence for a simultaneous and widespread collapse, large-scale site abandonment, or migration at the time of the events. However, there are indications for local adaptation. We conclude that early farming communities were resilient to the abrupt, severe climate changes at 9250 and 8200 cal BP.

  10. 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 (δ44/40Ca) 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 δ44/40Ca 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 δ44/40Ca 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 δ44/40Ca 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 (δ13C) comprised between - 6 ‰ and - 14 ‰ appears as the most likely causes of the δ13C 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.

  11. Disturbed Ca2+ Homeostasis Increases Glutaminyl Cyclase Expression; Connecting Two Early Pathogenic Events in Alzheimer’s Disease In Vitro

    PubMed Central

    De Kimpe, Line; Bennis, Anna; Zwart, Rob; van Haastert, Elise S.; Hoozemans, Jeroen J. M.; Scheper, Wiep

    2012-01-01

    A major neuropathological hallmark of Alzheimer’s disease (AD) is the deposition of aggregated β amyloid (Aβ) peptide in the senile plaques. Aβ is a peptide of 38–43 amino acids and its accumulation and aggregation plays a key role early in the disease. A large fraction of β amyloid is N-terminally truncated rendering a glutamine that can subsequently be cyclized into pyroglutamate (pE). This makes the peptide more resistant to proteases, more prone to aggregation and increases its neurotoxicity. The enzyme glutaminyl cyclase (QC) catalyzes this conversion of glutamine to pE. In brains of AD patients, the expression of QC is increased in the earliest stages of pathology, which may be an important event in the pathogenesis. In this study we aimed to investigate the regulatory mechanism underlying the upregulation of QC expression in AD. Using differentiated SK-N-SH as a neuronal cell model, we found that neither the presence of Aβ peptides nor the unfolded protein response, two early events in AD, leads to increased QC levels. In contrast, we demonstrated increased QC mRNA levels and enzyme activity in response to another pathogenic factor in AD, perturbed intracellular Ca2+ homeostasis. The QC promoter contains a putative binding site for the Ca2+ dependent transcription factors c-fos and c-jun. C-fos and c-jun are induced by the same Ca2+-related stimuli as QC and their upregulation precedes QC expression. We show that in the human brain QC is predominantly expressed by neurons. Interestingly, the Ca2+- dependent regulation of both c-fos and QC is not observed in non-neuronal cells. Our results indicate that perturbed Ca2+ homeostasis results in upregulation of QC selectively in neuronal cells via Ca2+- dependent transcription factors. This suggests that disruption of Ca2+ homeostasis may contribute to the formation of the neurotoxic pE Aβ peptides in Alzheimer’s disease. PMID:22970285

  12. 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

  13. Using Simcyp to project human oral pharmacokinetic variability in early drug research to mitigate mechanism-based adverse events.

    PubMed

    Shaffer, Christopher L; Scialis, Renato J; Rong, Haojing; Obach, R Scott

    2012-03-01

    Positive allosteric modulators ('potentiators') of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) have been shown to display a mechanism-based exposure-response continuum in preclinical species with procognitive electrophysiological and behavioral effects ('efficacy') at low exposures and motor coordination disruptions at progressively higher exposures. Due to the dose-capping nature of such motor coordination deficits, an exposure threshold-mediated adverse event (C(AE) ), the adequacy of separation between the maximal total plasma compound concentration (C(max) ) at a predicted clinically efficacious oral dose and this adverse event (AE) was explored in early drug research with three AMPAR potentiators considered potential candidates for clinical trials. In vitro metabolism studies in human liver microsomes and human hepatocytes demonstrated the metabolic clearance for each compound was predominately due to cytochromes P450 (CYP). Thus, for each compound's anticipated clinically efficacious dose, human C(max) variability following oral administration was assessed using Simcyp software, which combines its virtual human populations database using extensive demographic, physiological and genomic information with routinely collected compound-specific in vitro biochemical data to simulate and predict drug disposition. Using a combination of experimentally determined recombinant human CYP intrinsic clearances for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, human binding factors, expected fraction absorbed and estimated steady-state volume of distribution, Simcyp simulations demonstrated that two of the three potentiators had acceptable projected C(max) variability (i.e. the 95th percentile C(max) did not breach C(AE) ). This evaluation aided in the selection of compounds for preclinical progression, and represents a novel application of pharmacologically based pharmacokinetic (PBPK) software approaches to predict interpatient variability. PMID:22213407

  14. Early molecular events involved in Pinus pinaster Ait. somatic embryo development under reduced water availability: transcriptomic and proteomic analyses.

    PubMed

    Morel, Alexandre; Teyssier, Caroline; Trontin, Jean-François; Eliášová, Kateřina; Pešek, Bedřich; Beaufour, Martine; Morabito, Domenico; Boizot, Nathalie; Le Metté, Claire; Belal-Bessai, Leila; Reymond, Isabelle; Harvengt, Luc; Cadene, Martine; Corbineau, Françoise; Vágner, Martin; Label, Philippe; Lelu-Walter, Marie-Anne

    2014-09-01

    Maritime pine somatic embryos (SEs) require a reduction in water availability (high gellan gum concentration in the maturation medium) to reach the cotyledonary stage. This key switch, reported specifically for pine species, is not yet well understood. To facilitate the use of somatic embryogenesis for mass propagation of conifers, we need a better understanding of embryo development. Comparison of both transcriptome (Illumina RNA sequencing) and proteome [two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis with mass spectrometry (MS) identification] of immature SEs, cultured on either high (9G) or low (4G) gellan gum concentration, was performed, together with analysis of water content, fresh and dry mass, endogenous abscisic acid (ABA; gas chromatography-MS), soluble sugars (high-pressure liquid chromatography), starch and confocal laser microscope observations. This multiscale, integrated analysis was used to unravel early molecular and physiological events involved in SE development. Under unfavorable conditions (4G), the glycolytic pathway was enhanced, possibly in relation to cell proliferation that may be antagonistic to SE development. Under favorable conditions (9G), SEs adapted to culture constraint by activating specific protective pathways, and ABA-mediated molecular and physiological responses promoting embryo development. Our results suggest that on 9G, germin-like protein and ubiquitin-protein ligase could be used as predictive markers of SE development, whereas protein phosphatase 2C could be a biomarker for culture adaptive responses. This is the first characterization of early molecular mechanisms involved in the development of pine SEs following an increase in gellan gum concentration in the maturation medium, and it is also the first report on somatic embryogenesis in conifers combining transcriptomic and proteomic datasets. PMID:24460664

  15. 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/PS1ΔE9 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/PS1ΔE9-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

  16. 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 (D0.5D4.5), 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

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

    NASA Astrophysics Data System (ADS)

    Paredes, Jos M.; Foix, Nicols; Guerstein, G. Raquel; Guler, Mara V.; Irigoyen, Martn; 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 80-110m 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 3500km2, 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.

  18. A Novel DDB2-ATM Feedback Loop Regulates Human Cytomegalovirus Replication

    PubMed Central

    E, Xiaofei; Savidis, George; Chin, Christopher R.; Wang, Shixia; Lu, Shan; Brass, Abraham L.

    2014-01-01

    Human cytomegalovirus (HCMV) genome replication requires host DNA damage responses (DDRs) and raises the possibility that DNA repair pathways may influence viral replication. We report here that a nucleotide excision repair (NER)-associated-factor is required for efficient HCMV DNA replication. Mutations in genes encoding NER factors are associated with xeroderma pigmentosum (XP). One of the XP complementation groups, XPE, involves mutation in ddb2, which encodes DNA damage binding protein 2 (DDB2). Infectious progeny virus production was reduced by >2 logs in XPE fibroblasts compared to levels in normal fibroblasts. The levels of immediate early (IE) (IE2), early (E) (pp65), and early/late (E/L) (gB55) proteins were decreased in XPE cells. These replication defects were rescued by infection with a retrovirus expressing DDB2 cDNA. Similar patterns of reduced viral gene expression and progeny virus production were also observed in normal fibroblasts that were depleted for DDB2 by RNA interference (RNAi). Mature replication compartments (RCs) were nearly absent in XPE cells, and there were 1.5- to 2.0-log reductions in viral DNA loads in infected XPE cells relative to those in normal fibroblasts. The expression of viral genes (UL122, UL44, UL54, UL55, and UL84) affected by DDB2 status was also sensitive to a viral DNA replication inhibitor, phosphonoacetic acid (PAA), suggesting that DDB2 affects gene expression upstream of or events associated with the initiation of DNA replication. Finally, a novel, infection-associated feedback loop between DDB2 and ataxia telangiectasia mutated (ATM) was observed in infected cells. Together, these results demonstrate that DDB2 and a DDB2-ATM feedback loop influence HCMV replication. PMID:24335308

  19. Lesion development and replication kinetics during early infection in cattle inoculated with vesicular stomatitis New Jersey virus via scarification and black fly (Simulium vittatum) bite

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Vesicular stomatitis viruses are the causative agents of vesicular stomatitis, an economically important contagious disease of livestock that occurs in North, Central, and South America. Little is known regarding the early stages of infection in natural hosts. Twelve adult Holstein steers were inocu...

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

    PubMed Central

    Georgas, Evangelos; Bors, 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

  1. Ionophore-resistant mutants of Toxoplasma gondii reveal host cell permeabilization as an early event in egress.

    PubMed

    Black, M W; Arrizabalaga, G; Boothroyd, J C

    2000-12-01

    Toxoplasma gondii is an obligate intracellular pathogen within the phylum Apicomplexa. Invasion and egress by this protozoan parasite are rapid events that are dependent upon parasite motility and appear to be directed by fluctuations in intracellular [Ca(2+)]. Treatment of infected host cells with the calcium ionophore A23187 causes the parasites to undergo rapid egress in a process termed ionophore-induced egress (IIE). In contrast, when extracellular parasites are exposed to this ionophore, they quickly lose infectivity (termed ionophore-induced death [IID]). From among several Iie(-) mutants described here, two were identified that differ in several attributes, most notably in their resistance to IID. The association between the Iie(-) and Iid(-) phenotypes is supported by the observation that two-thirds of mutants selected as Iid(-) are also Iie(-). Characterization of three distinct classes of IIE and IID mutants revealed that the Iie(-) phenotype is due to a defect in a parasite-dependent activity that normally causes infected host cells to be permeabilized just prior to egress. Iie(-) parasites underwent rapid egress when infected cells were artificially permeabilized by a mild saponin treatment, confirming that this step is deficient in the Iie(-) mutants. A model is proposed that includes host cell permeabilization as a critical part of the signaling pathway leading to parasite egress. The fact that Iie(-) mutants are also defective in early stages of the lytic cycle indicates some commonality between these normal processes and IIE. PMID:11094090

  2. Microhemorrhage is an Early Event in the Pulmonary Fibrotic Disease of PECAM-1 Deficient FVB/n Mice

    PubMed Central

    Young, Lena C.; Woods, Steven J.; Groshong, Steven D.; Basaraba, Randall J.; Gilchrist, John M.; Higgins, David M.; Gonzalez-Juarrero, Mercedes; Bass, Todd A.; Muller, William A.; Schenkel, Alan R.

    2014-01-01

    Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1) deficient mice in the FVB/n strain exhibit fatal chronic pulmonary fibrotic disease. The illness occurs in the absence of a detectable pro-inflammatory event. PECAM-1 is vital to the stability of vascular permeability, leukocyte extravasation, clotting of platelets, and clearance of apoptotic cells. We show here that the spontaneous development of fibrotic disease in PECAM-1 deficient FVB/n mice is characterized by early loss of vascular integrity in pulmonary capillaries, resulting in spontaneous microbleeds. Hemosiderin-positive macrophages were found in interstitial spaces and bronchoalveolar lavage (BAL) fluid in relatively healthy animals. We also observed a gradually increasing presence of hemosiderin-positive macrophages and fibrin deposition in the advanced stages of disease, corresponding to the accumulation of collagen, IL-10 expression, and myofibroblasts expressing alpha smooth muscle actin (SMA). Together with the growing evidence that pulmonary microbleeds and coagulation play an active part in human pulmonary fibrosis, this data further supports our hypothesis that PECAM-1 expression is necessary for vascular barrier function control and regulation of homeostasis specifically, in the pulmonary environment. PMID:24972347

  3. 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 μg 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 μg 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 μg have potential to develop a symbiotic interaction, but suggest that μg alters their ability to form nodules upon return to 1g. (Research supported by NASA ESMD/ Advance Capabilities Division grant NNX10AR09A)

  4. 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

  5. High-resolution late Maastrichtian early Danian oceanic 87Sr/86Sr record: Implications for Cretaceous-Tertiary boundary events

    NASA Astrophysics Data System (ADS)

    Vonhof, H. B.; Smit, J.

    1997-04-01

    A high-resolution late Maastrichtian early Danian seawater 87Sr/86Sr reference curve is constructed from two Cretaceous-Tertiary boundary (K-T boundary) sections: Bidart (France) and El Kef (Tunisia). The 87Sr/86Sr curve shows maxima at 0.3 0.4 Ma before the K-T boundary and at the K-T boundary. The first maximum could mark the onset of a major outflow of the Deccan Traps. The second maximum, a rapid 0.000 06 87Sr/86Sr, shift, extends from 3 4 m below to 1 m above the K-T boundary. This profile probably results from diagenetic smoothing of an originally sharp K-T boundary 87Sr/86Sr anomaly, rather than from a gradual process. The sharp shift could result from (1) the vaporization of the Chicxulub target rocks, (2) global wildfires, and (3) acid-rain leaching of soils and sialic surface rocks. Of these three possibilities, only Sr release by soil leaching combined with increased rainfall associated with the K-T event appears to be sufficiently large to produce the observed K-T 87Sr/86Sr anomaly.

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

    NASA Astrophysics Data System (ADS)

    Hernndez-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.

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

    NASA Astrophysics Data System (ADS)

    Hernndez-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.

  8. 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.

  9. Activation of Peroxisome Proliferator-Activated Receptor Gamma by Human Cytomegalovirus for De Novo Replication Impairs Migration and Invasiveness of Cytotrophoblasts from Early Placentas ?

    PubMed Central

    Rauwel, Benjamin; Mariam, Bernard; Martin, Hlne; Nielsen, Ronni; Allart, Sophie; Pipy, Bernard; Mandrup, Susanne; Devignes, Marie Dominique; Evain-Brion, Danile; Fournier, Thierry; Davrinche, Christian

    2010-01-01

    Human cytomegalovirus (HCMV) contributes to pathogenic processes in immunosuppressed individuals, in fetuses, and in neonates. In the present report, by using reporter gene activation assays and confocal microscopy in the presence of a specific antagonist, we show for the first time that HCMV infection induces peroxisome proliferator-activated receptor gamma (PPAR?) transcriptional activity in infected cells. We demonstrate that the PPAR? antagonist dramatically impairs virus production and that the major immediate-early promoter contains PPAR response elements able to bind PPAR?, as assessed by electrophoretic mobility shift and chromatin immunoprecipitation assays. Due to the key role of PPAR? in placentation and its specific trophoblast expression within the human placenta, we then provided evidence that by activating PPAR? human cytomegalovirus dramatically impaired early human trophoblast migration and invasiveness, as assessed by using well-established in vitro models of invasive trophoblast, i.e., primary cultures of extravillous cytotrophoblasts (EVCT) isolated from first-trimester placentas and the EVCT-derived cell line HIPEC. Our data provide new clues to explain how early infection during pregnancy could impair implantation and placentation and therefore embryonic development. PMID:20042507

  10. 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...

  11. 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...

  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. 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 (15C, 20C and 25C) 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 20C to 25C compared with 15C. 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 25C compared with 15C. Thus, high ambient temperatures (20C to 25C) 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 32.8C (10% percentile) had an ADG which was on average 19 g lower per day than piglets with a rectal temperature of 37.3C (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 20C 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 20C during the farrowing period of loose housed sows. PMID:26094618

  14. Increased cytosine DNA-methyltransferase activity is target-cell-specific and an early event in lung cancer.

    PubMed Central

    Belinsky, S A; Nikula, K J; Baylin, S B; Issa, J P

    1996-01-01

    The association between increased DNA-methyltransferase (DNA-MTase) activity and tumor development suggest a fundamental role for this enzyme in the initiation and progression of cancer. A true functional role for DNA-MTase in the neoplastic process would be further substantiated if the target cells affected by the initiating carcinogen exhibit changes in enzyme activity. This hypothesis was addressed by examining DNA-MTase activity in alveolar type II (target) and Clara (nontarget) cells from A/J and C3H mice that exhibit high and low susceptibility, respectively, for lung tumor formation. Increased DNA-MTase activity was found only in the target alveolar type II cells of the susceptible A/J mouse and caused a marked increase in overall DNA methylation in these cells. Both DNA-MTase and DNA methylation changes were detected 7 days after carcinogen exposure and, thus, were early events in neoplastic evolution. Increased gene expression was also detected by RNA in situ hybridization in hypertrophic alveolar type II cells of carcinogen-treated A/J mice, indicating that elevated levels of expression may be a biomarker for premalignancy. Enzyme activity increased incrementally during lung cancer progression and coincided with increased expression of the DNA-MTase activity are strongly associated with neoplastic development and constitute a key step in carcinogenesis. The detection of premalignant lung disease through increased DNA-MTase expression and the possibility of blocking the deleterious effects of this change with specific inhibitors will offer new intervention strategies for lung cancer. Images Fig. 2 PMID:8633014

  15. 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 100μm. 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

  16. Thickened area of external granular layer and Ki-67 positive focus are early events of medulloblastoma in Ptch1?/? mice.

    PubMed

    Matsuo, Saori; Takahashi, Miwa; Inoue, Kaoru; Tamura, Kei; Irie, Kaoru; Kodama, Yukio; Nishikawa, Akiyoshi; Yoshida, Midori

    2013-09-01

    Patched1 (Ptch1) encodes a receptor for Sonic hedgehog (Shh) and is major gene related to human medulloblastoma (MB) in the Shh subgroup. MB is thought to arise from residual granule cell precursors (GCPs) located in the external granular layer (EGL) of the developing cerebellum. As the detailed preneoplastic changes of MB remain obscure, we immunohistochemically clarified the derived cell, early events of MBs, and the cerebellar developmental processes of Ptch1(+/-) (Ptch1) mice, an animal model of human MB of the Shh subgroup. In Ptch1 mice, the earliest proliferative lesions were detected at PND10 as focal thickened areas of outer layer of the EGL. This area was composed of GCP-like cells with atypia and nuclei disarrangement. In the latter cerebellar developmental period, GCP-like cell foci were detected at high incidence in the outermost area of the cerebellum. Their localization and morphological similarities indicated that the foci were derived from GCPs in the EGL. There were two types of the foci. A Ki-67-positive focus was found in Ptch1 mice only. This type resembled the GCPs in the outer layer of EGL characterized by having proliferating activity and a lack of neuronal differentiation. Another type of focus, Ki-67-negative, was observed in both genotypes and exhibited many of the same features of mature internal granule cells, suggesting that the focus had no preneoplastic potential. Due to morphological, immunohistochemical characteristics, our results indicate that the focal thickened area of EGL and Ki-67-positive foci are preneoplastic lesions of MB. PMID:23369240

  17. 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

  18. Plate tectonics hiati as the cause of global glaciations: 1. Early Proterozoic events and the rise of oxygen

    NASA Astrophysics Data System (ADS)

    Osmaston, M. F.

    2003-04-01

    Plate tectonics is the main way in which the Earth's internal heat is brought to the surface and lost, so it seems that global tectonics should not stop and start. Consequently the long-standing fact that, globally, no orogenic granitoid or greenstone U-Pb ages have been found in the 2.45--2.22 Ga interval has been attributed to defective sampling. Here I argue that this interval was indeed a prolonged hiatus in plate tectonics, being the first of two. The other, but differently caused, was in the late Proterozoic and is the topic of Part 2. The feature common to both hiati, and relevant to global glaciation, is that mid-ocean ridges (MORs) die and subside, potentially lowering sea-level by several kilometres, causing loss of atmospheric CO2 by weathering and an increase in planetary albedo. For the origin of the first hiatus we must first go back to formation of the core. The current iron-percolation model is invalidated by the fact that its corollary, the arrival of a water and siderophile-rich "late veneer" at the end of percolation, would be required to arrive some 60 Ma after the Moon, which never had a late veneer, was already in Earth orbit. The available alternative [1] would have given the early Earth a wet and low-viscosity convecting mantle able to dispose of the early heat with high efficiency; so that by 2.8 Ga MORs began to deepen, exposing cratons to massive weathering which lowered atmospheric CO2. The well-documented late Archaean acceleration of crustal addition to cratons, or, more precisely, of TTG-granitoid intrusion of greenstone belts, is also, paradoxically, evidence of waning mantle heat. Such wide-belt intrusion, grouped into quasi-coeval 'events', are examples of post-subduction magmatism (PSM), marking interruption of flat-slab subduction under a greenstone belt when a microcraton arrived [2]. On each occasion the TTG, derived from the subducted and reheated oceanic crust, advected subducting-plate heat to the surface that would otherwise have been returned to the mantle heat budget. This worsened the heat-budget problem, finally precipitating a collapse of mantle convection and the ensuing Huronian global glaciations at 2.35 Ga. The unparalleled deposition of banded iron-formation (BIF) during the early part of this hiatus supports this picture. Throughout the Archaean, Fe2+ had accumulated in the deep ocean, stabilized by acidic input from MORs, despite the efforts of oxygenic life (OL) in shallow water. Removal of this input enabled OL to "win its battle", the BIF was deposited and the ocean largely oxygenated. ?13C rose as OL really flowered at 2.22 Ga, when MORs resumed, patchily at first, and sea-level rose and flooded planated cratons. [1] Osmaston, M.F. (Goldschmidt 2002) GCA 66 (15A) A571.

  19. Induction of DNA Damage Signaling by Oxidative Stress in Relation to DNA Replication as Detected Using “Click Chemistry”

    PubMed Central

    Zhao, Hong; Dobrucki, Jurek; Rybak, Paulina; Traganos, Frank; Halicka, H. Dorota; Darzynkiewicz, Zbigniew

    2011-01-01

    Induction of DNA damage by oxidants such as H2O2 activates the complex network of DNA damage response (DDR) pathways present in cells to initiate DNA repair, halt cell cycle progression, and prepare an apoptotic reaction. We have previously reported that activation of Ataxia Telangiectasia Mutated protein kinase (ATM) and induction of γH2AX are among the early events of the DDR induced by exposure of cells to H2O2, and in human pulmonary carcinoma A549 cells, both events were expressed predominantly during S-phase. This study was designed to further explore a correlation between these events and DNA replication. Toward this end, we utilized 5-ethynyl-2′deoxyuridine (EdU) and the “click chemistry” approach to label DNA during replication, followed by exposure of A549 cells to H2O2. Multiparameter laser scanning cytometric analysis of these cells made it possible to identify DNA replicating cells and directly correlate H2O2-induced ATM activation and induction of γH2AX with DNA replication on a cell by cell basis. After pulse-labeling with EdU and exposure to H2O2, confocal microscopy was also used to examine the localization of DNA replication sites (“replication factories”) versus the H2AX phosphorylation sites (γH2AX foci) in nuclear chromatin in an attempt to observe the absence or presence of colocalization. The data indicate a close association between DNA replication and H2AX phosphorylation in A549 cells, suggesting that these DNA damage response events may be triggered by stalled replication forks and perhaps also by induction of DNA double-strand breaks at the primary DNA lesions induced by H2O2 PMID:21905210

  20. Histone lysine methylation and chromatin replication.

    PubMed

    Rivera, Carlos; Gurard-Levin, Zachary A; Almouzni, Geneviève; Loyola, Alejandra

    2014-12-01

    In eukaryotic organisms, the replication of the DNA sequence and its organization into chromatin are critical to maintain genome integrity. Chromatin components, such as histone variants and histone post-translational modifications, along with the higher-order chromatin structure, impact several DNA metabolic processes, including replication, transcription, and repair. In this review we focus on lysine methylation and the relationships between this histone mark and chromatin replication. We first describe studies implicating lysine methylation in regulating early steps in the replication process. We then discuss chromatin reassembly following replication fork passage, where the incorporation of a combination of newly synthesized histones and parental histones can impact the inheritance of lysine methylation marks on the daughter strands. Finally, we elaborate on how the inheritance of lysine methylation can impact maintenance of the chromatin landscape, using heterochromatin as a model chromatin domain, and we discuss the potential mechanisms involved in this process. PMID:24686120

  1. The evolution of replicators.

    PubMed

    Szathmry, E

    2000-11-29

    Replicators of interest in chemistry, biology and culture are briefly surveyed from a conceptual point of view. Systems with limited heredity have only a limited evolutionary potential because the number of available types is too low. Chemical cycles, such as the formose reaction, are holistic replicators since replication is not based on the successive addition of modules. Replicator networks consisting of catalytic molecules (such as reflexively autocatalytic sets of proteins, or reproducing lipid vesicles) are hypothetical ensemble replicators, and their functioning rests on attractors of their dynamics. Ensemble replicators suffer from the paradox of specificity: while their abstract feasibility seems to require a high number of molecular types, the harmful effect of side reactions calls for a small system size. No satisfactory solution to this problem is known. Phenotypic replicators do not pass on their genotypes, only some aspects of the phenotype are transmitted. Phenotypic replicators with limited heredity include genetic membranes, prions and simple memetic systems. Memes in human culture are unlimited hereditary, phenotypic replicators, based on language. The typical path of evolution goes from limited to unlimited heredity, and from attractor-based to modular (digital) replicators. PMID:11127914

  2. Mouse Norovirus 1 Utilizes the Cytoskeleton Network To Establish Localization of the Replication Complex Proximal to the Microtubule Organizing Center

    PubMed Central

    Hyde, Jennifer L.; Gillespie, Leah K.

    2012-01-01

    Human noroviruses (family Caliciviridae) are the leading cause of nonbacterial gastroenteritis worldwide. Although Human noroviruses are significant enteric pathogens, there exists no reliable vaccine or therapy to treat infected individuals. To date, attempts to cultivate Human noroviruses within the laboratory have met with little success; however, the related murine norovirus mouse norovirus 1 (MNV-1) has provided an ideal model system to study norovirus replication due to the ease with which the virus is cultivated and the ability to infect a small animal model with this virus. Previously we have identified the association between MNV-1 and components of the host secretory pathway and proposed a role for the viral open reading frame 1 proteins in the replication cycle. Here we describe for the first time a role for cytoskeletal components in early MNV-1 replication events. We show that the MNV-1 utilizes microtubules to position the replication complex adjacent to the microtubule organizing center. Chemical disruption of the microtubule network disperses the sites of MNV-1 replication throughout the cell and impairs production of viral protein and infectious virus. Furthermore, we demonstrate the ability of MNV-1 to redistribute acetylated tubulin to the replication complex and that this association is potentially mediated via the MNV-1 major structural protein, VP1. Transient expression of MNV-1 VP1 exhibited extensive colocalization with both ?-tubulin and acetylated tubulin and was observed to alter the distribution of acetylated tubulin in transfected cells. This study highlights the role of the cytoskeleton in early virus replication events and demonstrates the importance of this interaction in establishing the intracellular location of MNV-1 replication complexes. PMID:22301146

  3. The origin of replicators and reproducers

    PubMed Central

    Szathmry, Ers

    2006-01-01

    Replicators are fundamental to the origin of life and evolvability. Their survival depends on the accuracy of replication and the efficiency of growth relative to spontaneous decay. Infrabiological systems are built of two coupled autocatalytic systems, in contrast to minimal living systems that must comprise at least a metabolic subsystem, a hereditary subsystem and a boundary, serving respective functions. Some scenarios prefer to unite all these functions into one primordial system, as illustrated in the lipid world scenario, which is considered as a didactic example in detail. Experimentally produced chemical replicators grow parabolically owing to product inhibition. A selection consequence is survival of everybody. The chromatographized replicator model predicts that such replicators spreading on surfaces can be selected for higher replication rate because double strands are washed away slower than single strands from the surface. Analysis of real ribozymes suggests that the error threshold of replication is less severe by about one order of magnitude than thought previously. Surface-bound dynamics is predicted to play a crucial role also for exponential replicators: unlinked genes belonging to the same genome do not displace each other by competition, and efficient and accurate replicases can spread. The most efficient form of such useful population structure is encapsulation by reproducing vesicles. The stochastic corrector model shows how such a bag of genes can survive, and what the role of chromosome formation and intragenic recombination could be. Prebiotic and early evolution cannot be understood without the models of dynamics. PMID:17008217

  4. 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

  5. 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

  6. 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 ~612h 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

  7. Mechanism of chromosomal DNA replication initiation and replication fork stabilization in eukaryotes.

    PubMed

    Wu, LiHong; Liu, Yang; Kong, DaoChun

    2014-05-01

    Chromosomal DNA replication is one of the central biological events occurring inside cells. Due to its large size, the replication of genomic DNA in eukaryotes initiates at hundreds to tens of thousands of sites called DNA origins so that the replication could be completed in a limited time. Further, eukaryotic DNA replication is sophisticatedly regulated, and this regulation guarantees that each origin fires once per S phase and each segment of DNA gets duplication also once per cell cycle. The first step of replication initiation is the assembly of pre-replication complex (pre-RC). Since 1973, four proteins, Cdc6/Cdc18, MCM, ORC and Cdt1, have been extensively studied and proved to be pre-RC components. Recently, a novel pre-RC component called Sap1/Girdin was identified. Sap1/Girdin is required for loading Cdc18/Cdc6 to origins for pre-RC assembly in the fission yeast and human cells, respectively. At the transition of G1 to S phase, pre-RC is activated by the two kinases, cyclindependent kinase (CDK) and Dbf4-dependent kinase (DDK), and subsequently, RPA, primase-polα, PCNA, topoisomerase, Cdc45, polδ, and polɛ are recruited to DNA origins for creating two bi-directional replication forks and initiating DNA replication. As replication forks move along chromatin DNA, they frequently stall due to the presence of a great number of replication barriers on chromatin DNA, such as secondary DNA structures, protein/DNA complexes, DNA lesions, gene transcription. Stalled forks must require checkpoint regulation for their stabilization. Otherwise, stalled forks will collapse, which results in incomplete DNA replication and genomic instability. This short review gives a concise introduction regarding the current understanding of replication initiation and replication fork stabilization. PMID:24699916

  8. Chromatin Structure and Replication Origins: Determinants Of Chromosome Replication And Nuclear Organization

    PubMed Central

    Smith, Owen K.; Aladjem, Mirit I.

    2014-01-01

    The DNA replication program is, in part, determined by the epigenetic landscape that governs local chromosome architecture and directs chromosome duplication. Replication must coordinate with other biochemical processes occurring concomitantly on chromatin, such as transcription and remodeling, to insure accurate duplication of both genetic and epigenetic features and to preserve genomic stability. The importance of genome architecture and chromatin looping in coordinating cellular processes on chromatin is illustrated by two recent sets of discoveries. First, chromatin-associated proteins that are not part of the core replication machinery were shown to affect the timing of DNA replication. These chromatin-associated proteins could be working in concert, or perhaps in competition, with the transcriptional machinery and with chromatin modifiers to determine the spatial and temporal organization of replication initiation events. Second, epigenetic interactions are mediated by DNA sequences that determine chromosomal replication. In this review we summarize recent findings and current models linking spatial and temporal regulation of the replication program with epigenetic signaling. We discuss these issues in the context of the genomes three-dimensional structure with an emphasis on events occurring during the initiation of DNA replication. PMID:24905010

  9. Global Coronary Flow Reserve Associates with Adverse Cardiovascular Events Independently of Luminal Angiographic Severity, and Modifies the Effect of Early Revascularization

    PubMed Central

    Taqueti, Viviany R.; Hachamovitch, Rory; Murthy, Venkatesh L.; Naya, Masanao; Foster, Courtney R.; Hainer, Jon; Dorbala, Sharmila; Blankstein, Ron; Di Carli, Marcelo F.

    2014-01-01

    Background Coronary flow reserve (CFR, an integrated measure of focal, diffuse and small vessel coronary artery disease, CAD), identifies patients at risk for cardiac death. We sought to determine the association between CFR, angiographic CAD, and cardiovascular outcomes. Methods and Results Consecutive patients (n=329) referred for invasive coronary angiography after stress testing with myocardial perfusion positron emission tomography (PET), were followed (median 3.1 years) for cardiovascular death and heart failure admission. The extent and severity of angiographic disease was estimated using the CAD prognostic index (CADPI), and CFR measured noninvasively by PET. A modest inverse correlation was seen between CFR and CADPI (r=?0.26, p<0.0001). After adjusting for clinical risk score, ejection fraction, global ischemia, and early revascularization, CFR and CADPI independently associated with events (hazard ratio for unit decrease in CFR, 2.02; 95%CI 1.20-3.40, p=0.008, and for 10-unit increase in CADPI, 1.17; 95%CI 1.01-1.34, p=0.032). Subjects with low CFR experienced rates of events similar to that of subjects with high angiographic scores, and those with low CFR and/or high CADPI showed highest risk of events (p=0.001). There was a significant interaction (p=0.039) between CFR and early revascularization by CABG, such that patients with low CFR who underwent CABG, but not PCI, experienced event rates comparable to those with preserved CFR, independently of revascularization. Conclusions CFR associated with outcomes independently of angiographic CAD, and modified the effect of early revascularization. Diffuse atherosclerosis and associated microvascular dysfunction may contribute to the pathophysiology of cardiovascular death and heart failure, and impact upon the outcomes of revascularization. PMID:25400060

  10. DNA Virus Replication Compartments

    PubMed Central

    Schmid, Melanie; Speiseder, Thomas; Dobner, Thomas

    2014-01-01

    Viruses employ a variety of strategies to usurp and control cellular activities through the orchestrated recruitment of macromolecules to specific cytoplasmic or nuclear compartments. Formation of such specialized virus-induced cellular microenvironments, which have been termed viroplasms, virus factories, or virus replication centers, complexes, or compartments, depends on molecular interactions between viral and cellular factors that participate in viral genome expression and replication and are in some cases associated with sites of virion assembly. These virus-induced compartments function not only to recruit and concentrate factors required for essential steps of the viral replication cycle but also to control the cellular mechanisms of antiviral defense. In this review, we summarize characteristic features of viral replication compartments from different virus families and discuss similarities in the viral and cellular activities that are associated with their assembly and the functions they facilitate for viral replication. PMID:24257611

  11. 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

  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 (911' S, 15134' 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. 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

  14. 18-month occurrence of severe events among early diagnosed HIV-infected children before antiretroviral therapy in Abidjan, Cte d'Ivoire: A cohort study

    PubMed Central

    Harambat, Jrme; Fassinou, Patricia; Becquet, Renaud; Tour, Pety; Rouet, Franois; Dabis, Franois; Msellati, Philippe; Blanche, Stphane; Timit-Konan, Marguerite; Salamon, Roger; Leroy, Valriane

    2008-01-01

    Objective To assess the 18-month field effectiveness on severe events of a pediatric package combining early HIV-diagnosis and targeted cotrimoxazole prophylaxis in HIV-infected children from age six-week before the antiretroviral era, in Abidjan, Cte d'Ivoire. Methods Data from two consecutive prevention of HIV mother-to-child transmission programs were compared: the ANRS 1201/1202 Ditrame-Plus cohort (20012005) and the pooled data of the ANRS 049a Ditrame randomized trial and its following open-labeled cohort (19952000), used as a reference group. HIV-infected pregnant women ? 3236 weeks of gestation were offered a short-course peri-partum antiretroviral prophylaxis (ZDV in Ditrame, and ZDV 3TC+single-dose (sd) NVP in Ditrame-Plus). Neonatal prophylaxis was provided in Ditrame-Plus only: 7-day ZDV and sdNVP 4872 h after birth. A 6-week pediatric HIV-RNA diagnosis was provided on-line in the Ditrame-Plus while it was only oriented on clinical symptoms in Ditrame. Six-week HIV-infected children received a daily cotrimoxazole prophylaxis in Ditrame-Plus while no prophylaxis was provided in Ditrame. The determinants of severe events (death or hospitalization > 1 day) were assessed in a Cox regression model. Results Between 1995 and 2003, 98 out of the 1121 live-births were diagnosed as HIV-infected in peri-partum: 45 from Ditrame-Plus and 53 from Ditrame. The 18-month Kaplan-Meier cumulative probability of presenting a severe event was 66% in Ditrame-Plus (95% confidence interval [95%CI]: 50%81%) and 77% in Ditrame (95%CI: 65%89%), Log Rank test: p = 0.47. After adjustment on maternal WHO clinical stage, maternal death, 6-week pediatric viral load, birth-weight, and breastfeeding exposure, the 18-month risk of severe event was lower in Ditrame-Plus than in Ditrame (adjusted Hazard Ratio (aHR): 0.55, 95%CI: 0.31.1), although the difference was not statistically significant; p = 0.07). Maternal death was the only variable determinant of the occurrence of severe events in children (aHR: 3.73; CI: 2.211.2; p = 0.01). Conclusion Early cotrimoxazole from 6 weeks of age in HIV-infected infants seemed to reduce probability of severe events but the study lacked statistical power to prove this. Even with systematic cotrimoxazole prophylaxis, infant morbidity and mortality remained high pointing towards a need for early pediatric HIV-diagnosis and antiretroviral treatment in Africa. PMID:18492259

  15. 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

  16. 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 Cannire, Charles; Molenberg, Jean-Marc; Vincke, Caroline; Deman, Dborah; Grgoire, 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).

  17. Orbital control on carbon cycle alterations and hyperthermal events in a cooling world: the late Early to Mid Eocene record at Possagno (southern Alps, Italy)

    NASA Astrophysics Data System (ADS)

    Galeotti, Simone; Sprovieri, Mario; Moretti, Matteo; Rio, Domenico; Fornaciari, Eliana; Giusberti, Luca; Agnini, Claudia; Backman, Jan; Lanci, Luca; Luciani, Valeria

    2013-04-01

    The late Early Eocene to Middle Eocene ~50-45 Million years ago (Ma) time interval in the middle bathyal, pelagic/hemipelagic succession of the Western Tethys Possagno section (southern Alps, Veneto), contains several episodes of negative carbon isotope excursions (CIEs) and concomitant dissolution of carbonates. These episodes are superimposed on a long term global climate cooling that started at about 51 Ma following the Early Eocene Climatic Optimum (EECO). Spectral analysis indicates that CIEs and dissolution events are paced by orbital forcing, confirming the global significance of previous finding on the same interval from Western and Southern Atlantic and Equatorial Pacific sites. The frequency and magnitude of CIEs through time is controlled by long-term modulations of orbital parameters, including long eccentricity (400 kyr) and a 1.2 million year modulation. Highest frequency of events - at the orbital scale - is observed across the EECO, which provides an observational basis to validate theoretical models predicting a threshold effect resulting from orbital forcing superimposed on gradually changing mean global boundary conditions. The observation of the 1.2 million year beat (long-term modulation of obliquity) together with previously published observation of enhanced obliquity (41 kyr) forcing across major CIEs and dissolution intervals indicates that high latitude feedbacks to orbital forcing played a fundamental role in the emplacement of the hyperthermals. The observed orbital forcing signature closely match that of early Eocene hyperthermals, suggesting similar driving processes.

  18. A global profile of replicative polymerase usage

    PubMed Central

    Müller, Carolin A.; Miyabe, Izumi; Brooks, Tony; Retkute, Renata; Hubank, Mike; Nieduszyski, Conrad A.; Carr, Antony M.

    2014-01-01

    Three eukaryotic DNA polymerases are essential for genome replication. Polα-primase initiates each synthesis event and is rapidly replaced by processive DNA polymerases: Polε replicates the leading strand while Polδ performs lagging strand synthesis. However, it is not known whether this division of labour is maintained across the whole genome or how uniform it is within single replicons. Using S. 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 labour 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 this results from occasional leading strand initiation by Polδ followed by exchange for Polε. PMID:25664722

  19. A global profile of replicative polymerase usage.

    PubMed

    Daigaku, Yasukazu; Keszthelyi, Andrea; Mller, 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

  20. Associations of Mother-Child Reminiscing about Negative Past Events, Coping, and Self-Concept in Early Childhood

    ERIC Educational Resources Information Center

    Goodvin, Rebecca; Romdall, Lisa

    2013-01-01

    Parent-child reminiscing conversations in early childhood have received theoretical attention as a forum for children's self-concept development, but this has been little addressed in empirical work. This study examines associations between emotion reminiscing and children's self-concepts and, building from the reminiscing and

  1. 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.

  2. Adjuvanted influenza-H1N1 vaccination reveals lymphoid signatures of age-dependent early responses and of clinical adverse events.

    PubMed

    Sobolev, Olga; Binda, Elisa; O'Farrell, Sean; Lorenc, Anna; Pradines, Joel; Huang, Yongqing; Duffner, Jay; Schulz, Reiner; Cason, John; Zambon, Maria; Malim, Michael H; Peakman, Mark; Cope, Andrew; Capila, Ishan; Kaundinya, Ganesh V; Hayday, Adrian C

    2016-02-01

    Adjuvanted vaccines afford invaluable protection against disease, and the molecular and cellular changes they induce offer direct insight into human immunobiology. Here we show that within 24 h of receiving adjuvanted swine flu vaccine, healthy individuals made expansive, complex molecular and cellular responses that included overt lymphoid as well as myeloid contributions. Unexpectedly, this early response was subtly but significantly different in people older than ∼35 years. Wide-ranging adverse clinical events can seriously confound vaccine adoption, but whether there are immunological correlates of these is unknown. Here we identify a molecular signature of adverse events that was commonly associated with an existing B cell phenotype. Thus immunophenotypic variation among healthy humans may be manifest in complex pathophysiological responses. PMID:26726811

  3. 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.

  4. 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; Mjean, 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 [1.064.03], p = 0.03), echocardiographic left ventricular hypertrophy (HR = 2.04 [1.043.98], 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

  5. 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

  6. Increase in the intracellular free calcium concentration is not an obligatory early event in lipopeptide-induced B-cell activation.

    PubMed Central

    Hauschildt, S; Lückhoff, A; Langhorne, J; Wiesmüller, K H; Jung, G; Bessler, W; Cambier, J C

    1991-01-01

    We recently showed that synthetic lipopeptides, analogues of the N-terminal region of bacterial lipoprotein, induce DNA synthesis in B lymphocytes in the absence of enhanced phosphatidylinositol 4,5-bisphosphate hydrolysis and protein kinase C translocation. Here we demonstrate that lipopeptides are capable of inducing enhanced expression of MHC class II molecules and early increases in the intracellular free calcium concentration ([Ca2+]i) in B cells. However, they do not effect T cells. The increase in [Ca2+]i seen in B cells is due primarily to Ca2+ release from intracellular stores. Since lipopeptides differ in their capability to induce early increases in [Ca2+]i and since the calcium response does not correlate with the ability of lipopeptides to induce proliferation and expression of MHC class II molecules, we suggest that this biochemical event may not be essential for lipopeptide-mediated B-cell activation. PMID:1879881

  7. 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.

  8. Modeling DNA Replication.

    ERIC Educational Resources Information Center

    Bennett, Joan

    1998-01-01

    Recommends the use of a model of DNA made out of Velcro to help students visualize the steps of DNA replication. Includes a materials list, construction directions, and details of the demonstration using the model parts. (DDR)

  9. Accumulation of cell wall hydroxyproline-rich glycoprotein mRNA is an early event in maize embryo cell differentiation.

    PubMed Central

    Ruiz-Avila, L; Burgess, S R; Stiefel, V; Ludevid, M D; Puigdomnech, P

    1992-01-01

    The accumulation of the mRNA coding for a hydroxyproline-rich glycoprotein (HRGP), an abundant component of the wall from the cells of vegetative tissues, has been observed in maize embryo by in situ hybridization. The HRGP mRNA accumulates in the embryo axis and not in the scutellum and preferentially in dividing and provascular cells. The histone H4 mRNA is distributed in similar tissues but is restricted to defined groups of cells, indicating that these two gene products have a different steady-state level of accumulation during the cell cycle. The HRGP mRNA appears to be a useful marker for early formation of the vascular systems. The mRNA accumulation correlates in space and time with cells having a low content of cellulose in their walls, suggesting that the mRNA is produced in the early stages of cell wall formation before complete deposition of cellulose. Images PMID:1549604

  10. UV-triggered p21 degradation facilitates damaged-DNA replication and preserves genomic stability

    PubMed Central

    Mansilla, Sabrina F.; Soria, Gastn; Vallerga, Mara Beln; Habif, Martn; Martnez-Lpez, Wilner; Prives, Carol; Gottifredi, Vanesa

    2013-01-01

    Although many genotoxic treatments upregulate the cyclin kinase inhibitor p21, agents such as UV irradiation trigger p21 degradation. This suggests that p21 blocks a process relevant for the cellular response to UV. Here, we show that forced p21 stabilization after UV strongly impairs damaged-DNA replication, which is associated with permanent deficiencies in the recruitment of DNA polymerases from the Y family involved in translesion DNA synthesis), with the accumulation of DNA damage markers and increased genomic instability. Remarkably, such noxious effects disappear when disrupting the proliferating cell nuclear antigen (PCNA) interacting motif of stable p21, thus suggesting that the release of PCNA from p21 interaction is sufficient to allow the recruitment to PCNA of partners (such as Y polymerases) relevant for the UV response. Expression of degradable p21 only transiently delays early replication events and Y polymerase recruitment after UV irradiation. These temporary defects disappear in a manner that correlates with p21 degradation with no detectable consequences on later replication events or genomic stability. Together, our findings suggest that the biological role of UV-triggered p21 degradation is to prevent replication defects by facilitating the tolerance of UV-induced DNA lesions. PMID:23723248

  11. Key Immune Events of the Pathomechanisms of Early Cardioembolic Stroke: Multi-Database Mining and Systems Biology Approach.

    PubMed

    Wu, Chia-Chou; Chen, Bor-Sen

    2016-01-01

    While inflammation has generally been regarded as a negative factor in stroke recovery, this viewpoint has recently been challenged by demonstrating that inflammation is a necessary and sufficient factor for regeneration in the zebrafish brain injury model. This close relationship with inflammation suggests that a re-examination of the immune system's role in strokes is necessary. We used a systems biology approach to investigate the role of immune-related functions via their interactions with other molecular functions in early cardioembolic stroke. Based on protein interaction models and on microarray data from the blood of stroke subjects and healthy controls, networks were constructed to delineate molecular interactions at four early stages (pre-stroke, 3 h, 5 h and 24 h after stroke onset) of cardioembolic stroke. A comparative analysis of functional networks identified interactions of immune-related functions with other molecular functions, including growth factors, neuro/hormone and housekeeping functions. These provide a potential pathomechanism for early stroke pathophysiology. In addition, several potential targets of miRNA and methylation regulations were derived based on basal level changes observed in the core networks and literature. The results provide a more comprehensive understanding of stroke progression mechanisms from an immune perspective and shed light on acute stroke treatments. PMID:26927091

  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. Deciphering early events involved in hyperosmotic stress-induced programmed cell death in tobacco BY-2 cells

    PubMed Central

    Monetti, Emanuela; Kadono, Takashi; Bouteau, Franois

    2014-01-01

    Hyperosmotic stresses represent one of the major constraints that adversely affect plants growth, development, and productivity. In this study, the focus was on early responses to hyperosmotic stress- (NaCl and sorbitol) induced reactive oxygen species (ROS) generation, cytosolic Ca2+ concentration ([Ca2+]cyt) increase, ion fluxes, and mitochondrial potential variations, and on their links in pathways leading to programmed cell death (PCD). By using BY-2 tobacco cells, it was shown that both NaCl- and sorbitol-induced PCD seemed to be dependent on superoxide anion (O2) generation by NADPH-oxidase. In the case of NaCl, an early influx of sodium through non-selective cation channels participates in the development of PCD through mitochondrial dysfunction and NADPH-oxidase-dependent O2 generation. This supports the hypothesis of different pathways in NaCl- and sorbitol-induced cell death. Surprisingly, other shared early responses, such as [Ca2+]cyt increase and singlet oxygen production, do not seem to be involved in PCD. PMID:24420571

  14. 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; Mhlberger, 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

  15. Infants’ Causal Representations of State Change Events

    PubMed Central

    Muentener, Paul; Carey, Susan

    2010-01-01

    Five experiments extended studies of infants’ causal representations of Michottian launching events to 8-month-olds’ causal representations of physical state changes. Infants were habituated to events in which a potential causal agent moved behind a screen, after which a box partially visible on the other side of the screen underwent some change (motion or state change). After habituation the screen was removed, and infants observed full events in which the potential agent either did or did not contact the box (contact vs. gap events). Infants were credited with causal representations of the events if their attention was drawn both to gap events in which the effect nonetheless occurred and to events with contact in which the effect did not happen. The experiments varied the nature of the effect (motion vs. state change) and the nature of the possible causal agent (train, hand, novel intentional agent). Both the nature of the effect and the nature of the possible agent influenced the likelihood of causal attribution. The events involving motion of the patient replicated previous studies of infants’ representations of Michottian launching events: the toy train was taken as the source of the boxes motion. In contrast, infants attributed the cause of the box’s physical state change to a hand and novel self-moving entity with eyes, but not to a toy train. These data address early developing causal schemata, and bring new information to bear on theories of the origin of human causal cognition. PMID:20553762

  16. 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

  17. Replication of lightweight mirrors

    NASA Astrophysics Data System (ADS)

    Chen, Ming Y.; Matson, Lawrence E.; Lee, Heedong; Chen, Chenggang

    2009-08-01

    The fabrication of lightweight mirror assemblages via a replication technique offers great potential for eliminating the high cost and schedule associated with the grinding and polishing steps needed for conventional glass or SiC mirrors. A replication mandrel is polished to an inverse figure shape and to the desired finish quality. It is then, coated with a release layer, the appropriate reflective layer, and followed by a laminate for coefficient of thermal expansion (CTE) tailorability and strength. This optical membrane is adhered to a mirror structural substrate with a low shrinkage, CTE tailored adhesive. Afterwards, the whole assembly is separated from the mandrel. The mandrel is then cleaned and reused for the next replication run. The ultimate goal of replication is to preserve the surface finish and figure of the optical membrane upon its release from the mandrel. Successful replication requires a minimization of the residual stresses within the optical coating stack, the curing stresses from the adhesive and the thermal stress resulting from CTE mismatch between the structural substrate, the adhesive, and the optical membrane. In this paper, the results on replicated trials using both metal/metal and ceramic/ceramic laminates adhered to light weighted structural substrates made from syntactic foams (both inorganic and organic) will be discussed.

  18. DNA Replication Origins

    PubMed Central

    Leonard, Alan C.; Mchali, Marcel

    2013-01-01

    The onset of genomic DNA synthesis requires precise interactions of specialized initiator proteins with DNA at sites where the replication machinery can be loaded. These sites, defined as replication origins, are found at a few unique locations in all of the prokaryotic chromosomes examined so far. However, replication origins are dispersed among tens of thousands of loci in metazoan chromosomes, thereby raising questions regarding the role of specific nucleotide sequences and chromatin environment in origin selection and the mechanisms used by initiators to recognize replication origins. Close examination of bacterial and archaeal replication origins reveals an array of DNA sequence motifs that position individual initiator protein molecules and promote initiator oligomerization on origin DNA. Conversely, the need for specific recognition sequences in eukaryotic replication origins is relaxed. In fact, the primary rule for origin selection appears to be flexibility, a feature that is modulated either by structural elements or by epigenetic mechanisms at least partly linked to the organization of the genome for gene expression. PMID:23838439

  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; Lazăr, Cătălin; 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 Starčevo Criş culture in Romania (Cârcea, Gura Baciului and Negrileşti 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 Gumelniţa 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. Ancient DNA from South-East Europe Reveals Different Events during Early and Middle Neolithic Influencing the European Genetic Heritage.

    PubMed

    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 (Crcea, 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

  1. 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; Martn-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

  2. A novel type of detergent-resistant membranes may contribute to an early protein sorting event in epithelial cells.

    PubMed

    Alfalah, Marwan; Wetzel, Gabi; Fischer, Ina; Busche, Roger; Sterchi, Erwin E; Zimmer, Klaus-Peter; Sallmann, Hans-Peter; Naim, Hassan Y

    2005-12-30

    One sorting mechanism of apical and basolateral proteins in epithelial cells is based on their solubility profiles with Triton X-100. Nevertheless, apical proteins themselves are also segregated beyond the trans-Golgi network by virtue of their association or nonassociation with cholesterol/sphingolipid-rich microdomains (Jacob, R., and Naim, H. Y. (2001) Curr. Biol. 11, 1444-1450). Therefore, extractability with Triton X-100 does not constitute an absolute criterion of protein sorting. Here, we investigate the solubility patterns of apical and basolateral proteins with other detergents and demonstrate that the mild detergent Tween 20 is adequate to discriminate between apical and basolateral proteins during early stages in their biosynthesis. Although the mannose-rich forms of the apical proteins sucrase-isomaltase, lactase-phlorizin hydrolase, aminopeptidase N, and dipeptidylpeptidase IV reveal similar solubility profiles comprising soluble and nonsoluble fractions, the basolateral proteins, vesicular stomatitis virus G protein, major histocompatibility complex class I, and CD46 are entirely soluble with this detergent. The insoluble Tween 20 membranes are enriched in phosphatidylinositol and phosphatidylglycerol compatible with their synthesis in the endoplasmic reticulum and the existence of a novel class of detergent-resistant membranes. The association of the mannose-rich biosynthetic forms of the apical proteins, sucraseisomaltase, lactase-phlorizin hydrolase, aminopeptidase N, and dipeptidylpeptidase IV with the Tween 20-resistant membranes suggests an early polarized sorting mechanism prior to maturation in the Golgi apparatus. PMID:16230359

  3. 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.

  4. Comparative genomic hybridization identifies loss of 18q22-qter as an early and specific event in tumorigenesis of midgut carcinoids.

    PubMed

    Kytl, S; Hg, A; Nord, B; Cedermark, B; Frisk, T; Larsson, C; Kjellman, M

    2001-05-01

    Carcinoid tumors are rare neuroendocrine tumors occurring in the lung or in the digestive tract where they are further subclassified as foregut, midgut, or hindgut carcinoids. To gain a better understanding of the genetic basis of the different types of carcinoid tumors, we have characterized numerical imbalances in a series of midgut carcinoids, and compared the results to previous findings in carcinoids from the lung. Numerical imbalances were revealed in 16 of the 18 tumors, and the most commonly detected aberrations were losses of 18q22-qter (67%), 11q22-q23 (33%), and 16q21-qter (22%), and gain of 4p14-qter (22%). The total number of alterations found in the metastases was significantly higher than in the primary tumors, indicating the accumulation of acquired genetic changes in the tumor progression. Losses of 18q and 11q were present both in primary tumors and metastases, whereas loss of 16q and gain of 4 were only detected in metastases. Furthermore, the pattern of comparative genomic hybridization alterations varied depending on the total number of detected alterations. Taken together, the findings would suggest a progression of numerical imbalances, in which loss of 18q and 11q represent early events, and loss of 16q and gain of 4p are late events in the tumor progression of midgut carcinoids. When compared to previously published comparative genomic hybridization abnormalities in lung carcinoids, loss of 11q was found to occur in both tumor types, whereas loss of 18q and 16q and gain of 4 were not revealed in lung carcinoids. The results indicate that inactivation of a putative tumor suppressor gene in 18q22-qter represents a frequent and early event that is specific for the development of midgut carcinoids. PMID:11337378

  5. 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.

  6. DNA Replication Timing

    PubMed Central

    Rhind, Nicholas; Gilbert, David M.

    2013-01-01

    Patterns of replication within eukaryotic genomes correlate with gene expression, chromatin structure, and genome evolution. Recent advances in genome-scale mapping of replication kinetics have allowed these correlations to be explored in many species, cell types, and growth conditions, and these large data sets have allowed quantitative and computational analyses. One striking new correlation to emerge from these analyses is between replication timing and the three-dimensional structure of chromosomes. This correlation, which is significantly stronger than with any single histone modification or chromosome-binding protein, suggests that replication timing is controlled at the level of chromosomal domains. This conclusion dovetails with parallel work on the heterogeneity of origin firing and the competition between origins for limiting activators to suggest a model in which the stochastic probability of individual origin firing is modulated by chromosomal domain structure to produce patterns of replication. Whether these patterns have inherent biological functions or simply reflect higher-order genome structure is an open question. PMID:23838440

  7. High-Throughput Tag-Sequencing Analysis of Early Events Induced by Ochratoxin A in HepG-2 Cells.

    PubMed

    Zhang, Yu; Qi, Xiaozhe; Zheng, Juanjuan; Luo, YunBo; Huang, Kunlun; Xu, Wentao

    2016-01-01

    Ochratoxin A (OTA) is produced by fungi of the species Aspergillus and Penicillium. OTA has displayed hepatotoxicity in mammals. Although recent studies have indicated that OTA influences liver function, little is known regarding its impact on differential early liver toxicity. In this study, we report high-throughput tag-sequencing (Tag-seq) analysis of the transcriptome using Solexa Analyzer platform after 4 h of OTA treatment on HepG-2 cells. The analyses of differentially expressed genes revealed the substantial changes. A total of 21,449 genes were identified and quantified, with 2726 displaying significantly altered expression levels. Expression level data were then integrated with a network of gene-gene interactions, and biological pathways to obtain a systems-level view of changes in the transcriptome that occur with OTA resistance. Our data suggest that OTA exposure leads to an imbalance in zinc finger expression and shed light on splicing factor and mitochondrial-based mechanisms. PMID:26377828

  8. Early use of orthographic information in spoken word recognition: Event-related potential evidence from the Korean language.

    PubMed

    Kwon, Youan; Choi, Sungmook; Lee, Yoonhyoung

    2016-04-01

    This study examines whether orthographic information is used during prelexical processes in spoken word recognition by investigating ERPs during spoken word processing for Korean words. Differential effects due to orthographic syllable neighborhood size and sound-to-spelling consistency on P200 and N320 were evaluated by recording ERPs from 42 participants during a lexical decision task. The results indicate that P200 was smaller for words whose orthographic syllable neighbors are large in number rather than those that are small. In addition, a word with a large orthographic syllable neighborhood elicited a smaller N320 effect than a word with a small orthographic syllable neighborhood only when the word had inconsistent sound-to-spelling mapping. The results provide support for the assumption that orthographic information is used early during the prelexical spoken word recognition process. PMID:26669620

  9. Unraveling the Early Events of Amyloid-β Protein (Aβ) Aggregation: Techniques for the Determination of Aβ Aggregate Size

    PubMed Central

    Pryor, N. Elizabeth; Moss, Melissa A.; Hestekin, Christa N.

    2012-01-01

    The aggregation of proteins into insoluble amyloid fibrils coincides with the onset of numerous diseases. An array of techniques is available to study the different stages of the amyloid aggregation process. Recently, emphasis has been placed upon the analysis of oligomeric amyloid species, which have been hypothesized to play a key role in disease progression. This paper reviews techniques utilized to study aggregation of the amyloid-β protein (Aβ) associated with Alzheimer’s disease. In particular, the review focuses on techniques that provide information about the size or quantity of oligomeric Aβ species formed during the early stages of aggregation, including native-PAGE, SDS-PAGE, Western blotting, capillary electrophoresis, mass spectrometry, fluorescence correlation spectroscopy, light scattering, size exclusion chromatography, centrifugation, enzyme-linked immunosorbent assay, and dot blotting. PMID:22489141

  10. 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 (∼200-300 kb) 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

  11. Non-Verbal Reasoning Ability and Academic Achievement as Moderators of the Relation between Adverse Life Events and Emotional and Behavioural Problems in Early Adolescence: The Importance of Moderator and Outcome Specificity

    ERIC Educational Resources Information Center

    Flouri, Eirini; Tzavidis, Nikos

    2011-01-01

    This study was carried out to model the functional form of the effect of contextual risk (number of adverse life events) on emotional and behavioural problems in early adolescence, and to test how intelligence and academic achievement compare as moderators of this effect. The effect of number of adverse life events on emotional and behavioural…

  12. Pre-sowing Seed Treatments in Direct-seeded Early Rice: Consequences for Emergence, Seedling Growth and Associated Metabolic Events under Chilling Stress

    PubMed Central

    Wang, Weiqin; Chen, Qian; Hussain, Saddam; Mei, Junhao; Dong, Huanglin; Peng, Shaobing; Huang, Jianliang; Cui, Kehui; Nie, Lixiao

    2016-01-01

    Double direct-seeding for double rice cropping is a simplified, labor saving, and efficient cropping system to improve multiple-crop index and total rice production in central China. However, poor crop establishment of direct-seeded early rice due to chilling stress is the main obstacle to wide spread of this system. A series of experiments were conducted to unravel the effects of pre-sowing seed treatments on emergence, seedling growth and associated metabolic events of direct-seeded early rice under chilling stress. Two seed priming treatments and two seed coating treatments were used in all the experiments. A non-treated control treatment was also maintained for comparison. In both the field and growth chamber studies, seed priming with selenium or salicylic acid significantly enhanced the emergence and seedling growth of rice compared with non-treated control. Nevertheless, such positive effects were not apparent for seed coating treatments. Better emergence and vigorous seedling growth of rice after seed priming was associated with enhanced α-amylase activity, higher soluble sugars contents, and greater respiration rate in primed rice seedlings under chilling stress. Taking together, these findings may provide new avenues for understanding and advancing priming-induced chilling tolerance in direct-seeded early rice in double rice cropping system. PMID:26782108

  13. Pre-sowing Seed Treatments in Direct-seeded Early Rice: Consequences for Emergence, Seedling Growth and Associated Metabolic Events under Chilling Stress.

    PubMed

    Wang, Weiqin; Chen, Qian; Hussain, Saddam; Mei, Junhao; Dong, Huanglin; Peng, Shaobing; Huang, Jianliang; Cui, Kehui; Nie, Lixiao

    2016-01-01

    Double direct-seeding for double rice cropping is a simplified, labor saving, and efficient cropping system to improve multiple-crop index and total rice production in central China. However, poor crop establishment of direct-seeded early rice due to chilling stress is the main obstacle to wide spread of this system. A series of experiments were conducted to unravel the effects of pre-sowing seed treatments on emergence, seedling growth and associated metabolic events of direct-seeded early rice under chilling stress. Two seed priming treatments and two seed coating treatments were used in all the experiments. A non-treated control treatment was also maintained for comparison. In both the field and growth chamber studies, seed priming with selenium or salicylic acid significantly enhanced the emergence and seedling growth of rice compared with non-treated control. Nevertheless, such positive effects were not apparent for seed coating treatments. Better emergence and vigorous seedling growth of rice after seed priming was associated with enhanced α-amylase activity, higher soluble sugars contents, and greater respiration rate in primed rice seedlings under chilling stress. Taking together, these findings may provide new avenues for understanding and advancing priming-induced chilling tolerance in direct-seeded early rice in double rice cropping system. PMID:26782108

  14. Generation of unique poliovirus RNA replication organelles.

    PubMed

    Richards, Alexsia L; Soares-Martins, Jamria A P; Riddell, Geoffrey T; Jackson, William T

    2014-01-01

    Poliovirus (PV), a model for interactions of picornaviruses with host cells, replicates its genomic RNA in association with cellular membranes. The origin of PV replication membranes has not been determined. Hypotheses about the origin of replication membranes, based largely on localization of viral proteins, include modification of coat protein complex I (COPI) and/or COPII secretory pathway vesicles and subversion of autophagic membranes. Here, we use an antibody against double-stranded RNA (dsRNA) to identify replication complexes by detection of dsRNA replication intermediates. dsRNA signal is dependent on virus genome replication and colocalizes with the viral integral membrane protein 3A, which is part of the RNA replication complex. We show that early in infection, dsRNA does not colocalize with a marker for autophagic vesicles, making it unlikely that autophagosomes contribute to the generation of PV RNA replication membranes. We also find that dsRNA does not colocalize with a marker of the COPII coat, Sec31, and, in fact, we demonstrate proteasome-dependent loss of full-length Sec31 during PV infection. These data indicate that COPII vesicles are an unlikely source of PV replication membranes. We show that the Golgi resident G-protein Arf1 and its associated guanine nucleotide exchange factor (GEF), GBF1, transiently colocalize with dsRNA early in infection. In uninfected cells, Arf1 nucleates COPI coat formation, although during infection the COPI coat itself does not colocalize with dsRNA. Phosphatidylinositol-4-phosphate, which is associated with enterovirus-induced vesicles, tightly colocalizes with Arf1/GBF1 throughout infection. Our data point to a noncanonical role for some of the COPI-generating machinery in producing unique replication surfaces for PV RNA replication. IMPORTANCE Picornaviruses are a diverse and major cause of human disease, and their genomes replicate in association with intracellular membranes. There are multiple hypotheses to explain the nature and origin of these membranes, and a complete understanding of the host requirements for membrane rearrangement would provide novel drug targets essential for viral genome replication. Here, we study the model picornavirus, poliovirus, and show that some, but not all, components of the cellular machinery required for retrograde traffic from the Golgi apparatus to the endoplasmic reticulum are transiently present at the sites of viral RNA replication. We also show that the full-length Sec31 protein, which has been suggested to be present on PV RNA replication membranes, is lost during infection in a proteasome-dependent manner. This study helps to reconcile multiple hypotheses about the origin of poliovirus replication membranes and points to known host cell protein complexes that would make likely drug targets to inhibit picornavirus infections. PMID:24570367

  15. 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.

  16. The QT dispersion and QTc dispersion in patients presenting with acute neurological events and its impact on early prognosis

    PubMed Central

    Rahar, Kailash Kumar; Pahadiya, Hans Raj; Barupal, Kishan Gopal; Mathur, C. P.; Lakhotia, Manoj

    2016-01-01

    Aims: To find out and investigate whether the QT dispersion and QTc dispersion is related to type and prognosis of the acute stroke in patients presenting within 24 h of the onset of stroke. Settings and Design: This was a observational study conducted at Mahatma Gandhi Hospital, Dr. SN. Medical College, Jodhpur, during January 2014 to January 2015. Subjects and Methods: The patients presented within 24 h of onset of acute stroke (hemorrhagic, infarction, or transient ischemic event) were included in the study. The stroke was confirmed by computed tomography scan and magnetic resonance imaging. Patients with (i) altered sensorium because of metabolic, infective, seizures, trauma, or tumor; (ii) prior history of cardiovascular disease, electrocardiographic abnormalities because of dyselectrolytemia; and (iii) and patients who were on drugs (antiarrhythmic drugs, antipsychotic drugs, erythromycin, theophylline, etc.,) which known to cause electrocardiogram changes, were excluded from the study. National Institute of Health Stroke Score (NIHSS) was calculated at the time of admission and Modified Rankin Scale (MRS) at the time of discharge. Fifty age- and sex-matched healthy controls included. Statistical Analysis Used: Student's t-test, ANOVA, and area under curve for sensitivity and specificity for the test. Results: We included 52 patients (male/female: 27/25) and 50 controls (26/24). The mean age of patients was 63.17 08.90 years. Of total patients, infarct was found in 32 (61.53%), hemorrhage in 18 (34.61%), transient ischemic attack (TIA) in 1 (1.9%), and subarachnoid hemorrhage in 1 (1.9%) patient. The QT dispersion and QTc dispersion were significantly higher in cases as compare to controls. (87.30 24.42 vs. 49.60 08.79 ms; P < 0.001) and (97.53 27.36 vs. 56.28 09.86 ms; P < 0.001). Among various types of stroke, the mean QT dispersion and QTc dispersion were maximum and significantly higher in hemorrhagic stroke as compared to infarct and TIA (P < 0.001). The mean QT dispersion and QTc dispersion was found significantly high in nonsurvivors (n = 16) as compared to survivors group (n = 36) (P < 0.05). The mean QT dispersion was directly correlated with the NIHSS and functional outcome score MRS. Patients with greater QT and QTc dispersion having high NIHSS had poor prognosis. Conclusion: We concluded that patients presenting with acute neurological events having increased QT dispersion and QTc dispersion is related to high mortality and poor functional outcomes on hospital discharge and if the values of dispersion score are very high we can predict for hemorrhagic stroke.

  17. 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.

  18. Association of early systolic blood pressure response to exercise with future cardiovascular events in patients with uncomplicated mild-to-moderate hypertension.

    PubMed

    Cho, Min Soo; Jang, Sun-Joo; Lee, Chang Hoon; Park, Chong-Hun

    2012-09-01

    The relationship between blood pressure (BP) response during exercise and future cardiovascular events remains unclear. We assessed the association between an increase in early systolic BP (SBP) during exercise tests and future cardiovascular events in patients with sustained hypertension (sHT). Between 2002 and 2005, we enrolled 300 patients newly diagnosed with mild-to-moderate sHT without complications from the Asan Ambulatory Blood Pressure Monitoring registry. All the patients successfully performed treadmill tests, achieving target heart rate according to the Naughton/Balke protocol. The patients were divided into quartiles according to their SBP at 8?min (7.4 metabolic equivalent tasks). The primary outcome was the composite of all-cause death, new-onset ischemic heart disease and stroke. The 5-year survival rates did not differ significantly among quartiles 1-4 (100% vs. 96.6% vs. 94.4% vs. 98.3%, P=0.211). Relative to quartile 1, the 5-year event-free survival rates were significantly lower in patients in quartiles 3 (86.9% vs. 98.3%, P=0.023) and 4 (88.2% vs. 98.3%, P=0.023). After multivariable adjustment for covariates, the risk for the composite end point was higher for patients in quartiles 3 (Hazard ratio (HR) 4.69, 95% confidence interval (CI) 1.28-17.13, P=0.020) and 4 (HR 3.65, 95% CI 0.92-14.50, P=0.065) than in quartiles 1 and 2. Cardiovascular risk was significantly higher in patients with stage 4 SBP (>180?mm?Hg) even after adjustment (HR 4.00, 95% CI 1.19-13.44, P=0.025). Increased submaximal SBP response to exercise may be a predictor of future cardiovascular events in patients with mild-to-moderate sHT. PMID:22534519

  19. 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

  20. Reduced event-related low frequency EEG activity in patients with early onset schizophrenia and their unaffected siblings.

    PubMed

    Simmonite, Molly; Bates, Alan Thomas; Groom, Madeleine; Hollis, Chris; Liddle, Peter Francis

    2015-04-30

    Low-frequency oscillations in the electroencephalogram (EEG) have been found to be abnormal in patients with schizophrenia. It is unclear, however, whether these abnormalities are related to severity of illness or are a marker for risk. This study investigated total and evoked theta and delta activity in schizophrenia patients, unaffected siblings, and healthy controls (HCs). EEG data were recorded whilst 24 individuals with schizophrenia, 26 unaffected siblings of individuals with schizophrenia and 26 healthy control participants completed a Go/No-Go task. Event-related total activity and evoked theta and delta activity were calculated for correct hits (CH), failed inhibitions (FI) and correct inhibitions (CI) trials. Patients displayed significantly less total delta, evoked delta, total theta and evoked theta activity when compared with healthy controls. Unaffected siblings displayed abnormalities of evoked delta, but other measures were similar to those in control participants. The findings of this study add to evidence that abnormal low-frequency EEG oscillations contribute to impairments in information processing seen in schizophrenia. These findings also suggest abnormal evoked delta oscillations are associated with an increased familial risk of developing the disorder. PMID:25745977

  1. 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

  2. Initiation and early evolution of the Franklin magmatic event preserved in the 720 Ma Natkusiak Formation, Victoria Island, Canadian Arctic

    NASA Astrophysics Data System (ADS)

    Williamson, Nicole M. B.; Ootes, Luke; Rainbird, Robert H.; Bédard, Jean H.; Cousens, Brian

    2016-03-01

    Our understanding of the onset and evolution of flood basalt volcanism is rooted in the study of the character and internal architecture of its eruptive products. Neoproterozoic continental flood basalts of the ca. 720 Ma Franklin magmatic event are preserved as the Natkusiak Formation and are exposed within the Minto Inlier on Victoria Island, Northwest Territories, Canada. The 200 m volcanic succession evaluated in this study has features similar to those of other continental flood basalt provinces and consists of four volcanic units: a basal unit of laterally discontinuous flows with evidence for lava-sediment interactions, a mafic volcaniclastic deposit emplaced as a mass flow, a quartz-rich volcanic sandstone that records the re-establishment of small river channels, and a unit of thick, high-titanium tholeiitic sheet flows that mark the onset of the main phase of flood volcanism. The basal units show marked lateral thickness variations that imply the existence of paleotopography during their eruption and/or deposition. In addition, two newly discovered volcanic vent complexes within the Natkusiak succession preserve the products of explosive, vent-forming basaltic pyroclastic fall eruptions. Differences in major element geochemistry between the basal and upper basaltic flow units, in conjunction with the lithological characteristics of each volcanic unit, are used to correlate the units on a scale of over 100 km from the south of the Minto Inlier to the north.

  3. Mutations altering the gammaretrovirus endoproteolytic motif affect glycosylation of the envelope glycoprotein and early events of the virus life cycle

    SciTech Connect

    Argaw, Takele; Wilson, Carolyn A.

    2015-01-15

    Previously, we found that mutation of glutamine to proline in the endoproteolytic cleavage signal of the PERV-C envelope (RQKK to RPKK) resulted in non-infectious vectors. Here, we show that RPKK results in a non-infectious vector when placed in not only a PERV envelope, but also the envelope of a related gammaretrovirus, FeLV-B. The amino acid substitutions do not prevent envelope precursor cleavage, viral core and genome assembly, or receptor binding. Rather, the mutations result in the formation of hyperglycosylated glycoprotein and a reduction in the reverse transcribed minus strand synthesis and undetectable 2-LTR circular DNA in cells exposed to vectors with these mutated envelopes. Our findings suggest novel functions associated with the cleavage signal sequence that may affect trafficking through the glycosylation machinery of the cell. Further, the glycosylation status of the envelope appears to impact post-binding events of the viral life cycle, either membrane fusion, internalization, or reverse transcription. - Highlights: • Env cleavage signal impacts infectivity of gammaretroviruses. • Non-infectious mutants have hyper-glycosylated envelope that bind target cells. • Non-infectious mutants have defects in the formation of the double-stranded DNA. • Env cleavage motif has functions beyond cleavage of the env precursor.

  4. 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.

  5. 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, Jos 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

  6. Characterization of early events involved in human dendritic cell maturation induced by sensitizers: Cross talk between MAPK signalling pathways

    SciTech Connect

    Trompezinski, Sandra; Migdal, Camille; Tailhardat, Magalie; Le Varlet, Beatrice; Courtellemont, Pascal; Haftek, Marek; Serres, Mireille

    2008-08-01

    Dendritic cells (DCs), efficient-antigen presenting cells play an important role in initiating and regulating immune responses. DC maturation following exposure to nickel or DNCB induced an up-regulation of phenotypic markers and inflammatory cytokine secretion. Early intracellular mechanisms involved in DC maturation required to be precise. To address this purpose, DCs derived from human monocytes were treated with sensitizers (nickel, DNCB or thimerosal) in comparison with an irritant (SDS). Our data confirming the up-regulation of CD86, CD54 and cytokine secretion (IL-8 and TNF{alpha}) induced by sensitizers but not by SDS, signalling transduction involved in DC maturation was investigated using these chemicals. Kinase activity measurement was assessed using two new sensitive procedures (Face{sup TM} and CBA) requiring few cells. SDS did not induce changes in signalling pathways whereas NiSO{sub 4}, DNCB and thimerosal markedly activated p38 MAPK and JNK, in contrast Erk1/2 phosphorylation was completely inhibited by DNCB or thimerosal and only activated by nickel. A pre-treatment with p38 MAPK inhibitor (SB203580) suppressed Erk1/2 inhibition induced by DNCB or thimerosal demonstrating a direct interaction between p38 MAPK and Erk1/2. A pre-treatment with an antioxidant, N-acetyl-L-cysteine (NAC) markedly reduced Erk1/2 inhibition and p38 MAPK phosphorylation induced by DNCB and thimerosal, suggesting a direct activation of p38 MAPK via an oxidative stress and a regulation of MAPK signalling pathways depending on chemicals. Because of a high sensitivity of kinase activity measurements, these procedures will be suitable for weak or moderate sensitizer screening.

  7. Root secreted metabolites and proteins are involved in the early events of plant-plant recognition prior to competition.

    PubMed

    Badri, Dayakar V; De-la-Pea, Clelia; Lei, Zhentian; Manter, Daniel K; Chaparro, Jacqueline M; Guimares, Rejane L; Sumner, Lloyd W; Vivanco, Jorge M

    2012-01-01

    The mechanism whereby organisms interact and differentiate between others has been at the forefront of scientific inquiry, particularly in humans and certain animals. It is widely accepted that plants also interact, but the degree of this interaction has been constricted to competition for space, nutrients, water and light. Here, we analyzed the root secreted metabolites and proteins involved in early plant neighbor recognition by using Arabidopsis thaliana Col-0 ecotype (Col) as our focal plant co-cultured in vitro with different neighbors [A. thaliana Ler ecotype (Ler) or Capsella rubella (Cap)]. Principal component and cluster analyses revealed that both root secreted secondary metabolites and proteins clustered separately between the plants grown individually (Col-0, Ler and Cap grown alone) and the plants co-cultured with two homozygous individuals (Col-Col, Ler-Ler and Cap-Cap) or with different individuals (Col-Ler and Col-Cap). In particularly, we observed that a greater number of defense- and stress-related proteins were secreted when our control plant, Col, was grown alone as compared to when it was co-cultured with another homozygous individual (Col-Col) or with a different individual (Col-Ler and Col-Cap). However, the total amount of defense proteins in the exudates of the co-cultures was higher than in the plant alone. The opposite pattern of expression was identified for stress-related proteins. These data suggest that plants can sense and respond to the presence of different plant neighbors and that the level of relatedness is perceived upon initial interaction. Furthermore, the role of secondary metabolites and defense- and stress-related proteins widely involved in plant-microbe associations and abiotic responses warrants reassessment for plant-plant interactions. PMID:23056382

  8. Real-time QCM-D monitoring of cancer cell death early events in a dynamic context.

    PubMed

    Nowacki, Laetitia; Follet, Julie; Vayssade, Muriel; Vigneron, Pascale; Rotellini, Laura; Cambay, Florian; Egles, Christophe; Rossi, Claire

    2015-02-15

    Since a few years, the acoustic sensing of whole cell is the focus of increasing interest for monitoring the cytoskeletal cellular response to morphological modulators. We aimed at illustrating the potentialities of the quartz crystal microbalance with dissipation (QCM-D) technique for the real-time detection of the earliest morphological changes that occur at the cell-substrate interface during programmed cell death. Human breast cancer cells (MCF-7) grown on serum protein-coated gold sensors were placed in dynamic conditions under a continuous medium flow. The mass and viscoelasticity changes of the cells were tracked by monitoring the frequency and dissipation shifts during the first 4h of cell exposure to staurosporine, a well-known apoptosis inducer. We have identified a QCM-D signature characteristic of morphological modifications and cell detachment from the sensing surface that are related to the pro-apoptotic treatment. In particular, for low staurosporine doses below 1 M, we showed that recording the dissipation shift allows to detect an early cell response which is undetectable after the same duration by the classical analytical techniques in cell biology. Furthermore, this sensing method allows quantifying the efficiency of the drug effect in less than 4h without requiring labeling and without interfering in the system, thus preventing any loss of information. In the actual context of targeted cancer therapy development, we believe that these results bring new insights in favor of the use of the non invasive QCM-D technique for quickly probing the cancer cell sensitivity to death inducer drugs. PMID:25286354

  9. Early Events in the Pathogenesis of Chronic Obstructive Pulmonary Disease. Smoking-induced Reprogramming of Airway Epithelial Basal Progenitor Cells

    PubMed Central

    Shaykhiev, Renat

    2014-01-01

    The airway epithelium is the primary site of the earliest pathologic changes induced by smoking, contributing to the development of chronic obstructive pulmonary disease (COPD). The normal human airway epithelium is composed of several major cell types, including differentiated ciliated and secretory cells, intermediate undifferentiated cells, and basal cells (BC). BC contain the stem/progenitor cell population responsible for maintenance of the normally differentiated airway epithelium. Although inflammatory and immune processes play a significant role in the pathogenesis of COPD, the earliest lesions include hyperplasia of the BC population, suggesting that the disease may start with this cell type. Apart from BC hyperplasia, smoking induces a number of COPD-relevant airway epithelial remodeling phenotypes that are likely initiated in the BC population, including mucous cell hyperplasia, squamous cell metaplasia, epithelialmesenchymal transition, altered ciliated and nonmucous secretory cell differentiation, and suppression of junctional barrier integrity. Significant progress has been recently made in understanding the biology of human airway BC, including gene expression features, stem/progenitor, and other functions, including interaction with other airway cell types. Accumulating evidence suggests that human airway BC function as both sensors and cellular sources of various cytokines and growth factors relevant to smoking-associated airway injury, as well as the origin of various molecular and histological phenotypes relevant to the pathogenesis of COPD. In the context of these considerations, we suggest that early BC-specific smoking-induced molecular changes are critical to the pathogenesis of COPD, and these represent a candidate target for novel therapeutic approaches to prevent COPD progression in susceptible individuals. PMID:25525728

  10. Replicated spectrographs in astronomy

    NASA Astrophysics Data System (ADS)

    Hill, Gary J.

    2014-06-01

    As telescope apertures increase, the challenge of scaling spectrographic astronomical instruments becomes acute. The next generation of extremely large telescopes (ELTs) strain the availability of glass blanks for optics and engineering to provide sufficient mechanical stability. While breaking the relationship between telescope diameter and instrument pupil size by adaptive optics is a clear path for small fields of view, survey instruments exploiting multiplex advantages will be pressed to find cost-effective solutions. In this review we argue that exploiting the full potential of ELTs will require the barrier of the cost and engineering difficulty of monolithic instruments to be broken by the use of large-scale replication of spectrographs. The first steps in this direction have already been taken with the soon to be commissioned MUSE and VIRUS instruments for the Very Large Telescope and the Hobby-Eberly Telescope, respectively. MUSE employs 24 spectrograph channels, while VIRUS has 150 channels. We compare the information gathering power of these replicated instruments with the present state of the art in more traditional spectrographs, and with instruments under development for ELTs. Design principles for replication are explored along with lessons learned, and we look forward to future technologies that could make massively-replicated instruments even more compelling.

  11. SIMS Replications in Ontario.

    ERIC Educational Resources Information Center

    Russell, Howard<