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1

Regulation of Early Events in Chromosome Replication  

Microsoft Academic Search

Eukaryotic genomes are replicated from large numbers of replication origins distributed on multiple chromosomes. The activity of these origins must be coordinated so that the entire genome is efficiently and accurately replicated yet no region of the genome is ever replicated more than once. The past decade has seen significant advances in understanding how the initiation of DNA replication is

John F. X. Diffley

2004-01-01

2

Early events in DNA replication require cyclin E and are blocked by p21CIP1.  

PubMed

Using immunodepletion of cyclin E and the inhibitor protein p21WAF/CIP1, we demonstrate that the cyclin E protein, in association with Cdk2, is required for the elongation phase of replication on single-stranded substrates. Although cyclin E/Cdk2 is likely to be the major target by which p21 inhibits the initiation of sperm DNA replication, p21 can inhibit single-stranded replication through a mechanism dependent on PCNA. While the cyclin E/Cdk2 complex appears to have a role in the initiation of DNA replication, another Cdk kinase, possibly cyclin A/Cdk, may be involved in a later step controlling the switch from initiation to elongation. The provision of a large maternal pool of cyclin E protein shows that regulators of replication are constitutively present, which explains the lack of a protein synthesis requirement for replication in the early embryonic cell cycle. PMID:7642695

Jackson, P K; Chevalier, S; Philippe, M; Kirschner, M W

1995-08-01

3

An early event in murine cytomegalovirus replication inhibits presentation of cellular antigens to cytotoxic T lymphocytes.  

PubMed Central

Cytomegalovirus (CMV) infection of simian virus 40 (SV40)-immune mice inhibits priming of SV40-specific helper and cytotoxic T lymphocytes (CTL) in vivo (A. E. Campbell, J. S. Slater, and W. S. Futch, Virology 173:268-275, 1989; J. S. Slater, W. S. Futch, V. J. Cavanaugh and A. E. Campbell, Virology 185:132-139, 1991). We now demonstrate that murine CMV (MCMV) infection of SV40-transformed macrophages and fibroblasts prevents presentation of SV40 T antigen to SV40-specific CTL. MCMV-infected macrophages failed to stimulate SV40-immune CTL precursors in vitro. In addition, MCMV-infected, SV40-transformed macrophage and fibroblast target cells lost their susceptibility to lysis by major histocompatibility complex class I-restricted, SV40-specific CTL clones. MCMV infection did not alter the synthesis of SV40 T antigen in the target cells. MCMV early gene expression was required for inhibition of SV40 T-antigen presentation; immediate-early gene expression was insufficient for this effect. Early viral gene expression also resulted in significant reduction of H-2K and H-2D molecules on the surface of MCMV-infected fibroblasts. However, this reduction occurred independently from suppression of antigen presentation to CTL. The same target cells which were resistant to lysis by SV40 CTL were susceptible to lysis by MCMV-specific CTL. MCMV early gene products therefore interfere with the processing and/or presentation of SV40 T-antigen determinants to CTL independent of alterations in the major histocompatibility complex. Images

Campbell, A E; Slater, J S; Cavanaugh, V J; Stenberg, R M

1992-01-01

4

An early event in murine cytomegalovirus replication inhibits presentation of cellular antigens to cytotoxic T lymphocytes.  

PubMed

Cytomegalovirus (CMV) infection of simian virus 40 (SV40)-immune mice inhibits priming of SV40-specific helper and cytotoxic T lymphocytes (CTL) in vivo (A. E. Campbell, J. S. Slater, and W. S. Futch, Virology 173:268-275, 1989; J. S. Slater, W. S. Futch, V. J. Cavanaugh and A. E. Campbell, Virology 185:132-139, 1991). We now demonstrate that murine CMV (MCMV) infection of SV40-transformed macrophages and fibroblasts prevents presentation of SV40 T antigen to SV40-specific CTL. MCMV-infected macrophages failed to stimulate SV40-immune CTL precursors in vitro. In addition, MCMV-infected, SV40-transformed macrophage and fibroblast target cells lost their susceptibility to lysis by major histocompatibility complex class I-restricted, SV40-specific CTL clones. MCMV infection did not alter the synthesis of SV40 T antigen in the target cells. MCMV early gene expression was required for inhibition of SV40 T-antigen presentation; immediate-early gene expression was insufficient for this effect. Early viral gene expression also resulted in significant reduction of H-2K and H-2D molecules on the surface of MCMV-infected fibroblasts. However, this reduction occurred independently from suppression of antigen presentation to CTL. The same target cells which were resistant to lysis by SV40 CTL were susceptible to lysis by MCMV-specific CTL. MCMV early gene products therefore interfere with the processing and/or presentation of SV40 T-antigen determinants to CTL independent of alterations in the major histocompatibility complex. PMID:1313914

Campbell, A E; Slater, J S; Cavanaugh, V J; Stenberg, R M

1992-05-01

5

Inhibiting early-stage events in HIV-1 replication by small-molecule targeting of the HIV-1 capsid.  

PubMed

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

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

2012-08-01

6

Inhibition of early and late events of the HIV-1 replication cycle by cytoplasmic Fab intrabodies against the matrix protein, p17.  

PubMed Central

BACKGROUND: The HIV-1 matrix (MA) protein, p17, contains two subcellular localization signals that facilitate both nuclear import of the viral preintegration complex early during infection and virus particle assembly late in infection. The dual role of MA in both the afferent and efferent arms of the HIV-1 life cycle makes it an important target for intracellular immunization-based gene therapy strategies. MATERIALS AND METHODS: Here we report, using a new bicistronic vector, that an intracellular Fab antibody, or Fab intrabody, directed against a carboxy-terminal epitope of MA from the Clade B HIV-1 genotype, can inhibit HIV-1 infection when expressed in the cytoplasm of actively dividing CD4+ T cells. RESULTS: Marked inhibition of proviral gene expression occurred when single-round HIV-1 CAT virus was used for infections. In challenge experiments using both laboratory strains and syncytium-inducing primary isolates of HIV-1, a substantial reduction in the infectivity of virions released from the cells was also observed. CONCLUSIONS: This novel strategy of simultaneously blocking early and late events of the HIV-1 life cycle may prove useful in clinical gene therapy approaches for the treatment of HIV-1 infection and AIDS, particularly when combined with genetic or pharmacologic-based strategies that inhibit other HIV-1 target molecules simultaneously. Images FIG. 2 FIG. 3 FIG. 5 FIG. 6 FIG. 8

Levin, R.; Mhashilkar, A. M.; Dorfman, T.; Bukovsky, A.; Zani, C.; Bagley, J.; Hinkula, J.; Niedrig, M.; Albert, J.; Wahren, B.; GA?ttlinger, H. G.; Marasco, W. A.

1997-01-01

7

Early traumatic events in psychopaths.  

PubMed

The relationship between diverse early traumatic events and psychopathy was studied in 194 male inmates. Criminal history transcripts were revised, and clinical interviews were conducted to determine the level of psychopathy using the Psychopathy Checklist-Revised (PCL-R) Form, and the Early Trauma Inventory was applied to assess the incidence of abuse before 18 years of age. Psychopathic inmates presented a higher victimization level and were more exposed to certain types of intended abuse than sociopathic inmates, while the sum of events and emotional abuse were associated with the PCL-R score. Our studies support the influence of early adverse events in the development of psychopathic offenders. PMID:23550705

Borja, Karina; Ostrosky, Feggy

2013-07-01

8

Early responding to traumatic events.  

PubMed

How to respond optimally following traumatic events remains a Holy Grail. A number of early interventions lack evidence of effect. Practical, pragmatic support provided in an empathic manner is likely to be an appropriate initial response and complement the high levels of resilience shown by individuals exposed to traumatic events. PMID:24785764

Bisson, Jonathan I

2014-05-01

9

Loss of heterozygosity preferentially occurs in early replicating regions in cancer genomes  

PubMed Central

Erroneous repair of DNA double-strand breaks by homologous recombination (HR) leads to loss of heterozygosity (LOH). Analysing 22 392 and 74 415 LOH events in 363 glioblastoma and 513 ovarian cancer samples, respectively, and using three different metrics, we report that LOH selectively occurs in early replicating regions; this pattern differs from the trends for point mutations and somatic deletions, which are biased toward late replicating regions. Our results are independent of BRCA1 and BRCA2 mutation status. The LOH events are significantly clustered near RNA polII-bound transcription start sites, consistent with the reports that slow replication near paused RNA polII might initiate HR-mediated repair. The frequency of LOH events is higher in the chromosomes with shorter inter-homolog distance inside the nucleus. We propose that during early replication, HR-mediated rescue of replication near paused RNA polII using homologous chromosomes as template leads to LOH. The difference in the preference for replication timing between different classes of genomic alterations in cancer genomes also provokes a testable hypothesis that replicating cells show changing preference between various DNA repair pathways, which have different levels of efficiency and fidelity, as the replication progresses.

Pedersen, Brent S.; De, Subhajyoti

2013-01-01

10

Loss of heterozygosity preferentially occurs in early replicating regions in cancer genomes.  

PubMed

Erroneous repair of DNA double-strand breaks by homologous recombination (HR) leads to loss of heterozygosity (LOH). Analysing 22,392 and 74,415 LOH events in 363 glioblastoma and 513 ovarian cancer samples, respectively, and using three different metrics, we report that LOH selectively occurs in early replicating regions; this pattern differs from the trends for point mutations and somatic deletions, which are biased toward late replicating regions. Our results are independent of BRCA1 and BRCA2 mutation status. The LOH events are significantly clustered near RNA polII-bound transcription start sites, consistent with the reports that slow replication near paused RNA polII might initiate HR-mediated repair. The frequency of LOH events is higher in the chromosomes with shorter inter-homolog distance inside the nucleus. We propose that during early replication, HR-mediated rescue of replication near paused RNA polII using homologous chromosomes as template leads to LOH. The difference in the preference for replication timing between different classes of genomic alterations in cancer genomes also provokes a testable hypothesis that replicating cells show changing preference between various DNA repair pathways, which have different levels of efficiency and fidelity, as the replication progresses. PMID:23793816

Pedersen, Brent S; De, Subhajyoti

2013-09-01

11

Synchronous contextual irregularities affect early scene processing: replication and extension.  

PubMed

Whether contextual regularities facilitate perceptual stages of scene processing is widely debated, and empirical evidence is still inconclusive. Specifically, it was recently suggested that contextual violations affect early processing of a scene only when the incongruent object and the scene are presented a-synchronously, creating expectations. We compared event-related potentials (ERPs) evoked by scenes that depicted a person performing an action using either a congruent or an incongruent object (e.g., a man shaving with a razor or with a fork) when scene and object were presented simultaneously. We also explored the role of attention in contextual processing by using a pre-cue to direct subjects? attention towards or away from the congruent/incongruent object. Subjects? task was to determine how many hands the person in the picture used in order to perform the action. We replicated our previous findings of frontocentral negativity for incongruent scenes that started ~ 210 ms post stimulus presentation, even earlier than previously found. Surprisingly, this incongruency ERP effect was negatively correlated with the reaction times cost on incongruent scenes. The results did not allow us to draw conclusions about the role of attention in detecting the regularity, due to a weak attention manipulation. By replicating the 200-300 ms incongruity effect with a new group of subjects at even earlier latencies than previously reported, the results strengthen the evidence for contextual processing during this time window even when simultaneous presentation of the scene and object prevent the formation of prior expectations. We discuss possible methodological limitations that may account for previous failures to find this an effect, and conclude that contextual information affects object model selection processes prior to full object identification, with semantic knowledge activation stages unfolding only later on. PMID:24593900

Mudrik, Liad; Shalgi, Shani; Lamy, Dominique; Deouell, Leon Y

2014-04-01

12

Aurintricarboxylic acid inhibits the early stage of vaccinia virus replication by targeting both cellular and viral factors.  

PubMed

Aurintricarboxylic acid (ATA) has been shown to inhibit the replication of viruses from several different families, including human immunodeficiency virus, vesicular stomatitis virus, and the coronavirus causing severe acute respiratory syndrome. This study characterizes the inhibitory effect of ATA on vaccinia virus replication in HeLa, Huh7, and AD293 cells. Vaccinia virus replication is significantly abrogated upon ATA treatment, which is associated with the inhibition of early viral gene transcription. This inhibitory effect may be attributed to two findings. First, ATA blocks the phosphorylation of extracellular signal-regulated kinase 1/2, an event shown to be essential for vaccinia virus replication. Second, ATA inhibits the phosphatase activity of the viral enzyme H1L, which is required to initiate viral transcription. Thus, ATA inhibits vaccinia virus replication by targeting both cellular and viral factors essential for the early stage of replication. PMID:17192307

Myskiw, Chad; Deschambault, Yvon; Jefferies, Kristel; He, Runtao; Cao, Jingxin

2007-03-01

13

Aurintricarboxylic Acid Inhibits the Early Stage of Vaccinia Virus Replication by Targeting both Cellular and Viral Factors?  

PubMed Central

Aurintricarboxylic acid (ATA) has been shown to inhibit the replication of viruses from several different families, including human immunodeficiency virus, vesicular stomatitis virus, and the coronavirus causing severe acute respiratory syndrome. This study characterizes the inhibitory effect of ATA on vaccinia virus replication in HeLa, Huh7, and AD293 cells. Vaccinia virus replication is significantly abrogated upon ATA treatment, which is associated with the inhibition of early viral gene transcription. This inhibitory effect may be attributed to two findings. First, ATA blocks the phosphorylation of extracellular signal-regulated kinase 1/2, an event shown to be essential for vaccinia virus replication. Second, ATA inhibits the phosphatase activity of the viral enzyme H1L, which is required to initiate viral transcription. Thus, ATA inhibits vaccinia virus replication by targeting both cellular and viral factors essential for the early stage of replication.

Myskiw, Chad; Deschambault, Yvon; Jefferies, Kristel; He, Runtao; Cao, Jingxin

2007-01-01

14

Differential Host Response, Rather Than Early Viral Replication Efficiency, Correlates with Pathogenicity Caused by Influenza Viruses  

PubMed Central

Influenza viruses exhibit large, strain-dependent differences in pathogenicity in mammalian hosts. Although the characteristics of severe disease, including uncontrolled viral replication, infection of the lower airway, and highly inflammatory cytokine responses have been extensively documented, the specific virulence mechanisms that distinguish highly pathogenic strains remain elusive. In this study, we focused on the early events in influenza infection, measuring the growth rate of three strains of varying pathogenicity in the mouse airway epithelium and simultaneously examining the global host transcriptional response over the first 24 hours. Although all strains replicated equally rapidly over the first viral life-cycle, their growth rates in both lung and tracheal tissue strongly diverged at later times, resulting in nearly 10-fold differences in viral load by 24 hours following infection. We identified separate networks of genes in both the lung and tracheal tissues whose rapid up-regulation at early time points by specific strains correlated with a reduced viral replication rate of those strains. The set of early-induced genes in the lung that led to viral growth restriction is enriched for both NF-?B binding site motifs and members of the TREM1 and IL-17 signaling pathways, suggesting that rapid, NF-?B –mediated activation of these pathways may contribute to control of viral replication. Because influenza infection extending into the lung generally results in severe disease, early activation of these pathways may be one factor distinguishing high- and low-pathogenicity strains.

Askovich, Peter S.; Sanders, Catherine J.; Rosenberger, Carrie M.; Diercks, Alan H.; Dash, Pradyot; Navarro, Garnet; Vogel, Peter; Doherty, Peter C.; Thomas, Paul G.; Aderem, Alan

2013-01-01

15

USF Binding Sequences from the HS4 Insulator Element Impose Early Replication Timing on a Vertebrate Replicator  

PubMed Central

The nuclear genomes of vertebrates show a highly organized program of DNA replication where GC-rich isochores are replicated early in S-phase, while AT-rich isochores are late replicating. GC-rich regions are gene dense and are enriched for active transcription, suggesting a connection between gene regulation and replication timing. Insulator elements can organize independent domains of gene transcription and are suitable candidates for being key regulators of replication timing. We have tested the impact of inserting a strong replication origin flanked by the ?-globin HS4 insulator on the replication timing of naturally late replicating regions in two different avian cell types, DT40 (lymphoid) and 6C2 (erythroid). We find that the HS4 insulator has the capacity to impose a shift to earlier replication. This shift requires the presence of HS4 on both sides of the replication origin and results in an advance of replication timing of the target locus from the second half of S-phase to the first half when a transcribed gene is positioned nearby. Moreover, we find that the USF transcription factor binding site is the key cis-element inside the HS4 insulator that controls replication timing. Taken together, our data identify a combination of cis-elements that might constitute the basic unit of multi-replicon megabase-sized early domains of DNA replication.

Cadoret, Jean-Charles; Ma, Meiji Kit-Wan; Boggetto, Nicole; West, Adam G.; Prioleau, Marie-Noelle

2012-01-01

16

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

PubMed Central

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 ITN3–4, 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.

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

2012-01-01

17

Checkpoint proteins control morphogenetic events during DNA replication stress in Saccharomyces cerevisiae  

PubMed Central

In response to DNA replication stress in Saccharomyces cerevisiae, the DNA replication checkpoint maintains replication fork stability, prevents precocious chromosome segregation, and causes cells to arrest as large-budded cells. The checkpoint kinases Mec1 and Rad53 act in this checkpoint. Treatment of mec1 or rad53? mutants with replication inhibitors results in replication fork collapse and inappropriate partitioning of partially replicated chromosomes, leading to cell death. We describe a previously unappreciated function of various replication stress checkpoint proteins, including Rad53, in the control of cell morphology. Checkpoint mutants have aberrant cell morphology and cell walls, and show defective bud site selection. Rad53 shows genetic interactions with septin ring pathway components, and, along with other checkpoint proteins, controls the timely degradation of Swe1 during replication stress, thereby facilitating proper bud growth. Thus, checkpoint proteins play an important role in coordinating morphogenetic events with DNA replication during replication stress.

Enserink, Jorrit M.; Smolka, Marcus B.; Zhou, Huilin; Kolodner, Richard D.

2006-01-01

18

Mouse STAT2 Restricts Early Dengue Virus Replication  

PubMed Central

Summary Dengue virus encodes several interferon antagonists. Among these the NS5 protein binds STAT2, a necessary component of the type-I interferon signaling pathway, and targets it for degradation. We now demonstrate that the ability of dengue NS5 to associate with and degrade STAT2 is species specific. Thus, NS5 is able to bind and degrade human STAT2 but not mouse STAT2. This difference was exploited to demonstrate, absent manipulation of the viral genome, that NS5 mediated IFN antagonism is essential for efficient virus replication. Moreover, we demonstrate that differences in NS5 mediated binding and degradation between human and mouse STAT2 maps to a region within the STAT2 coiled-coil domain. By using STAT2?/? mice, we also demonstrate that mouse STAT2 restricts early dengue virus replication in vivo. These results suggest that overcoming this restriction through transgenic mouse technology may help in the development of a long-sought immune-competent mouse model of dengue virus infection.

Ashour, Joseph; Morrison, Juliet; Laurent-Rolle, Maudry; Belicha-Villanueva, Alan; Plumlee, Courtney Ray; Bernal-Rubio, Dabeiba; Williams, Kate; Harris, Eva; Fernandez-Sesma, Ana; Schindler, Christian; Garcia-Sastre, Adolfo

2012-01-01

19

A Post-Entry Role for CD63 in Early HIV-1 Replication  

PubMed Central

Macrophages and CD4+ 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+ 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.

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

2011-01-01

20

Transcription from the SV40 early-early and late-early overlapping promoters in the absence of DNA replication.  

PubMed Central

Transcription for a hybrid SV40 promoter-beta globin coding sequence recombinant initiates from both early-early (EE) and late-early (LE) SV40 start sites (EES and LES) in the absence of DNA replication. The 72-bp repeat is essential to potentiate the elements of the two overlapping EE and LE promoters (EEP and LEP). Two current models, which can account for the EE to LE shift in RNA chain initiation during the SV40 replication cycle, are that LE transcription is linked to replication and occurs on newly replicated DNA molecules or that there are two promoter elements, a stronger EEP and a weaker LEP, T antigen repressing the EEP late in infection. Our results support the second model. A 5'-TATTTAT-3' to 5'-TATCGAT-3' mutation in the putative SV40 TATA box decreases transcription from EES, increases transcription from LES, and inhibits DNA replication. Therefore, this element acts as a classical TATA box for transcription, and yet is also important for DNA replication. Images Fig. 2. Fig. 3. Fig. 4. Fig. 5.

Wasylyk, B; Wasylyk, C; Matthes, H; Wintzerith, M; Chambon, P

1983-01-01

21

Changes in nucleosome repeat lengths precede replication in the early replicating metallothionein II gene region of cells synchronized in early S phase  

SciTech Connect

Previous investigations showed that inhibition of DNA synthesis by hydroxyurea, aphidicolin, or 5-fluorodeoxyuridine produced large changes in the composition and nucleosome repeat lengths of bulk chromatin. There the authors report results of investigations to determine whether the changes in nucleosome repeat lengths might be localized in the initiated replicons, as postulated. In most experiments, Chinese hamster (line CHO) cells were synchronized in G1, or they were synchronized in early S phase by allowing G1 cells to enter S phase in medium containing 1 mM hydroxyurea or 5 {mu}g mL{sup {minus}1} aphidicolin, a procedure believed to produce an accumulation of initiated replicons that arise from normally early replicating DNA. Measurements of nucleosome repeat lengths of bulk chromatin, the early replicating unexpressed metallothionein II (MTII) gene region, and a later replicating repeated sequence indicate that the changes in repeat lengths occur preferentially in the early replicating MTII gene region as G1 cells enter and become synchronized in early S phase. During that time, the MTII gene region is not replicated nor is there any evidence for induction of MTII messenger RNA. Thus, the results are consistent with the hypothesis that changes in chromatin structure occur preferentially in the early replicating (presumably initiated) replicons at initiation or that changes in chromatin structure can precede replication during inhibition of DNA synthesis. The shortened repeat lengths that precede MTII replication are, potentially, reversible, because they become elongated when the synchronized early S-phase cells are released to resume cell cycle progression.

D'Anna, J.A.; Tobey, R.A. (Los Alamos National Lab., NM (USA))

1989-04-04

22

Two early replicated, developmentally controlled genes of Physarum display different patterns of DNA replication by two-dimensional agarose gel electrophoresis  

Microsoft Academic Search

The nature of replication origins in eukaryotic chromosomes has been examined in some detail only in yeast, Drosophila, and mammalian cells. We have used highly synchronous cultures of plasmodia of the myxomycete Physarum and two-dimensional agarose gel electrophoresis to examine replication of two developmentally controlled, early replicated genes over time in S-phase. A single, discrete origin of replication was found

John D. Diller; Helmut W. Sauer

1993-01-01

23

Kinetochores Coordinate Pericentromeric Cohesion and Early DNA Replication by Cdc7-Dbf4 Kinase Recruitment  

PubMed Central

Summary Centromeres play several important roles in ensuring proper chromosome segregation. Not only do they promote kinetochore assembly for microtubule attachment, but they also support robust sister chromatid cohesion at pericentromeres and facilitate replication of centromeric DNA early in S phase. However, it is still elusive how centromeres orchestrate all these functions at the same site. Here, we show that the budding yeast Dbf4-dependent kinase (DDK) accumulates at kinetochores in telophase, facilitated by the Ctf19 kinetochore complex. This promptly recruits Sld3–Sld7 replication initiator proteins to pericentromeric replication origins so that they initiate replication early in S phase. Furthermore, DDK at kinetochores independently recruits the Scc2–Scc4 cohesin loader to centromeres in G1 phase. This enhances cohesin loading and facilitates robust pericentromeric cohesion in S phase. Thus, we have found the central mechanism by which kinetochores orchestrate early S phase DNA replication and robust sister chromatid cohesion at microtubule attachment sites.

Natsume, Toyoaki; Muller, Carolin A.; Katou, Yuki; Retkute, Renata; Gierlinski, Marek; Araki, Hiroyuki; Blow, J. Julian; Shirahige, Katsuhiko; Nieduszynski, Conrad A.; Tanaka, Tomoyuki U.

2013-01-01

24

Giemsa staining of the sites replicating DNA early in human lymphocyte chromosomes  

Microsoft Academic Search

A timetable for the initiation of DNA replication in human lymphocyte chromosomes has been established by a technique which allows detection of areas of chromosomes replicating at a given interval of the S-phase. The resolution of the method, using 33258 Hoechst-Giemsa staining, is more refined than that obtained with 3H-thymidine autoradiography. Early replicating regions coincide with R-bands. The timetable is

My. A. Kim; R. Johannsmann; K.-H. Grzeschik

1975-01-01

25

Reconstructing Early Events in Eukaryotic Evolution.  

PubMed

Resolving the order of events that occurred during the transition from prokaryotic to eukaryotic cells remains one of the greatest problems in cell evolution. One view, the Archezoa hypothesis, proposes that the endosymbiotic origin of mitochondria occurred relatively late in eukaryotic evolution and that several mitochondrion-lacking protist groups diverged before the establishment of the organelle. Phylogenies based on small subunit ribosomal RNA and several protein-coding genes supported this proposal, placing amitochondriate protists such as diplomonads, parabasalids, and Microsporidia as the earliest diverging eukaryotic lineages. However, trees of other molecules, such as tubulins, heat shock protein 70, TATA box-binding protein, and the largest subunit of RNA polymerase II, indicate that Microsporidia are not deeply branching eukaryotes but instead are close relatives of the Fungi. Furthermore, recent discoveries of mitochondrion-derived genes in the nuclear genomes of entamoebae, Microsporidia, parabasalids, and diplomonads suggest that these organisms likely descend from mitochondrion-bearing ancestors. Although several protist lineages formally remain as candidates for Archezoa, most evidence suggests that the mitochondrial endosymbiosis took place prior to the divergence of all extant eukaryotes. In addition, discoveries of proteobacterial-like nuclear genes coding for cytoplasmic proteins indicate that the mitochondrial symbiont may have contributed more to the eukaryotic lineage than previously thought. As genome sequence data from parabasalids and diplomonads accumulate, it is becoming clear that the last common ancestor of these protist taxa and other extant eukaryotic groups already possessed many of the complex features found in most eukaryotes but lacking in prokaryotes. However, our confidence in the deeply branching position of diplomonads and parabasalids among eukaryotes is weakened by conflicting phylogenies and potential sources of artifact. Our current picture of early eukaryotic evolution is in a state of flux. PMID:10527924

Roger

1999-10-01

26

Vaccinia Virus Activation of CCR5 Invokes Tyrosine Phosphorylation Signaling Events That Support Virus Replication  

PubMed Central

Vaccinia virus, a poxvirus, produces structurally distinct forms of virions for which the immediate events following cell entry are ill-defined. We provide evidence that intracellular mature virus (IMV) enters both permissive and nonpermissive T-cell lines and that introduction of CCR5 into nonpermissive mouse fibroblasts or human primary T cells renders the cells permissive for vaccinia replication. Notably, T cells expressing CCR5 in which tyrosine 339 in the intracellular region is replaced by phenylalanine no longer support virus replication or virus-inducible activation of specific host cell signaling effectors IRS-2, Grb2, and Erk1/2. We show that following IMV entry into the cell, the intact but not the tyrosine-deficient CCR5 is rapidly internalized and colocalizes with virus. This colocalization precedes virus-inducible signaling and replication.

Rahbar, Ramtin; Murooka, Thomas T.; Hinek, Anna A.; Galligan, Carole L.; Sassano, Antonella; Yu, Celeste; Srivastava, Kishore; Platanias, Leonidas C.; Fish, Eleanor N.

2006-01-01

27

Vaccinia virus activation of CCR5 invokes tyrosine phosphorylation signaling events that support virus replication.  

PubMed

Vaccinia virus, a poxvirus, produces structurally distinct forms of virions for which the immediate events following cell entry are ill-defined. We provide evidence that intracellular mature virus (IMV) enters both permissive and nonpermissive T-cell lines and that introduction of CCR5 into nonpermissive mouse fibroblasts or human primary T cells renders the cells permissive for vaccinia replication. Notably, T cells expressing CCR5 in which tyrosine 339 in the intracellular region is replaced by phenylalanine no longer support virus replication or virus-inducible activation of specific host cell signaling effectors IRS-2, Grb2, and Erk1/2. We show that following IMV entry into the cell, the intact but not the tyrosine-deficient CCR5 is rapidly internalized and colocalizes with virus. This colocalization precedes virus-inducible signaling and replication. PMID:16809330

Rahbar, Ramtin; Murooka, Thomas T; Hinek, Anna A; Galligan, Carole L; Sassano, Antonella; Yu, Celeste; Srivastava, Kishore; Platanias, Leonidas C; Fish, Eleanor N

2006-07-01

28

Expert Panel Workshop on Early-Life Events and Cancer  

Cancer.gov

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

29

Early events in geotropism of seedling shoots  

NASA Technical Reports Server (NTRS)

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

Pickard, B. G.

1985-01-01

30

Reconstructing Early Events in Eukaryotic Evolution  

Microsoft Academic Search

Resolving the order of events that occurred during the transition from prokaryotic to eukaryotic cells remains one of the greatest problems in cell evolution. One view, the Archezoa hypoth- esis, proposes that the endosymbiotic origin of mitochondria oc- curred relatively late in eukaryotic evolution and that several mi- tochondrion-lacking protist groups diverged before the establishment of the organelle. Phylogenies based

Andrew J. Roger

1999-01-01

31

Spatial distributions of early and late replicating chromatin in interphase chromosome territories.  

PubMed

The surface area of chromosome territories has been suggested as a preferred site for genes, specific RNAs, and accumulations of splicing factors. Here, we investigated the localization of sites of replication within individual chromosome territories. In vivo replication labeling with thymidine analogues IdUrd and CldUrd was combined with chromosome painting by fluorescent in situ hybridization on three-dimensionally preserved human fibroblast nuclei. Spatial distributions of replication labels over the chromosome territory, as well as the territory volume and shape, were determined by 3D image analysis. During late S-phase a previously observed shape difference between the active and inactive X-chromosome in female cells was maintained, while the volumes of the two territories did not differ significantly. Domains containing early or mid to late replicating chromatin were distributed throughout territories of chromome 8 and the active X. In the inactive X-chromosome early replicating chromatin was observed preferentially near the territory surface. Most important, we established that the process of replication takes place in foci throughout the entire chromosome territory volume, in early as well as in late S-phase. This demonstrates that activity of macromolecular enzyme complexes takes place throughout chromosome territories and is not confined to the territory surface as suggested previously. PMID:9743599

Visser, A E; Eils, R; Jauch, A; Little, G; Bakker, P J; Cremer, T; Aten, J A

1998-09-15

32

The 6-Aminoquinolone WC5 Inhibits Human Cytomegalovirus Replication at an Early Stage by Interfering with the Transactivating Activity of Viral Immediate-Early 2 Protein ? †  

PubMed Central

WC5 is a 6-aminoquinolone that potently inhibits the replication of human cytomegalovirus (HCMV) but has no activity, or significantly less activity, against other herpesviruses. Here we investigated the nature of its specific anti-HCMV activity. Structure-activity relationship studies on a small series of analogues showed that WC5 possesses the most suitable pattern of substitutions around the quinolone scaffold to give potent and selective anti-HCMV activity. Studies performed to identify the possible target of WC5 indicated that it prevents viral DNA synthesis but does not significantly affect DNA polymerase activity. In yield reduction experiments with different multiplicities of infection, the anti-HCMV activity of WC5 appeared to be highly dependent on the viral inoculum, suggesting that WC5 may act at an initial stage of virus replication. Consistently, time-of-addition and time-of-removal studies demonstrated that WC5 affects a phase of the HCMV replicative cycle that precedes viral DNA synthesis. Experiments to monitor the effects of the compound on virus attachment and entry showed that it does not inhibit either process. Evaluation of viral mRNA and protein expression revealed that WC5 targets an event of the HCMV replicative cycle that follows the transcription and translation of immediate-early genes and precedes those of early and late genes. In cell-based assays to test the effects of WC5 on the transactivating activity of the HCMV immediate-early 2 (IE2) protein, WC5 markedly interfered with IE2-mediated transactivation of viral early promoters. Finally, WC5 combined with ganciclovir in checkerboard experiments exhibited highly synergistic activity. These findings suggest that WC5 deserves further investigation as a candidate anti-HCMV drug with a novel mechanism of action.

Loregian, Arianna; Mercorelli, Beatrice; Muratore, Giulia; Sinigalia, Elisa; Pagni, Silvana; Massari, Serena; Gribaudo, Giorgio; Gatto, Barbara; Palumbo, Manlio; Tabarrini, Oriana; Cecchetti, Violetta; Palu, Giorgio

2010-01-01

33

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

PubMed

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

Overmeer, René M; Moser, Jill; Volker, Marcel; Kool, Hanneke; Tomkinson, Alan E; van Zeeland, Albert A; Mullenders, Leon H F; Fousteri, Maria

2011-02-01

34

Early Events in Mycobacterium tuberculosis Infection in Cynomolgus Macaques  

Microsoft Academic Search

Little is known regarding the early events of infection of humans with Mycobacterium tuberculosis. The cynomolgus macaque is a useful model of tuberculosis, with strong similarities to human tuberculosis. In this study, eight cynomolgus macaques were infected bronchoscopically with low-dose M. tuberculosis; clinical, immunologic, microbiologic, and pathologic events were assessed 3 to 6 weeks postinfection. Gross pathological abnormalities were observed

Philana Ling Lin; Santosh Pawar; Amy Myers; A. Pegu; C. Fuhrman; T. A. Reinhart; S. V. Capuano; E. Klein; J. L. Flynn

2006-01-01

35

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

PubMed

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

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

2004-12-01

36

Replication of poliovirus RNA containing two VPg coding sequences leads to a specific deletion event.  

PubMed Central

Studies of the poliovirus genome-linked protein VPg have shown that this small viral protein is required for replication of virus-specific RNA (Q. Reuer, R. J. Kuhn, and E. Wimmer, J. Virol. 64:2967-2975, 1990). To understand the mechanism of RNA replication, we constructed a recombinant poliovirus genome encoding two tandemly arranged VPg coding sequences that were nearly identical in both nucleotide and amino acid sequence. Following transfection of this two-VPg-containing RNA into HeLa cells, we found a specific and selective deletion in the progeny virus genome. Sequence analysis of the recovered viral RNA indicated that the complete nucleotide sequence encoding the second (3C-proximal) VPg coding sequences was removed, restoring the authentic genome sequences in the poliovirus genome. Analysis of viral RNAs following transfection suggested that the deletion event occurred during genome replication. Deletion could have occurred via homologous recombination between two VPg sequences or via intramolecular deletion with loop-out of the template. In vitro translation of the two-VPg-containing transcript RNA indicated aberrant processing of the viral polyprotein. This result suggested that selection of the wild-type genotype in the transfected cells may occur at the level of viral protein synthesis. Images

Cao, X; Kuhn, R J; Wimmer, E

1993-01-01

37

DNA breaks early in replication process associated with 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.

38

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

PubMed Central

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

Zabka, Aneta; Polit, Justyna Teresa; Maszewski, Janusz

2012-01-01

39

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

PubMed Central

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.

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

2006-01-01

40

Early Jurassic mass extinction: A global long-term event  

Microsoft Academic Search

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,

Crispin T. S. Little; Michael J. Benton

1995-01-01

41

Early Reproductive Events and Breast Cancer: Workshop Statement  

Cancer.gov

The National Cancer Institute convened the Early Reproductive Events and Breast Cancer Workshop on February 24-26, 2003. This scientific Workshop was held to present and review the information available on the risk of breast cancer associated with pregnancy. The Workshop brought together a cross-section of experts to discuss the scientific data available regarding the reproductive events in a woman's life that may impact her subsequent risk of breast cancer.

42

The extract of Elaeocarpus sylvestris inhibits human cytomegalovirus immediate early gene expression and replication in vitro.  

PubMed

Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality in newborn infants, immunocompromised individuals with HIV/AIDS and organ transplant recipients. In order to identify a novel antiviral candidate for HCMV-related diseases, crude ethanol extracts from plants were screened for their potential inhibitory activity on HCMV replication in vitro. Ethanol (70%) extract of Elaeocarpus sylvestris leaves (ESE) markedly inhibited the replication of the HCMV Towne strain without exhibiting any significant adverse effects on the viability of human foreskin fibroblasts (HFF). In addition, ESE significantly downregulated HCMV immediate early (IE) gene expression. Taken together, this is the first study, to the best of our knowledge, demonstrating that ESE has a potent antiviral activity against HCMV by downregulating HCMV IE gene expression and replication. PMID:24270403

To, Kim Phuong; Kang, Se Chan; Song, Yoon-Jae

2014-02-01

43

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

ERIC Educational Resources Information Center

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…

Alat, Kazim

2002-01-01

44

Summary Report: Early Reproductive Events and Breast Cancer Workshop  

Cancer.gov

The Early Reproductive Events and Breast Cancer Workshop convened February 24-26, 2003, and the outcomes of the meeting were reviewed and discussed at the joint meeting of the NCI Board of Scientific Advisors (BSA) and Board of Scientific Counselors (BSC) held March 3, 2003.

45

The Effects of Age at Drinking Onset and Stressful Life Events on Alcohol Use in Adulthood: A Replication and Extension Using a Population-Based Twin Sample  

PubMed Central

Background A study by Dawson and colleagues (Alcohol Clin Exp Res 2007; 31:69) using data from National Epidemiologic Survey on Alcohol and Related Condition found earlier drinking onset age, and higher levels of past-year stressful life events (SLE) were associated with higher past-year alcohol consumption. The aims of our study were as follows: (i) to attempt to replicate this interaction; (ii) to extend it by examining sex and event dependence as potential moderators of the effect; and (iii) to estimate the roles of genetic and environmental factors in mediating the overlap of early drinking onset and SLE in their relations with alcohol consumption. Methods Data were from 1,382 female and 2,218 male drinkers interviewed as part of the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. Regression models were used to evaluate the main and interactive effects of early drinking onset and moderate or severe past-year SLE on past-year drinking density (PYDD), a weighted quantity-frequency measure of alcohol consumption. Analyses adjusted for demographic covariates and were stratified by sex and whether SLE were independent or dependent on the person’s actions, as rated by interviewers. Structural twin models were used to estimate the degree to which early drinking onset, SLE, and their interaction accounted for additive genetic, common environmental and individual-specific variance in PYDD. Results We replicated the prior finding of a main effect of higher alcohol consumption among individuals reporting earlier drinking onset. Age at drinking onset accounted for about 5% of the variation in PYDD, and this association was mostly attributable to overlapping genetic influences. Evidence for an interaction between onset age and SLE was generally weak, possibly because of lower power and other methodological differences from Dawson and colleagues’ study. However, there was some evidence consistent with an interaction of higher PYDD among early drinking men who experienced independent SLE and early drinking women with dependent SLE. Conclusions We confirmed prior findings of an association between early age at drinking onset with higher past-year drinking among young- and middle-aged adults and found limited evidence supporting a replication for higher stress-related drinking among early-onset drinkers. The association is consistent with early onset and stress-related drinking being attributable to overlapping genetic liability. Among early drinkers, our results suggest sex differences in consumption with regard to event dependence.

Lee, Lewina O.; Young Wolff, Kelly C.; Kendler, Kenneth S.; Prescott, Carol A.

2012-01-01

46

Anoxia as the cause of the mid-Early Cambrian (Botomian) extinction event  

Microsoft Academic Search

New and revised Early Cambrian biostratigraphic data allow a quantitative analysis of changes in biotic diversity and extinction rate. The mid-Early Cambrian extinction can now be resolved into two distinct events: the well-known early Toyonian Hawke Bay regression event, and a newly observed but more severe disruption during the early Botomian, here named the Sinsk event. During the Sinsk event,

Andrey Yu. Zhuravlev; Rachel A. Wood

1996-01-01

47

Nigericin is a potent inhibitor of the early stage of vaccinia virus replication.  

PubMed

Poxviruses remain a significant public health concern due to their potential use as bioterrorist agents and the spread of animal borne poxviruses, such as monkeypox virus, to humans. Thus, the identification of small molecule inhibitors of poxvirus replication is warranted. Vaccinia virus is the prototypic member of the Orthopoxvirus genus, which also includes variola and monkeypox virus. In this study, we demonstrate that the carboxylic ionophore nigericin is a potent inhibitor of vaccinia virus replication in several human cell lines. In HeLa cells, we found that the 50% inhibitory concentration of nigericin against vaccinia virus was 7.9 nM, with a selectivity index of 1038. We present data demonstrating that nigericin targets vaccinia virus replication at a post-entry stage. While nigericin moderately inhibits both early vaccinia gene transcription and translation, viral DNA replication and intermediate and late gene expression are severely compromised in the presence of nigericin. Our results demonstrate that nigericin has the potential to be further developed into an effective antiviral to treat poxvirus infections. PMID:20951746

Myskiw, Chad; Piper, Jessica; Huzarewich, Rhiannon; Booth, Tim F; Cao, Jingxin; He, Runtao

2010-12-01

48

miRNA regulation of BK polyomavirus replication during early infection  

PubMed Central

Viral microRNAs (miRNAs) play an important role during infection by posttranscriptionally regulating both host and viral gene expression. However, the function of many viral miRNAs remains poorly understood. In this study, we investigated the role of the BK polyomavirus (BKPyV) miRNA in regulating virus replication. The function of the polyomavirus miRNA was investigated in archetype BKPyV, which is the transmissible form of the virus and thought to establish a persistent infection in the host urinary tract. In agreement with previous studies, we show that the BKPyV miRNA targets early mRNAs. Importantly, we show that the miRNA plays a significant role in limiting archetype BKPyV replication in a natural host cell model of infection. This regulation is accomplished through the balance of regulatory elements located within the noncoding control region that control early gene expression and miRNA expression before genome replication. We therefore provide evidence for a unique function of the polyomavirus miRNA that may have important implications for the mechanism of viral persistence.

Broekema, Nicole M.; Imperiale, Michael J.

2013-01-01

49

Cytomegalovirus Replication and “Herpesvirus Burden” as Risk Factor of Cardiovascular Events in the First Year After Renal Transplantation  

Microsoft Academic Search

Cytomegalovirus (CMV) infection alone or in combination with other pathogens (“pathogen burden”) has been postulated as a factor producing arteriosclerosis in some solid organ transplant recipients. The aim of this study was to assess whether the patients with CMV replication and\\/or “herpesvirus burden” experienced a greater incidence of cardiovascular events during the first year after kidney transplantation. One hundred twenty-one

E. Gómez; A. Laurés; J. M. Baltar; S. Melón; B. D??ez; M. de Oña

2005-01-01

50

DNA Replication  

NSDL National Science Digital Library

This animation, which shows DNA replication and the interactions of the various enzymes, can be used to illustrate to students the order of events in DNA replication, as well as emphasize which enzymes are involved in the process.

American Society For Microbiology;

2002-01-01

51

Femtosecond relativistic electron beam triggered early bioradical events  

NASA Astrophysics Data System (ADS)

With the recent advent of table-top terawatt Ti:Sa laser amplifier systems, laser plasma interactions provide high-energy, femtosecond electron bunches, which might conjecture direct observation of radiation events in media of biological interest. We report on the first femtolysis studies using such laser produced relativistic electron pulses in the 2.5-15 MeV range. A real-time observation of elementary radical events is performed on water molecules and media containing an important disulfide biomolecule. The primary yield of a reducing radical produced in clusters of excitation-ionisation events (spurs) has been determined at t~3.5 10-12 s. These data provide important information about the initial energy loss and spatial distribution of early radical events. Femtolysis studies devoted to a disulfide biomolecule is noteworthy as it is the first time that a primary ionisation event can be controlled by an ultrafast radical anion formation in the prethermal regime. This innovating domain foreshadows the development of new applications in radiobiology (microdosimetry at the nanometric scale). In the near future, electron femtolysis studies would clearly enhance the understanding of radiation-induced damages in biological confined spaces (aqueous groove of DNA and protein pockets).

Gauduel, Yann A.; Fritzler, Sven; Hallou, Abdeslem; Glinec, Y.; Malka, Victor

2004-09-01

52

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

PubMed

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

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

2013-11-01

53

Hepatitis C Virus entry: the early steps in the viral replication cycle  

PubMed Central

Approximately 170 million are infected with the hepatitis C virus (HCV) world wide and an estimated 2.7 million are HCV RNA positive in the United States alone. The acute phase of the HCV infection, in majority of individuals, is asymptomatic. A large percentage of those infected with HCV are unable to clear the virus and become chronically infected. The study of the HCV replication cycle was hampered due to difficulties in growing and propagating the virus in an in vitro setting. The advent of the HCV pseudo particle (HCVpp) and HCV cell culture (HCVcc) systems have made possible the study of the HCV replication cycle, in vitro. Studies utilizing the HCVpp and HCVcc systems have increased our insight into the early steps of the viral replication cycle of HCV, such as the identification of cellular co-receptors for binding and entry. The aim of this article is to provide a review of the outstanding literature on HCV entry, specifically looking at cellular co-receptors involved and putting the data in the context of the systems used (purified viral envelope proteins, HCVpp system, HCVcc system and/or patient sera) and to also give a brief description of the cellular co-receptors themselves.

Sabahi, Ali

2009-01-01

54

Tobacco mosaic virus and the study of early events in virus infections.  

PubMed Central

In order to establish infections, viruses must be delivered to the cells of potential hosts and must then engage in activities that enable their genomes to be expressed and replicated. With most viruses, the events that precede the onset of production of progeny virus particles are referred to as the early events and, in the case of positive-strand RNA viruses, they include the initial interaction with and entry of host cells and the release (uncoating) of the genome from the virus particles. Though the early events remain one of the more poorly understood areas of plant virology, the virus with which most of the relevant research has been performed is tobacco mosaic virus (TMV). In spite of this effort, there remains much uncertainty about the form or constituent of the virus that actually enters the initially invaded cell in a plant and about the mechanism(s) that trigger the subsequent uncoating (virion disassembly) reactions. A variety of approaches have been used in attempts to determine the fate of TMV particles that are involved in the establishment of an infection and these are briefly described in this review. In some recent work, it has been proposed that the uncoating process involves the bidirectional release of coat protein subunits from the viral RNA and that these activities may be mediated by cotranslational and coreplicational disassembly mechanisms.

Shaw, J G

1999-01-01

55

Early Immunologic Events at the Tick-Host Interface  

PubMed Central

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.

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

2012-01-01

56

Role of Transmitted Gag CTL Polymorphisms in Defining Replicative Capacity and Early HIV-1 Pathogenesis  

PubMed Central

Initial studies of 88 transmission pairs in the Zambia Emory HIV Research Project cohort demonstrated that the number of transmitted HLA-B associated polymorphisms in Gag, but not Nef, was negatively correlated to set point viral load (VL) in the newly infected partners. These results suggested that accumulation of CTL escape mutations in Gag might attenuate viral replication and provide a clinical benefit during early stages of infection. Using a novel approach, we have cloned gag sequences isolated from the earliest seroconversion plasma sample from the acutely infected recipient of 149 epidemiologically linked Zambian transmission pairs into a primary isolate, subtype C proviral vector, MJ4. We determined the replicative capacity (RC) of these Gag-MJ4 chimeras by infecting the GXR25 cell line and quantifying virion production in supernatants via a radiolabeled reverse transcriptase assay. We observed a statistically significant positive correlation between RC conferred by the transmitted Gag sequence and set point VL in newly infected individuals (p?=?0.02). Furthermore, the RC of Gag-MJ4 chimeras also correlated with the VL of chronically infected donors near the estimated date of infection (p?=?0.01), demonstrating that virus replication contributes to VL in both acute and chronic infection. These studies also allowed for the elucidation of novel sites in Gag associated with changes in RC, where rare mutations had the greatest effect on fitness. Although we observed both advantageous and deleterious rare mutations, the latter could point to vulnerable targets in the HIV-1 genome. Importantly, RC correlated significantly (p?=?0.029) with the rate of CD4+ T cell decline over the first 3 years of infection in a manner that is partially independent of VL, suggesting that the replication capacity of HIV-1 during the earliest stages of infection is a determinant of pathogenesis beyond what might be expected based on set point VL alone.

Carlson, Jonathan M.; Schaefer, Malinda; Yu, Tianwei; Lahki, Shabir; Prentice, Heather A.; Yue, Ling; Vishwanathan, Sundaram A.; Kilembe, William; Goepfert, Paul; Price, Matthew A.; Gilmour, Jill; Mulenga, Joseph; Farmer, Paul; Derdeyn, Cynthia A.; Tang, Jiaming; Heckerman, David; Kaslow, Richard A.; Allen, Susan A.; Hunter, Eric

2012-01-01

57

[Early defibrillation with automated external defibrillators during sports events].  

PubMed

Sports-related cardiovascular events may occur in both young athletes and the general population, the latter having a higher absolute risk. In mass gathering sports events, the availability of an onsite emergency response plan including early access to automated external defibrillators by trained lay rescuers has been shown to improve survival among spectators and staff with out-of-hospital cardiac arrest and to reduce subsequent neurological deficit. In addition, in athletes experiencing cardiac arrest, the implementation of public access defibrillation programs demonstrated a favorable mortality trend, with survival rates comparable to those observed in adult sedentary subjects. In Italy and much of Europe, current emergency action plans at sporting events still need full implementation. In particular, in Italy no scientific statements on this topic have been developed. In order to compensate this lack of information, an ad hoc task force has been established with representatives of the major scientific societies involved in sports-based health and disease prevention, with the aim to address public access defibrillation programs for sporting events, and to promote awareness of appropriate cardiovascular emergency care at sports arenas. PMID:23096387

Giada, Franco; Santomauro, Maurizio; Biffi, Alessandro; Casasco, Maurizio

2012-10-01

58

Impact Constraints on Major Events in Early Mars History  

NASA Technical Reports Server (NTRS)

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.

Frey, H. V.

2004-01-01

59

Early Low-Titer Neutralizing Antibodies Impede HIV-1 Replication and Select for Virus Escape  

PubMed Central

Single genome sequencing of early HIV-1 genomes provides a sensitive, dynamic assessment of virus evolution and insight into the earliest anti-viral immune responses in vivo. By using this approach, together with deep sequencing, site-directed mutagenesis, antibody adsorptions and virus-entry assays, we found evidence in three subjects of neutralizing antibody (Nab) responses as early as 2 weeks post-seroconversion, with Nab titers as low as 1?20 to 1?50 (IC50) selecting for virus escape. In each of the subjects, Nabs targeted different regions of the HIV-1 envelope (Env) in a strain-specific, conformationally sensitive manner. In subject CH40, virus escape was first mediated by mutations in the V1 region of the Env, followed by V3. HIV-1 specific monoclonal antibodies from this subject mapped to an immunodominant region at the base of V3 and exhibited neutralizing patterns indistinguishable from polyclonal antibody responses, indicating V1–V3 interactions within the Env trimer. In subject CH77, escape mutations mapped to the V2 region of Env, several of which selected for alterations of glycosylation. And in subject CH58, escape mutations mapped to the Env outer domain. In all three subjects, initial Nab recognition was followed by sequential rounds of virus escape and Nab elicitation, with Nab escape variants exhibiting variable costs to replication fitness. Although delayed in comparison with autologous CD8 T-cell responses, our findings show that Nabs appear earlier in HIV-1 infection than previously recognized, target diverse sites on HIV-1 Env, and impede virus replication at surprisingly low titers. The unexpected in vivo sensitivity of early transmitted/founder virus to Nabs raises the possibility that similarly low concentrations of vaccine-induced Nabs could impair virus acquisition in natural HIV-1 transmission, where the risk of infection is low and the number of viruses responsible for transmission and productive clinical infection is typically one.

Bar, Katharine J.; Tsao, Chun-yen; Iyer, Shilpa S.; Decker, Julie M.; Yang, Yongping; Bonsignori, Mattia; Chen, Xi; Hwang, Kwan-Ki; Montefiori, David C.; Liao, Hua-Xin; Hraber, Peter; Fischer, William; Li, Hui; Wang, Shuyi; Sterrett, Sarah; Keele, Brandon F.; Ganusov, Vitaly V.; Perelson, Alan S.; Korber, Bette T.; Georgiev, Ivelin; McLellan, Jason S.; Pavlicek, Jeffrey W.; Gao, Feng; Haynes, Barton F.; Hahn, Beatrice H.; Kwong, Peter D.; Shaw, George M.

2012-01-01

60

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

NASA Astrophysics Data System (ADS)

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.

Laiterä, Tiina; Lehto, Kirsi

2009-12-01

61

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

NASA Astrophysics Data System (ADS)

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

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

2011-11-01

62

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

PubMed Central

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

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

2014-01-01

63

Updated and revised nomenclature for description of early pregnancy events.  

PubMed

The nomenclature used to describe clinical events in early pregnancy has been criticized for lack of clarity and promoting confusion. There is no agreed glossary of terms or consensus regarding important gestational milestones. In particular there are old and poorly descriptive terms such as 'missed abortion' and 'blighted ovum', which have persisted since their introduction many years ago (Robinson, 1975) and have not undergone revision despite the widespread application of ultrasound for accurate clinical assessment and diagnosis. The authors are aware of these shortcomings in terminology and are keen to provide an updated glossary. We hope that this paper will facilitate the introduction of a revised terminology in an attempt to provide clarity and to enhance uptake and use in the literature as well as clinical assessment and documentation. PMID:16006453

Farquharson, Roy G; Jauniaux, Eric; Exalto, Niek

2005-11-01

64

Replicative mechanisms of CNV formation preferentially occur as intrachromosomal events: evidence from Potocki-Lupski duplication syndrome  

PubMed Central

Copy number variations (CNVs) in the human genome contribute significantly to disease. De novo CNV mutations arise via genomic rearrangements, which can occur in ‘trans’, i.e. via interchromosomal events, or in ‘cis’, i.e. via intrachromosomal events. However, what molecular mechanisms occur between chromosomes versus between or within chromatids has not been systematically investigated. We hypothesized that distinct CNV mutational mechanisms, based on their intrinsic properties, may occur in a biased intrachromosomal versus interchromosomal manner. Here, we studied 62 genomic duplications observed in association with sporadic Potocki–Lupski syndrome (PTLS), in which multiple mutational mechanisms appear to be operative. Intriguingly, more interchromosomal than intrachromosomal events were identified in recurrent PTLS duplications mediated by non-allelic homologous recombination, whereas the reciprocal distribution was found for replicative mechanisms and non-homologous end-joining, likely reflecting the differences in spacial proximity of homologous chromosomes during different mutational processes.

Sun, Zhe; Liu, Pengfei; Jia, Xueyuan; Withers, Marjorie A.; Jin, Li; Lupski, James R.; Zhang, Feng

2013-01-01

65

Replicative mechanisms of CNV formation preferentially occur as intrachromosomal events: evidence from Potocki-Lupski duplication syndrome.  

PubMed

Copy number variations (CNVs) in the human genome contribute significantly to disease. De novo CNV mutations arise via genomic rearrangements, which can occur in 'trans', i.e. via interchromosomal events, or in 'cis', i.e. via intrachromosomal events. However, what molecular mechanisms occur between chromosomes versus between or within chromatids has not been systematically investigated. We hypothesized that distinct CNV mutational mechanisms, based on their intrinsic properties, may occur in a biased intrachromosomal versus interchromosomal manner. Here, we studied 62 genomic duplications observed in association with sporadic Potocki-Lupski syndrome (PTLS), in which multiple mutational mechanisms appear to be operative. Intriguingly, more interchromosomal than intrachromosomal events were identified in recurrent PTLS duplications mediated by non-allelic homologous recombination, whereas the reciprocal distribution was found for replicative mechanisms and non-homologous end-joining, likely reflecting the differences in spacial proximity of homologous chromosomes during different mutational processes. PMID:23161748

Sun, Zhe; Liu, Pengfei; Jia, Xueyuan; Withers, Marjorie A; Jin, Li; Lupski, James R; Zhang, Feng

2013-02-15

66

Early cytokine dysregulation and viral replication are associated with mortality during lethal influenza infection.  

PubMed

Abstract Infection with influenza A virus (IAV) leads to acute lung injury and possibly fatal complications, especially in immunocompromised, elderly, or chronically infected individuals. Therefore, it is important to study the factors that lead to pathology and mortality in infected hosts. In this report, we analyze immune responses to infection at a sublethal (0.1 LD50) and lethal (1 LD50) dose of the highly pathogenic IAV A/Puerto Rico/8/34 (PR8). Our experiments revealed that infection with a 1 LD50 dose induced peak viral titers at day 2 compared to day 4 in the 0.1 LD50 dose. Moreover, early cytokine dysregulation was observed in the lethal dose with significantly elevated levels of IFN-?, TNF-?, CXCL9, IL-6, and MCP-1 produced at day 2. Early inflammatory responses following infection with 1 LD50 correlated with a greater influx of neutrophils into the lung. However, depletion of neutrophils enhanced morbidity following IAV infection. Though no differences in CD8+ cell function were observed, CD4+ effector responses were impaired in the lungs 8 days after infection with 1 LD50. Histological analysis revealed significant pathology in lethally infected mice at day 2 and day 6 postinfection, when viral titers remained high. Treating lethally infected mice with oseltamivir inhibited viral titers to sublethal levels, and abrogated the pathology associated with the lethal dose. Together, these results suggest that early cytokine dysregulation and viral replication play a role in pulmonary damage and high mortality in lethally infected mice. PMID:24787235

Vogel, Alexander J; Harris, Seth; Marsteller, Nathan; Condon, Shirley A; Brown, Deborah M

2014-06-01

67

Response of Jakobshavn Isbræ to early Holocene abrupt climate events  

NASA Astrophysics Data System (ADS)

Located in central-west Greenland, the Fjord Stade moraine complex represents an important phase of Greenland Ice Sheet deglaciation since the Last Glacial Maximum. However, the Fjord Stade moraines are only indirectly dated to between ~ 10 and 7.7 cal ka BP, making it difficult to evaluate the relationship between past ice-margin fluctuations and temperature change given current chronological uncertainties. In addition, the Fjord Stade moraine complex consists of two separate moraines, the older Marrait moraine and the younger Tasiussaq moraine. This distinction has often been neglected, making correlation of different moraine segments across central-west Greenland problematic. Here, we present new mapping and radiocarbon-dated lake sediments, with previously published 10Be surface exposure ages to precisely constrain the age of the Marrait and Tasiussaq moraines at the mouth of Jakobshavn Isbræ, Greenland’s largest outlet glacier. Following local deglaciation at 10.2±0.1 ka (n = 5), preliminary data suggests Jakobshavn Isbræ advanced to deposit that Marrait moraine at ~9.2-9.1 cal yr BP based on radiocarbon dates from a threshold lake adjacent to the Marrait moraine. Following deposition of the Marrait moraine, 10Be ages indicate Jakobshavn Isbræ experienced a second advance culminating in deposition of the Tasiussaq moraine just before 8.0±0.2 ka (n = 5). Our chronology suggests that the Fjord Stade moraines located at the mouth of Jakobshavn Isfjord, represent advances of the ice margin in response to early Holocene, centennial-scale abrupt climate events (i.e. 9.3 and 8.2 ka events).

Young, N. E.; Briner, J. P.; Rood, D. H.; Finkel, R. C.

2010-12-01

68

A Timescale for Major Events in Early Mars Crustal Evolution  

NASA Technical Reports Server (NTRS)

The population of visible and buried impact basins greater than 200 km diameter revealed by high resolution gridded MOLA data and the cumulative frequency curves derived for these provide 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 assigned 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 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.

Frey, H. V.

2004-01-01

69

Discovery of Gramine Derivatives That Inhibit the Early Stage of EV71 Replication in Vitro.  

PubMed

Enterovirus 71 (EV71) is a notable causative agent of hand, foot, and mouth disease in children, which is associated with an increased incidence of severe neurological disease and death, yet there is no specific treatment or vaccine for EV71 infections. In this study, the antiviral activity of gramine and 21 gramine derivatives against EV71 was investigated in cell-based assays. Eighteen derivatives displayed some degree of inhibitory effects against EV71, in that they could effectively inhibit virus-induced cytopathic effects (CPEs), but the anti-EV71 activity of the lead compound gramine was not observed. Studies on the preliminary modes of action showed that these compounds functioned by targeting the early stage of the EV71 lifecycle after viral entry, rather than inactivating the virus directly, inhibiting virus adsorption or affecting viral release from the cells. Among these derivatives, one (compound 4s) containing pyridine and benzothiazole units showed the most potency against EV71. Further studies demonstrated that derivative 4s could profoundly inhibit viral RNA replication, protein synthesis, and virus-induced apoptosis in RD cells. These results indicate that derivative 4s might be a feasible therapeutic agent against EV71 infection and that these gramine derivatives may provide promising lead scaffolds for the further design and synthesis of potential antiviral agents. PMID:24979400

Wei, Yanhong; Shi, Liqiao; Wang, Kaimei; Liu, Manli; Yang, Qingyu; Yang, Ziwen; Ke, Shaoyong

2014-01-01

70

The extent of early viral replication is a critical determinant of the natural history of simian immunodeficiency virus infection.  

PubMed Central

Different patterns of viral replication correlate with the natural history of disease progression in humans and macaques infected with human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV), respectively. However, the viral and host factors influencing these patterns of viral replication in vivo are poorly understood. We intensively studied viral replication in macaques receiving identical inocula of SIV. Marked differences in viral replication patterns were apparent within the first week following inoculation, a time prior to the development of measurable specific immune effector responses to viral antigens. Plasma viral RNA levels measured on day 7 postinoculation correlated with levels measured in the postacute phase of infection. Differences in the susceptibility of host cells from different animals to in vitro SIV infection correlated with the permissiveness of the animals for early in vivo viral replication and hence with the postacute set point level of plasma viremia. These results suggest that host factors that exert their effects prior to full development of specific immune responses are critical in establishing the in vivo viral replication pattern and associated clinical course in subjects infected with SIV and, by extension, with HIV-1.

Lifson, J D; Nowak, M A; Goldstein, S; Rossio, J L; Kinter, A; Vasquez, G; Wiltrout, T A; Brown, C; Schneider, D; Wahl, L; Lloyd, A L; Williams, J; Elkins, W R; Fauci, A S; Hirsch, V M

1997-01-01

71

Early Events of B Cell Activation by Antigen  

NSDL National Science Digital Library

The activation of B cells confers long-lasting protection from a plethora of infectious diseases through the generation of plasma cells that produce high-affinity antibodies and memory cells. Engagement of the B cell receptor (BCR) with cognate antigen initiates intracellular signaling and subsequent internalization of antigen. Membrane-bound antigens are now considered the predominant forms that initiate B cell activation in vivo. We have shown that upon recognition of antigen on the surface of a presenting cell, the B cell undergoes a dramatic change in morphology characterized by rapid spreading followed by more prolonged contraction along the presenting surface. This two-phase response increases the amount of antigen that the B cell accumulates, internalizes, and subsequently presents to T cells. Thus, the spreading and contraction response shapes the outcome of B cell activation. We used a combination of planar lipid bilayers and total internal reflection fluorescence microscopy to investigate the early events that occur after engagement of the BCR and before B cell spreading. We observed the rapid formation of BCR-antigen microclusters, which we redefine as “microsignalosomes” because they mediate the coordinated recruitment of intracellular effectors, such as the kinases Lyn and Syk, the adaptor Vav, and phospholipase C–γ2 (PLC-γ2). We identified an essential role for the co-receptor CD19 in mediating spreading, and thus B cell activation, in response to membrane-bound antigen. Preliminary evidence suggests that the cellular morphology changes described in vitro are likely to occur upon recognition of antigen presented on the surface of macrophages in lymph nodes in vivo.

David Depoil (Cancer Research UK London Research Institute;Lymphocyte Interaction Laboratory REV); Michele Weber (Cancer Research UK London Research Institute;Lymphocyte Interaction Laboratory REV); Bebhinn Treanor (Cancer Research UK London Research Institute;Lymphocyte Interaction Laboratory REV); Sebastian J. Fleire (NYU Langone Medical Center;Cancer Institute REV); Yolanda R. Carrasco (Madrid;National Centre of Biotechnology-CSIC REV); Naomi E. Harwood (Cancer Research UK London Research Institute;Lymphocyte Interaction Laboratory REV)

2009-03-24

72

EXAMINING THE STRUCTURE OF THE SCHEDULE OF SEXIST EVENTS: REPLICATION AND EXTENSION  

Microsoft Academic Search

The current study reexamined the factor structure of the Lifetime and Recent scales of the Schedule of Sexist Events (SSE; Klonoff & Landrine, 1995) and conducted the first factor analysis of the SSE-Appraisal scale (Landrine & Klonoff, 1997). Factor analyses conducted with data from 245 women yielded, for SSE-Lifetime and SSE-Appraisal scales, two reliable factors that can be scored as

Alicia V. Matteson; Bonnie Moradi

2005-01-01

73

Examining the Structure of the Schedule of Sexist Events: Replication and Extension  

ERIC Educational Resources Information Center

The current study reexamined the factor structure of the Lifetime and Recent scales of the Schedule of Sexist Events (SSE; Klonoff & Landrine, 1995) and conducted the first factor analysis of the SSE-Appraisal scale ( Landrine & Klonoff, 1997). Factor analyses conducted with data from 245 women yielded, for SSE-Lifetime and SSE-Appraisal scales,…

Matteson, Alicia V.; Moradi, Bonnie

2005-01-01

74

The central localization of the small and early replicating chromosomes in human diploid metaphase figures  

Microsoft Academic Search

Centromere-center distances are analyzed in 700 metaphase plates, which belong to four different samples. The descriptive analysis of the chromosome distribution shows that smaller, earlier replicating, gene-dense chromosomes are preferentially found near the metaphase plate center, surrounded by longer chromosomes which finish their replication rather late during S phase. This general pattern is highly constant in diploid metaphase samples and

Luc Hens; Micheline Kirsch-Volders; Luc Verschaeve; Charles Susanne

1982-01-01

75

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

PubMed Central

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.

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

2012-01-01

76

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

PubMed Central

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

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

2009-01-01

77

Isolation of Cell Lines That Show Novel, Murine Leukemia Virus-Specific Blocks to Early Steps of Retroviral Replication  

Microsoft Academic Search

In order to identify cellular proteins required for early stages of retroviral replication, a high volume screening with mammalian somatic cells was performed. Ten pools of chemically mutagenized Chinese hamster ovary (CHO-K1) cells were challenged with a murine leukemia virus (MLV) vector pseudotyped with the vesicular stomatitis virus glycoprotein (VSV-G), and cells that failed to be transduced were enriched by

James W. Bruce; Kenneth A. Bradley; Paul Ahlquist; John A. T. Young

2005-01-01

78

An EAS event observed in the early stage of development  

NASA Astrophysics Data System (ADS)

Since 1969 the experiments of Brazil-Japan Collaboration showed the occurrence of a series of events, showing a region with a high concentration of electromagnetic particles, surrounded by isolated and/or groups of showers. These events were named "halo events" or "super-families". Currently, we have more than a dozen of such events. The first of them, due to its aspect, was named "Andromeda". We present here the main characteristics of a similar halo event, named C21S087I075. It has a halo region with many high energy showers in its border. Other small energy showers spread over the central and surrounding blocks (S088, S100, S101, I074). These isolated showers, classified as of hadronic or electromagnetic origin, present a fractional energy distribution compatible with that of a Centauro candidate event (C16S087I037), reported at this symposium [S.L.C. Barroso, P.C. Beggio, J.A. Chinellato, A.O. Carvalho, A. Mariano, R. Oliveira, E.H. Shibuya, in this issue of XIV ISVHECRI]. Moreover, the lateral distribution in the halo region is similar to that observed in other 3 halo events.

Barroso, S. L. C.; Beggio, P. C.; de Carvalho, A. O.; Chinellato, J. A.; Mariano, A.; de Oliveira, R.; Shibuya, E. H.; Brazil-Japan Collaboration of Chacaltaya Emulsion Chamber Experiment

2008-01-01

79

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

ERIC Educational Resources Information Center

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…

Flecken, Monique

2011-01-01

80

Sigma-1 Receptor Regulates Early Steps of Viral RNA Replication at the Onset of Hepatitis C Virus Infection  

PubMed Central

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 Ca2+ 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.

Friesland, Martina; Mingorance, Lidia; Chung, Josan; Chisari, Francis V.

2013-01-01

81

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

PubMed

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

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

2013-06-01

82

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...

83

Aneuploidy as an Early Mechanistic Event in Metal Carcinogenesis  

PubMed Central

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.

Wise, Sandra S.; Wise, John Pierce

2014-01-01

84

Updated and revised nomenclature for description of early pregnancy events  

Microsoft Academic Search

The nomenclature used to describe clinical events in earl y pregnancy has been criticized for lack of clarity and pro- moting confusion. There is no agreed glossary of terms or consensus regarding important gestational milestones. In particular there are old and poorly descriptive terms such as 'missed abortion' and 'blighted ovum', which have per- sisted since their introduction many years

Roy G. Farquharson; Eric Jauniaux; Niek Exalto; Liverpool L

2005-01-01

85

Early Transcriptional Events in Cell Growth: The Egr Family  

Microsoft Academic Search

How eucaryotic cells respond to growth signals is a topic of considerable interest. Though much atten- tion has focused on second messenger pathways, in recent years, progress has been made on elucidat- ing the transcriptional events that lie more distally in the signal transduction process. Indeed, mitogens regulate the induction of several genes without the need for de novo protein

Vikas P. Sukhatme

86

Timing of Childhood Events and Early-Adult Household Formation.  

ERIC Educational Resources Information Center

Identified a number of risk factors contributing to early household formation. Found that for girls, factors included mother's educational level and birth order; for boys, parental divorce at any stage of childhood. Risk factors common to boys and girls were age of mother at time of child's birth and race. (HTH)

Hill, Martha S.; And Others

1996-01-01

87

Early Bone Healing Events following Rat Molar Tooth Extraction  

Microsoft Academic Search

Healing of the rat tooth extraction socket occurs rapidly, indicating a mechanism for cancellous bone formation occurring swiftly throughout the matrix. The residual periodontal ligament is evident at 2 days after extraction and its rich collagen type III fibre content may form a template for future cancellous bone formation. In the remainder of the early tooth extraction socket, fibronectin staining

Hugh Devlin

2000-01-01

88

The Expression of N-Terminal Deletion DNA Pilot Proteins Inhibits the Early Stages of ?X174 Replication?  

PubMed Central

The ?X174 DNA pilot protein H contains four predicted C-terminal coiled-coil domains. The region of the gene encoding these structures was cloned, expressed in vivo, and found to strongly inhibit wild-type replication. DNA and protein synthesis was investigated in the absence of de novo H protein synthesis and in wild-type-infected cells expressing the inhibitory proteins (?H). The expression of the ?H proteins interfered with early stages of DNA replication, which did not require de novo H protein synthesis, suggesting that the inhibitory proteins interfere with the wild-type H protein that enters the cell with the penetrating DNA. As transcription and protein synthesis are dependent on DNA replication in positive single-stranded DNA life cycles, viral protein synthesis was also reduced. However, unlike DNA synthesis, efficient viral protein synthesis required de novo H protein synthesis, a novel function for this protein. A single amino acid change in the C terminus of protein H was both necessary and sufficient to confer resistance to the inhibitory ?H proteins, restoring both DNA and protein synthesis to wild-type levels. ?H proteins derived from the resistant mutant did not inhibit wild-type or resistant mutant replication. The inhibitory effects of the ?H proteins were lessened by the coexpression of the internal scaffolding protein, which may suppress H-H protein interactions. While coexpression relieved the block in DNA biosynthesis, viral protein synthesis remained suppressed. These data indicate that protein H's role in DNA replication and stimulating viral protein synthesis can be uncoupled.

Ruboyianes, Mark V.; Chen, Min; Dubrava, Mathew S.; Cherwa, James E.; Fane, Bentley A.

2009-01-01

89

The expression of N-terminal deletion DNA pilot proteins inhibits the early stages of phiX174 replication.  

PubMed

The phiX174 DNA pilot protein H contains four predicted C-terminal coiled-coil domains. The region of the gene encoding these structures was cloned, expressed in vivo, and found to strongly inhibit wild-type replication. DNA and protein synthesis was investigated in the absence of de novo H protein synthesis and in wild-type-infected cells expressing the inhibitory proteins (DeltaH). The expression of the DeltaH proteins interfered with early stages of DNA replication, which did not require de novo H protein synthesis, suggesting that the inhibitory proteins interfere with the wild-type H protein that enters the cell with the penetrating DNA. As transcription and protein synthesis are dependent on DNA replication in positive single-stranded DNA life cycles, viral protein synthesis was also reduced. However, unlike DNA synthesis, efficient viral protein synthesis required de novo H protein synthesis, a novel function for this protein. A single amino acid change in the C terminus of protein H was both necessary and sufficient to confer resistance to the inhibitory DeltaH proteins, restoring both DNA and protein synthesis to wild-type levels. DeltaH proteins derived from the resistant mutant did not inhibit wild-type or resistant mutant replication. The inhibitory effects of the DeltaH proteins were lessened by the coexpression of the internal scaffolding protein, which may suppress H-H protein interactions. While coexpression relieved the block in DNA biosynthesis, viral protein synthesis remained suppressed. These data indicate that protein H's role in DNA replication and stimulating viral protein synthesis can be uncoupled. PMID:19640994

Ruboyianes, Mark V; Chen, Min; Dubrava, Mathew S; Cherwa, James E; Fane, Bentley A

2009-10-01

90

Early Events During Neoplastic Progression in Barrett's Esophagus  

PubMed Central

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.

Reid, Brian J.

2014-01-01

91

National Cancer Institute Boards Accept Scientific Workshop Findings on Early Reproductive Events and Breast Cancer  

Cancer.gov

On March 3, 2003, the NCI's Board of Scientific Advisors and Board of Scientific Counselors reviewed and unanimously accepted the findings of an "Early Reproductive Events and Breast Cancer Workshop."

92

Early molecular events in the induction phase of contact sensitivity.  

PubMed Central

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

Enk, A H; Katz, S I

1992-01-01

93

Early Mechanistic Events in Biotin Dissociation from Streptavidin  

SciTech Connect

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

Hyre, D. E.

2002-01-01

94

Early-replicating DNA from mosquito cells is associated with a distinct EcoRI fragment.  

PubMed

In an effort to define an origin of bi-directional DNA replication (OBR) in mosquito genomic DNA, we applied methods that take advantage of characteristic features of single-stranded DNA to methotrexate-resistant Aedes albopictus cells. The Mtx-5011-256 cells contained approximately 1000 copies of a 200 kb amplicon containing the dihydrofolate reductase locus, which likely contained one or more replication origins. When Mtx-5011-256 cells were synchronized by treatment with hydroxyurea, released into the S phase of the cell cycle, and labeled in vivo with tritiated DNA precursors, a 1.9 kb EcoRI fragment was preferentially labeled in EcoRI-digested genomic DNA. Similarly, we detected a 1.9 kb EcoRI fragment in DNA from wild type cells after cell cycle synchronization and in vivo labeling. In a complementary method, unlabeled single-stranded DNA was isolated from Mtx-5011-256 cells, labeled in vitro, and hybridized to EcoRI-digested genomic DNA from mosquito cells. The labeled probe hybridized preferentially to a 1.9 kb fragment. Finally, a 1.9 kb EcoRI fragment was detected when nascent DNA was recovered from unsynchronized cells, made double-stranded by in vitro labeling, and digested with EcoRI. Taken together, these results suggest that in Aedes albopictus mosquito cells, many replication origins used at different times during S are flanked by EcoRI sites that define a 1.9 kb fragment, which has become more abundant in Mtx-5011-256 cells because it occurs in the dhfr amplicon. Tentative mapping of this origin to amplicon DNA remains ambiguous, further suggesting that a repeated sequence element occurs at or near the origin of replication. PMID:10070745

Wang, Z H; Fallon, A M

1999-01-01

95

Characterization of mitochondrial replication and transcription control during rat early development in vivo and in vitro  

Microsoft Academic Search

In vitro culture (IVC), used in assisted reproductive technologies, is a major environmental stress on the embryo. To evaluate the effect of IVC on mitochondrial transcription and the control of mtDNA replication, we measured the mtDNA copy number and relative amount of mRNA for mitochondrial-related genes in individual rat oocytes, zygotes and embryos using real-time PCR. The average mtDNA copy

Yuichi Kameyama; France Filion; Jae Gyu Yoo; Lawrence C Smith

2007-01-01

96

Endotoxin Stimulates Liver Macrophages To Release Mediators That Inhibit an Early Step in Hepadnavirus Replication  

PubMed Central

Hepadnaviruses are known to be sensitive to various extracellular mediators. Therefore, bacterial endotoxin, which induces the secretion of proinflammatory mediators in the liver, was studied for its effect on hepadnavirus infection in vitro using the duck hepatitis B virus (DHBV) model. In initial experiments, endotoxin was shown to inhibit DHBV replication in primary duck hepatocyte cultures prepared by standard collagenase perfusion. As a primary endotoxin target, hepatic nonparenchymal cells (NPC) contaminating primary hepatocyte cultures, and among these probably macrophages (Kupffer cells), were identified to secrete polypeptide mediators into the cell culture medium. When added during DHBV infection, these mediators elicited the principal antiviral effect in a dose-dependent fashion. On the molecular level, they inhibited accumulation of viral proteins as well as amplification of the nuclear extrachromosomal DHBV DNA templates. In hepatocytes with an established DHBV infection, DHBV protein and progeny virus production was inhibited while the levels of established nuclear DHBV DNA templates and viral transcripts remained unaffected. Finally, in hepatocytes infected with a replication-deficient recombinant DHBV-green fluorescent protein (GFP) virus, the endotoxin-induced mediators markedly reduced GFP expression from chimeric DHBV-GFP transcripts, indicating that the major effect is at a level of translation of viral RNAs. Taken together, the data obtained demonstrate that antiviral mediators, and among these the cytokines alpha interferon (IFN-?) and IFN-?, are released from hepatic NPC, most probably liver macrophages, upon endotoxin stimulation; furthermore, these mediators act at a posttranscriptional step of hepadnavirus replication.

Klocker, Uta; Schultz, Ursula; Schaller, Heinz; Protzer, Ulrike

2000-01-01

97

The future is now: early life events preset adult behaviour.  

PubMed

To consider the evidence that human and animal behaviours are epigenetically programmed by lifetime experiences. Extensive PubMed searches were carried out to gain a broad view of the topic, in particular from the perspective of human psychopathologies such as mood and anxiety disorders. The selected literature cited is complemented by previously unpublished data from the authors' laboratories. Evidence that physiological and behavioural functions are particularly sensitive to the programming effects of environmental factors such as stress and nutrition during early life, and perhaps at later stages of life, is reviewed and extended. Definition of stimulus- and function-specific critical periods of programmability together with deeper understanding of the molecular basis of epigenetic regulation will deliver greater appreciation of the full potential of the brain's plasticity while providing evidence-based social, psychological and pharmacological interventions to promote lifetime well-being. PMID:23790203

Patchev, A V; Rodrigues, A J; Sousa, N; Spengler, D; Almeida, O F X

2014-01-01

98

Temperature variability and early clustering of record breaking events  

NASA Astrophysics Data System (ADS)

As the number of studies using record breaking statistics in climatology is growing rapidly, the criteria for choosing time period become essential. To that end, here we examine the evolution of monthly mean temperatures and its dependence on beginning and final year. Specifically, we use the variability index Alpha (Anderson and Kostinski, J, Appl. Met. and Clim., 2010) such that = 0 indicates no trend in variability. Generally, Alpha has decreased between 1900 and 2010 (indicating decreasing variability) for stations from the contiguous United States (United States Historical Climatology Network, version 2). We find, somewhat surprisingly, that the observed decrease is due to an early clustering of records. While detailed results depend on whether the data is gridded, detrended, etc., the general finding appears remarkably robust and holds globally as well.

Kostinski, A. B.; Anderson, A. L.

2012-12-01

99

The replication origin decision point is a mitogen-independent, 2-aminopurine-sensitive, G1-phase event that precedes restriction point control.  

PubMed Central

At a distinct point during G1 phase (the origin decision point [ODP]), Chinese hamster ovary (CHO) cell nuclei experience a transition (origin choice) that is required for specific recognition of the dihydrofolate reductase (DHFR) origin locus by Xenopus egg extracts. We have investigated the relationship between the ODP and progression of CHO cells through G1 phase. Selection of the DHFR origin at the ODP was rapidly inhibited by treatment of early G1-phase cells with the protein kinase inhibitor 2-aminopurine (2-AP). Inhibition of the ODP required administration of 2-AP at least 3 h prior to phosphorylation of the retinoblastoma tumor suppressor protein (Rb) and the restriction point (R point). Cells deprived of either serum or isoleucine from metaphase throughout early G1 phase acquired the capacity to replicate in Xenopus egg extract (replication licensing) and subsequently passed through the ODP on the same schedule as cells cultured in complete growth medium. After growth arrest at the R point with hypophosphorylated Rb protein, serum- or isoleucine-deprived cells experienced a gradual loss of replication licensing. However, recognition of the DHFR origin by Xenopus egg cytosol remained stable in growth-arrested cells until the point at which all nuclei had lost the capacity to initiate replication. These results provide evidence that the ODP requires a mitogen-independent protein kinase that is activated after replication licensing and prior to R-point control.

Wu, J R; Gilbert, D M

1997-01-01

100

Imaging early signaling events in T lymphocytes with fluorescent biosensors.  

PubMed

Many recent advances in our understanding of T lymphocyte functions in adaptive immunity are derived from sophisticated imaging techniques used to visualize T lymphocyte behavior in vitro and in vivo. A current challenge is to couple such imaging techniques with methods that will allow researchers to visualize signaling phenomenon at the single-cell level. Fluorescent biosensors, either synthetic or genetically encoded, are emerging as important tools for revealing the spatio-temporal regulation of intracellular biochemical events, such as specific enzyme activities or fluctuations in metabolites. In this review, we revisit the development of fluorescent Ca(2+) sensors with which the first experiments visualizing T lymphocyte activation at the single-cell were performed, and which have since become routine tools in immunology. We then examine a number of examples of how fluorescence resonance energy transfer (FRET)-based biosensors have been developed and applied to T lymphocyte migration, adhesion and T-cell receptor (TCR)-mediated signal transduction. These include the study of small GTPases such as RhoA, Rac and Rap1, the tyrosine kinases Lck and ZAP-70, and metabolites such as cAMP and Ca(2+) . Future development and use of biosensors should allow immunologists to reconcile the vast wealth of existing biochemical data concerning T-cell functions with the power of dynamic live-cell imaging. PMID:24166755

Randriamampita, Clotilde; Lellouch, Annemarie C

2014-02-01

101

Both Cyclin B levels and DNA-replication checkpoint control the early embryonic mitoses in Drosophila  

PubMed Central

Summary The earliest embryonic mitoses in Drosophila, as in other animals except mammals, are viewed as synchronous and of equal duration. However, we observed that total cell-cycle length steadily increases after cycle 7, solely owing to the extension of interphase. Between cycle 7 and cycle 10, this extension is DNA-replication checkpoint independent, but correlates with the onset of Cyclin B oscillation. In addition, nuclei in the middle of embryos have longer metaphase and shorter anaphase than nuclei at the two polar regions. Interestingly, sister chromatids move faster in anaphase in the middle than the posterior region. These regional differences correlate with local differences in Cyclin B concentration. After cycle 10, interphase and total cycle duration of nuclei in the middle of the embryo are longer than at the poles. Because interphase also extends in checkpoint mutant (grapes) embryo after cycle 10, although less dramatic than wild-type embryos, interphase extension after cycle 10 is probably controlled by both Cyclin B limitation and the DNA-replication checkpoint.

Ji, Jun-Yuan; Squirrell, Jayne M.; Schubiger, Gerold

2013-01-01

102

Early Low-Titer Neutralizing Antibodies Impede HIV1 Replication and Select for Virus Escape  

Microsoft Academic Search

Single genome sequencing of early HIV-1 genomes provides a sensitive, dynamic assessment of virus evolution and insight into the earliest anti-viral immune responses in vivo. By using this approach, together with deep sequencing, site-directed mutagenesis, antibody adsorptions and virus-entry assays, we found evidence in three subjects of neutralizing antibody (Nab) responses as early as 2 weeks post-seroconversion, with Nab titers

Katharine J. Bar; Chun-yen Tsao; Shilpa S. Iyer; Julie M. Decker; Yongping Yang; Mattia Bonsignori; Xi Chen; Kwan-Ki Hwang; David C. Montefiori; Hua-Xin Liao; Peter Hraber; William Fischer; Hui Li; Shuyi Wang; Sarah Sterrett; Brandon F. Keele; Vitaly V. Ganusov; Alan S. Perelson; Bette T. Korber; Ivelin Georgiev; Jason S. McLellan; Jeffrey W. Pavlicek; Feng Gao; Barton F. Haynes; Beatrice H. Hahn; Peter D. Kwong; George M. Shaw

2012-01-01

103

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

PubMed Central

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.

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

2013-01-01

104

Rare examples of early VLF events observed in association with ISUAL-detected gigantic jets  

NASA Astrophysics Data System (ADS)

We examine narrowband VLF observations and investigate the association of early VLF perturbations with gigantic jets recorded by the Imager of Sprites and Upper Atmospheric Lightnings (ISUAL) instrument aboard FORMOSAT-2. From its inception in 2004 to April 2013, the ISUAL instrument has recorded 90 gigantic jets using a triggered camera. Stanford VLF receivers located around the world are used to detect perturbations to VLF transmitter signals associated with lightning. While nine gigantic jet events occurred within 100 km of a VLF transmitter-receiver great circle path, only four early VLF events were detected in association with three ISUAL gigantic jets. One of these is a moderate event of 0.4 dB amplitude change, and the others are very small. The recovery time of these events are less than a couple of minutes and so do not constitute the "long recovery" early VLF events that have been postulated to be associated with gigantic jets. We speculate on possible explanations for the lack of other events on monitored paths, including a lack of significant ionization produced in the D region ionosphere by the gigantic jet event, weak transmitter signals recorded by the receivers, or mode effects on transmitter paths.

Marshall, R. A.; Adachi, T.; Hsu, R.-R.; Chen, A. B.

2014-01-01

105

Early Intervention Project: Can Its Claims Be Substantiated and Its Effects Replicated?  

Microsoft Academic Search

A comprehensive report to the National Institute of Health on the diagnosis, etiology, epidemiology, and treatment of autism indicated that early intervention has the potential of being an effective intervention (Bristol et al., 1996). In spite of this positive outlook, several research and methodological questions remain regarding time of treatment initiation, intensity of treatment and duration of treatment, random assignment,

Frank M. Gresham; Donald L. MacMillan

1998-01-01

106

Replication Evidence in Support of the Psychometric Properties of the Devereux Early Childhood Assessment  

ERIC Educational Resources Information Center

The Devereux Early Childhood Assessment (DECA) was developed to assess the social-emotional functioning of preschool children. The developers of the DECA report initial validity and reliability evidence in support of the use of the instrument with 2- to 5-year-old children across the United States. There is further need to collect independent…

Jaberg, Peter E.; Dixon, David J.; Weis, Glenna M.

2009-01-01

107

Replication forks and replication checkpoints in repair  

Microsoft Academic Search

Eukaryotic cells replicate their DNA and coordinate their response to DNA damage and replication\\u000a blocks by activating appropriate repair processes, regulating recombination, chromatin assembly and\\u000a chromosome partitioning. Replication forks stall at specific problematic genomic regions, and forks\\u000a collapse unless protected by replication checkpoint proteins. These events have been associated with\\u000a recombination and chromosomal rearrangements that lead to genomic instability and

Dana Branzei; Marco Foiani

108

Early replication timing of the chicken alpha-globin gene domain correlates with its open chromatin state in cells of different lineages.  

PubMed

The vertebrate alpha-globin gene domain is an open chromatin domain overlapping a neighboring house-keeping gene. The tissue-specific cluster of alpha-globin genes and the overlapping housekeeping gene share the same replication origin. We have studied the replication timing of chicken alpha-globin genes in cells of different lineages using the FISH-based approach and found that alpha-globin genes replicate early both in erythroid and in non-erythroid cells, i.e. regardless of their transcriptional activity. Early replication timing of chicken alpha-globin genes in cells of different lineages was in good correlation with the open chromatin configuration of the alpha-globin gene domain in both erythroid and non-erythroid cells. We propose that active transcription of the housekeeping gene overlapping the alpha-globin gene domain enables an access of Origin Recognition Complex (ORC) proteins to the replication origin resulting in early replication of alpha-globin genes even in non-erythroid cells. PMID:19187796

Klochkov, Denis B; Gavrilov, Alexey A; Vassetzky, Yegor S; Razin, Sergey V

2009-05-01

109

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

PubMed

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

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

110

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

PubMed Central

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.

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

111

Replication Evidence in Support of the Psychometric Properties of the Devereux Early Childhood Assessment  

Microsoft Academic Search

The Devereux Early Childhood Assessment (DECA) was developed to assess the social-emotional functioning of preschool children. The developers of the DECA report initial validity and reliability evidence in support of the use of the instrument with 2- to 5-year-old children across the United States. There is further need to collect independent validity and reliability evidence in support of the use

Peter E. Jaberg; David J. Dixon; Glenna M. Weis

2009-01-01

112

A Further Extension of the Tahiti-Darwin SOI, Early ENSO Events and Darwin Pressure  

Microsoft Academic Search

An extension of the Tahiti minus Darwin Southern Oscillation Index (SOI) from 1882 back to 1876 is reported following the recovery of early Darwin mean sea-level pressure data spanning the period 1865-81. As a result, we are able to compare, for the first time, the major 1877-78 and 1982-83 ENSO events on the basis of this commonly used index. Early

Robert J. Allan; Neville Nicholls; Phil D. Jones; Ian J. Butterworth

1991-01-01

113

Evidence for an early pliocene cold event in the southern oceans  

SciTech Connect

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.

Burckle, L.H.; Mortlock, R.A. (Columbia Univ., Palisades, NY (United States)); Rudolph, S. (State Univ. of New York, Oswego, NY (United States))

1993-01-01

114

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

NASA Astrophysics Data System (ADS)

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 Radiometer—EOS (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.

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

2013-03-01

115

Early Reproductive Events and Breast Cancer: Workshop Agenda, February 24-26, 2003  

Cancer.gov

Updated: 02/26/2003 Updated: 02/26/2003 Early Reproductive Events and Breast Cancer: Workshop Agenda, February 24-26, 2003 Co-Moderators: Martin Abeloff, M.D., Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Carolyn Runowicz, M.D., University

116

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

ERIC Educational Resources Information Center

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,…

Rice, Judith Anne

117

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

ERIC Educational Resources Information Center

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…

National Scientific Council on the Developing Child, 2006

2006-01-01

118

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

NASA Astrophysics Data System (ADS)

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.

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

2013-12-01

119

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

NASA Astrophysics Data System (ADS)

We performed a series of three replicated field scale irrigation experiments.We examined the link between irrigation, flow paths, and pesticide transport.Irrigation amount and soil moisture threshold control solute transport.We observed remobilization of stored pesticides occurring together with soil water mobilization.

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

120

Identifying early events of gene expression in breast cancer with systems biology phylogenetics.  

PubMed

Advanced omics technologies such as deep sequencing and spectral karyotyping are revealing more of cancer heterogeneity at the genetic, genomic, gene expression, epigenetic, proteomic, and metabolomic levels. With this increasing body of emerging data, the task of data analysis becomes critical for mining and modeling to better understand the relevant underlying biological processes. However, the multiple levels of heterogeneity evident within and among populations, healthy and diseased, complicate the mining and interpretation of biological data, especially when dealing with hundreds to tens of thousands of variables. Heterogeneity occurs in many diseases, such as cancers, autism, macular degeneration, and others. In cancer, heterogeneity has hampered the search for validated biomarkers for early detection, and it has complicated the task of finding clonal (driver) and nonclonal (nonexpanded or passenger) aberrations. We show that subtyping of cancer (classification of specimens) should be an a priori step to the identification of early events of cancers. Studying early events in oncogenesis can be done on histologically normal tissues from diseased individuals (HNTDI), since they most likely have been exposed to the same mutagenic insults that caused the cancer in their neighboring tissues. Polarity assessment of HNTDI data variables by using healthy specimens as outgroup(s), followed by the application of parsimony phylogenetic analysis, produces a hierarchical classification of specimens that reveals the early events of the disease ontogeny within its subtypes as shared derived changes (abnormal changes) or synapomorphies in phylogenetic terminology. PMID:23548567

Abu-Asab, M S; Abu-Asab, N; Loffredo, C A; Clarke, R; Amri, H

2013-01-01

121

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

NASA Astrophysics Data System (ADS)

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; Gröcke 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 (Föllmi 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 Parañà-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 (Föllmi 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. Föllmi, 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

Morales, Chloé; Schnyder, Johann; Spangenberg, Jorge; Adatte, Thierry; Westermann, Stephane; Föllmi, Karl

2010-05-01

122

Energetic Particle Cross-field Propagation Early in a Solar Event  

NASA Astrophysics Data System (ADS)

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.

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

2013-08-01

123

Impact of LIP formation on marine productivity during early Aptian and latest Cenomanian Oceanic Anoxic Events  

Microsoft Academic Search

Of all the Cretaceous Oceanic Anoxic Events (OAEs), the Early Aptian OAE1a and latest Cenomanian OAE2 are truly global in nature and typically represented by carbonate crisis and Corg-rich black shales. They correlate with onset and climax of the mid-Cretaceous greenhouse, a time of exceptional warmth with accelerated burial of organic matter, carbon and strontium isotope excursions, and major biotic

E. Erba; R. Duncan

2003-01-01

124

Anti-radical power gives insight into early lipid oxidation events during frying  

Microsoft Academic Search

The aim of this research was to use anti-radical power (ARP) to study early lipid oxidation events during frying. The 2,2-diphenyl-1-picrylhydrazyl radical (DPPH¿) test was used to determine the ARP. As oil does not dissolve completely in methanol, which is generally used for the DPPH¿ test, butanol was used instead. Changing the solvent did not influence the value of the

Wil AM van Loon; Jozef PH Linssen; Aagje Legger; Alphons GJ Voragen

2006-01-01

125

Thymidine Kinase 1 Upregulation Is an Early Event in Breast Tumor Formation  

PubMed Central

Prognostic markers play an important role in our understanding of tumors and how to treat them. Thymidine kinase 1 (TK1), a proliferation marker involved in DNA repair, has been shown to have independent prognostic potential. This prognostic potential includes the novel concept that upregulation of serum TK1 levels is an early event in cancer development. This same effect may also be seen in tumor tissue. In order to demonstrate that TK1 upregulation is an early event in tumor tissue formation, tissue arrays were obtained and stained for TK1 by immunohistochemistry. Using a progressive breast tissue array, precancerous tissue including breast adenosis, simple hyperplasia, and atypical hyperplasia stained positive for TK1 expression. Different stages of breast carcinoma tissue also stained positive for TK1 including nonspecific infiltrating duct, infiltrating lobular, and infiltrating duct with lymph node metastasis carcinomas. This indicates that TK1 upregulation is an early event in breast carcinoma development, and may be useful in identifying precancerous tissue. Further work is needed to better understand the differences seen between TK1 positive and negative tissues.

Alegre, Melissa M.; Robison, Richard A.; O'Neill, Kim L.

2012-01-01

126

Polyomavirus JC in the Context of Immunosuppression: A Series of Adaptive, DNA Replication-Driven Recombination Events in the Development of Progressive Multifocal Leukoencephalopathy  

PubMed Central

Polyomavirus JC (JCV) is the etiological agent of progressive multifocal leukoencephalopathy (PML), a demyelinating infection of oligodendrocytes in the brain. PML, a frequently fatal opportunistic infection in AIDS, has also emerged as a consequence of treatment with several new immunosuppressive therapeutic agents. Although nearly 80% of adults are seropositive, JCV attains an ability to infect glial cells in only a minority of people. Data suggest that JCV undergoes sequence alterations that accompany this ability, and these changes can be derived from an archetype strain by mutation, deletion, and duplication. While the introductory source and primary tissue reservoir of JCV remain unknown, lymphoid cells have been identified as potential intermediaries in progression of JCV to the brain. This review is focused on sequence changes in the noncoding control region (NCCR) of the virus. We propose an adaptive mechanism that involves a sequential series of DNA replication-driven NCCR recombination events involving stalled DNA replication forks at NCCR palindromic secondary structures. We shall describe how the NCCR sequence changes point to a model in which viral DNA replication drives NCCR recombination, allowing JCV adaptation to different cell types in its progression to neurovirulence.

Johnson, Edward M.; Wortman, Margaret J.; Dagdanova, Ayuna V.; Lundberg, Patric S.; Daniel, Dianne C.

2013-01-01

127

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

PubMed Central

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 helix’s 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.

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

2012-01-01

128

Human Cytomegalovirus Replicates Abortively in Polymorphonuclear Leukocytes after Transfer from Infected Endothelial Cells via Transient Microfusion Events  

Microsoft Academic Search

Using a recently developed model for in vitro generation of pp65-positive polymorphonuclear leukocytes (PMNLs), we demonstrated that PMNLs from immunocompetent subjects may harbor both infectious hu- man cytomegalovirus (HCMV) and viral products (pp65, p72, DNA, and immediate-early (IE) and pp67 late mRNAs) as early as 60 min after coculture with human umbilical vein endothelial cells (HUVEC) or human embryonic lung

GIUSEPPE GERNA; ELENA PERCIVALLE; FAUSTO BALDANTI; SILVANO SOZZANI; P. Lanzarini; E. Genini; D. Lilleri; M. G. Revello

2000-01-01

129

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

NASA Astrophysics Data System (ADS)

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.

Allen, R. M.; Kanamori, H.

2001-12-01

130

Early events triggering delayed vasoconstrictor receptor upregulation and cerebral ischemia after subarachnoid hemorrhage  

PubMed Central

Background Upregulation of vasoconstrictor receptors in cerebral arteries, including endothelin B (ETB) and 5-hydroxytryptamine 1B (5-HT1B) receptors, has been suggested to contribute to delayed cerebral ischemia, a feared complication after subarachnoid hemorrhage (SAH). This receptor upregulation has been shown to be mediated by intracellular signalling via the mitogen activated protein kinase kinase (MEK1/2) - extracellular regulated kinase 1/2 (ERK1/2) pathway. However, it is not known what event(s) that trigger MEK-ERK1/2 activation and vasoconstrictor receptor upregulation after SAH. We hypothesise that the drop in cerebral blood flow (CBF) and wall tension experienced by cerebral arteries in acute SAH is a key triggering event. We here investigate the importance of the duration of this acute CBF drop in a rat SAH model in which a fixed amount of blood is injected into the prechiasmatic cistern either at a high rate resulting in a short acute CBF drop or at a slower rate resulting in a prolonged acute CBF drop. Results We demonstrate that the duration of the acute CBF drop is determining for a) degree of early ERK1/2 activation in cerebral arteries, b) delayed upregulation of vasoconstrictor receptors in cerebral arteries and c) delayed CBF reduction, neurological deficits and mortality. Moreover, treatment with an inhibitor of MEK-ERK1/2 signalling during an early time window from 6 to 24 h after SAH was sufficient to completely prevent delayed vasoconstrictor receptor upregulation and improve neurological outcome several days after the SAH. Conclusions Our findings suggest a series of events where 1) the acute CBF drop triggers early MEK-ERK1/2 activation, which 2) triggers the transcriptional upregulation of vasoconstrictor receptors in cerebral arteries during the following days, where 3) the resulting enhanced cerebrovascular contractility contribute to delayed cerebral ischemia.

2013-01-01

131

Autobiographical memory of adolescence and early adulthood events: an investigation in schizophrenia.  

PubMed

The reminiscence bump corresponds to a marked increase in autobiographical memories of events that occurred when normal people were aged 10 to 30 years, a critical period for the formation of identity. The reminiscence bump was studied in 27 patients diagnosed with schizophrenia and 27 control participants. They were asked to recall 20 specific autobiographical events that had occurred during their lifetime and to indicate the subjective states of awareness associated with the recalled memories using the Remember/Know procedure. Finally, participants were asked to state whether recalled memories related to private or public events. Patients diagnosed with schizophrenia recalled less specific memories than controls and exhibited an earlier reminiscence bump. They recalled more public, and less private events than controls, and they gave fewer Remember responses. The reminiscence bump peaked in the 16 to 25-year period for patients and the 21 to 25-year period for controls. These findings indicate that patients diagnosed with schizophrenia exhibit an early and abnormal reminiscence bump, with an impairment of conscious recollection associated with memories highly relevant to personal identity. They suggest that schizophrenia is associated with an impairment of autobiographical memories of events that had occurred during the last stage of personal identity development. PMID:17286890

Cuervo-Lombard, Christine; Jovenin, Nicolas; Hedelin, Guy; Rizzo-Peter, Lydia; Conway, Martin A; Danion, Jean-Marie

2007-03-01

132

Genetic and epigenetic changes in mammary epithelial cells may mimic early events in carcinogenesis.  

PubMed

Studies of human mammary epithelial cells from healthy individuals are providing novel insights into how early epigenetic and genetic events affect genomic integrity and fuel carcinogenesis. Key epigenetic changes, such as the hypermethylation of the p16 (INK4a) promoter sequences, create a previously unappreciated preclonal phase of tumorigenesis in which a subpopulation of mammary epithelial cells are positioned for progression to malignancy (Romanov et al. , 2001, Nature , 409:633-637; Tlsty et al. , 2001, J. Mammary Gland Biol. Neoplasia , 6:235-243). These key changes precede the clonal outgrowth of premalignant lesions and occur frequently in healthy, disease-free women. Understanding more about these early events should provide novel molecular candidates for prevention and therapy of breast cancer that target the process instead of the consequences of genomic instability. This review will highlight some of the key alterations that have been studied in human mammary epithelial cells in culture and relate them to events observed in vivo and discussed in accompanying reviews in this volume. PMID:15557799

Tlsty, Thea D; Crawford, Yongping G; Holst, Charles R; Fordyce, Colleen A; Zhang, Jianmin; McDermott, Kimberly; Kozakiewicz, Krystyna; Gauthier, Mona L

2004-07-01

133

A capillary cytometer method to quantitate viable virus particles based on early detection of viral antigens and cellular events within single cells.  

PubMed

The traditional plaque forming and TCID(50) methods to determine replication competent virus titres rely on several cycles of replication and infection to generate a plaque with an incubation period of 24-72 h post-infection typically required. We developed a method to quantify infective viral particles based on early detection of cellular events by capillary cytometry. The method uses a capillary cytometer as a precise cell counter that can discriminate infected from non-infected cells. The general protocol was developed using a Guava PCA, genetically modified HSV-1 virus and polyclonal antibodies against antigens expressed on the cell membrane. Infection was detected after 1 h incubation and a plateau in the number of infected cells was observed between 7 and 9 h. A good correlation between titres obtained by the plaque forming method and the proposed method was observed for a ratio of infected to total cells between 0.5 and 0.05. The rapid and automated analysis (10 s/1000 events acquired per sample) makes the method particularly useful for high-throughput applications. The proposed method can be extended easily to determine the titre of other viruses providing a powerful tool for virology and antiviral screening. PMID:16854472

Pheasey, Nigel; John, Justin; Love, Colin; Coffin, Rob; Ward, John M; Boushaba, Rihab; Hoare, Mike; Levy, M Susana

2006-11-01

134

EO/IR satellite constellations for the early detection and tracking of collision events  

NASA Astrophysics Data System (ADS)

The detection and tracking of collision events involving existing Low Earth Orbit (LEO) Resident Space Objects (RSOs) is becoming increasingly important with the higher LEO space objects traffic volume which is anticipated to increase even further in the near future. Changes in velocity that can lead to a collision are hard to detect early on time, and before the collision happens. Several collision events can happen at the same time and continuous monitoring of the LEO orbit is necessary in order to determine and implement collision avoidance strategies. We present a simulation of a constellation system consisting of multiple platforms carrying EO/IR sensors for the detection of such collisions. The presented simulation encompasses the full complexity of LEO trajectories changes which can collide with currently operating satellites. Efficient multitarget filter with information-theoretic multisensor management is implemented and evaluated on different constellations.

Zatezalo, A.; El-Fallah, A.; Mahler, R.; Mehra, R. K.; Pham, K.

2010-04-01

135

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

PubMed Central

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

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

2013-01-01

136

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

NASA Astrophysics Data System (ADS)

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.

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

2014-05-01

137

Visualizing Lipid Raft Dynamics and Early Signaling Events during Antigen Receptor-mediated B-Lymphocyte Activation  

Microsoft Academic Search

Recent biochemical evidence indicates that an early event in signal transduction by the B-cell antigen receptor (BCR) is its translocation to specialized membrane subdomains known as lipid rafts. We have taken a microscopic approach to image lipid rafts and early events associated with BCR signal transduction. Lipid rafts were visualized on primary splenic B lymphocytes from wild-type or anti-hen egg

Neetu Gupta; Anthony L. DeFranco

2003-01-01

138

On the earliest record of Cretaceous tyrannosauroids in western North America: implications for an Early Cretaceous Laurasian interchange event  

Microsoft Academic Search

The sudden appearance of Asian dinosaur clades within Lower Cretaceous strata of western North America has long been recognised as a biotic dispersion event related to initial establishment of a Beringian land bridge. To date, uncertainty exists regarding the timing of the Early Cretaceous Laurasian interchange event (EKLInE) and the pattern of associated biotic dispersal. Here, we report a tyrannosauroid

Lindsay E. Zanno; Peter J. Makovicky

2011-01-01

139

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

NASA Astrophysics Data System (ADS)

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.

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

2013-08-01

140

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

PubMed Central

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.

1984-01-01

141

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

NASA Astrophysics Data System (ADS)

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

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

2014-06-01

142

Early events in protein folding: Is there something more than hydrophobic burst?  

PubMed Central

The presence of native contacts in the denatured state of many proteins suggests that elements of the biologically active structure of these molecules are formed during the initial stage of the folding process. The rapidity with which these events take place makes it difficult to study them in vitro, but, by the same token, suitable for studies in silico. With the help of all-atom, explicit solvent, molecular dynamics simulations we have followed in time, starting from elongated structureless conformations, the early events in the folding of src-SH3 domain and of proteins G, L, and CI2. It is observed that within the first 50 ns two important events take place, essentially independent of each other: hydrophobic collapse and formation of a few selected native contacts. The same contacts are also found in simulations carried out in the presence of guanidinium chloride in order to reproduce the conditions used to characterize experimentally the denatured state and testify to the fact that these contacts are to be considered a resilient characterizing property of the denaturated state.

Camilloni, Carlo; Sutto, Ludovico; Provasi, Davide; Tiana, Guido; Broglia, Ricardo A.

2008-01-01

143

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

ERIC Educational Resources Information Center

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…

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

2012-01-01

144

Dysregulation of glucose metabolism is an early event in sporadic Parkinson's disease?  

PubMed Central

Unlike most other cell types, neurons preferentially metabolize glucose via the pentose phosphate pathway (PPP) to maintain their antioxidant status. Inhibiting the PPP in neuronal cell models causes cell death. In rodents, inhibition of this pathway causes selective dopaminergic cell death leading to motor deficits resembling parkinsonism. Using postmortem human brain tissue, we characterized glucose metabolism via the PPP in sporadic Parkinson's disease (PD), Alzheimer's disease (AD), and controls. AD brains showed increased nicotinamide adenine dinucleotide phosphate (NADPH) production in areas affected by disease. In PD however, increased NADPH production was only seen in the affected areas of late-stage cases. Quantifying PPP NADPH-producing enzymes glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase by enzyme-linked immunosorbent assay, showed a reduction in the putamen of early-stage PD and interestingly in the cerebellum of early and late-stage PD. Importantly, there was no decrease in enzyme levels in the cortex, putamen, or cerebellum of AD. Our results suggest that down-regulation of PPP enzymes and a failure to increase antioxidant reserve is an early event in the pathogenesis of sporadic PD.

Dunn, Laura; Allen, George FG.; Mamais, Adamantios; Ling, Helen; Li, Abi; Duberley, Kate E.; Hargreaves, Iain P.; Pope, Simon; Holton, Janice L.; Lees, Andrew; Heales, Simon J.; Bandopadhyay, Rina

2014-01-01

145

Immunological and Virological Events in Early HIV Infection Predict Subsequent Rate of Progression  

PubMed Central

Background Variability in HIV disease progression cannot fully be predicted by CD4 T-cell counts or viral load. Because central memory T cells (TCM) play a critical role in the pathogenesis of SIV disease, we hypothesized that quantifying these cells in early HIV-infection could provide prognostic information. Methods We measured expression of CD45RO, CCR5, CCR7, CD27, and CD28 to enumerate naïve and memory subsets in samples from recently-infected individuals. We also quantified proliferation, CD127 expression, and cell-associated viral load. Disease progression was compared across subgroups defined by these measurements, using Kaplan-Meier survival curves and multivariate Cox proportional hazards regression. Results 466 subjects contributed 101 events. The proportion or absolute count of TCM did not correlate with disease progression, defined as the time to AIDS or death. However, significant associations were observed for: proliferation within CD4 or CD8 T cells, loss of naïve or CD127+ CD8 T cells, and CD4 cell-associated proviral load. Conclusion Our results demonstrate that the extent of the immunopathogenesis established early in HIV infection predicts the course of future disease. Since antiretroviral drug treatment reverses such defects in part, our study provides mechanistic clues to why early use of antiretrovirals may prove beneficial.

Ganesan, Anuradha; Chattopadhyay, Pratip K.; Brodie, Tess M.; Qin, Jing; Gu, Wenjuan; Mascola, John R.; Michael, Nelson L.; Follmann, Dean A.; Roederer, Mario

2009-01-01

146

The herpes simplex virus immediate-early protein, ICP4, is required to potentiate replication of human immunodeficiency virus in CD4+ lymphocytes.  

PubMed Central

The interaction of human immunodeficiency virus (HIV) and herpes simplex virus (HSV) was investigated in an acute whole-virus coinfection system. CD4+ lymphoid CEM cells were infected with HIV-1 and, 24 h later, superinfected with HSV-1 (strain KOS) or HSV mutants possessing defined deletions in genes specifying the immediate-early transcriptional regulatory proteins ICP0, ICP4, or ICP27. Marked potentiation of HIV replication was demonstrated with the KOS strain, the ICP0 mutant, and the ICP27 mutant, but not with the ICP4 mutant, indicating that ICP4 is essential and ICP0 and ICP27 are nonessential for this effect. These studies demonstrate that HSV can be a potent stimulator of HIV replication and gene expression in coinfected CD4+ cells through the activity of the HSV regulatory protein ICP4.

Albrecht, M A; DeLuca, N A; Byrn, R A; Schaffer, P A; Hammer, S M

1989-01-01

147

In Vivo Replication of Recombinant Murine Cytomegalovirus Driven by the Paralogous Major Immediate-Early Promoter-Enhancer of Human Cytomegalovirus  

PubMed Central

Transcription of the major immediate-early (MIE) genes of cytomegaloviruses (CMV) is driven by a strong promoter-enhancer (MIEPE) complex. Transactivator proteins encoded by these MIE genes are essential for productive infection. Accordingly, the MIEPE is a crucial control point, and its regulation by activators and repressors is pertinent to virus replication. Since the MIEPE contains multiple regulatory elements, it was reasonable to assume that specific sequence motifs are irreplaceable for specifying the cell-type tropism and replication pattern. Recent work on murine CMV infectivity (A. Angulo, M. Messerle, U. H. Koszinowski, and P. Ghazal, J. Virol. 72:8502–8509, 1998) has documented the proposed enhancing function of the enhancer in that its resection or its replacement by a nonregulatory stuffer sequence resulted in a significant reduction of infectivity, even though replication competence was maintained by a basal activity of the spared authentic MIE promoter. Notably, full capacity for productive in vitro infection of fibroblasts was restored in recombinant viruses by the human CMV enhancer. Using two-color in situ hybridization with MIEPE-specific polynucleotide probes, we demonstrated that a murine CMV recombinant in which the complete murine CMV MIEPE is replaced by the paralogous human CMV core promoter and enhancer (recombinant virus mCMVhMIEPE) retained the potential to replicate in vivo in all tissues relevant to CMV disease. Notably, mCMVhMIEPE was also found to replicate in the liver, a site at which transgenic hCMV MIEPE is silenced. We conclude that productive in vivo infection with murine CMV does not strictly depend on a MIEPE type-specific regulation.

Grzimek, Natascha K. A.; Podlech, Jurgen; Steffens, Hans-Peter; Holtappels, Rafaela; Schmalz, Susanne; Reddehase, Matthias J.

1999-01-01

148

An Early Warning System for Hypoglycemic/Hyperglycemic Events Based on Fusion of Adaptive Prediction Models  

PubMed Central

Introduction Early warning of future hypoglycemic and hyperglycemic events can improve the safety of type 1 diabetes mellitus (T1DM) patients. The aim of this study is to design and evaluate a hypoglycemia/hyperglycemia early warning system (EWS) for T1DM patients under sensor-augmented pump (SAP) therapy. Methods The EWS is based on the combination of data-driven online adaptive prediction models and a warning algorithm. Three modeling approaches have been investigated: (i) autoregressive (ARX) models, (ii) auto-regressive with an output correction module (cARX) models, and (iii) recurrent neural network (RNN) models. The warning algorithm performs postprocessing of the models? outputs and issues alerts if upcoming hypoglycemic/hyperglycemic events are detected. Fusion of the cARX and RNN models, due to their complementary prediction performances, resulted in the hybrid autoregressive with an output correction module/recurrent neural network (cARN)-based EWS. Results The EWS was evaluated on 23 T1DM patients under SAP therapy. The ARX-based system achieved hypoglycemic (hyperglycemic) event prediction with median values of accuracy of 100.0% (100.0%), detection time of 10.0 (8.0) min, and daily false alarms of 0.7 (0.5). The respective values for the cARX-based system were 100.0% (100.0%), 17.5 (14.8) min, and 1.5 (1.3) and, for the RNN-based system, were 100.0% (92.0%), 8.4 (7.0) min, and 0.1 (0.2). The hybrid cARN-based EWS presented outperforming results with 100.0% (100.0%) prediction accuracy, detection 16.7 (14.7) min in advance, and 0.8 (0.8) daily false alarms. Conclusion Combined use of cARX and RNN models for the development of an EWS outperformed the single use of each model, achieving accurate and prompt event prediction with few false alarms, thus providing increased safety and comfort.

Daskalaki, Elena; N?rgaard, Kirsten; Zuger, Thomas; Prountzou, Aikaterini; Diem, Peter; Mougiakakou, Stavroula

2013-01-01

149

Early event of protein folding studied by time-resolved photoacoustic calorimetry  

NASA Astrophysics Data System (ADS)

Recently, various methods including temperature jump and hydro-dynamics focusing have been used to study early event of protein folding. In this paper, we propose to use time-resolved photoacoustic (PAC) to study protein folding from nanoseconds to microseconds. The experiment use photolabile linkers to "cage" proteins or peptide systems that differ from their native equilibrium structures. Pulse laser was used to break the photolabile linker and initiate the refolding of the protein toward its native state. This novel method is very different from denature and temperature jump experiments because folding can start from a well-defined initial state. An acoustic microphone was used to detect the folding induced heat and volume changes of b-sheet peptides and mutants. Time-resolved PAC provides a new method to directly probe the folding funnel energy landscape.

Fann, Wunshain; Chen, Hsin-Liang; Huang, Jen-Tse; Chen, Pei-Yeh R.; Tien Lee, Chung; Chan, Sunney I.

2003-03-01

150

Accuracy of episodic autobiographical memory in children with early thyroid hormone deficiency using a staged event.  

PubMed

Autobiographical memory (AM) is a highly constructive cognitive process that often contains memory errors. No study has specifically examined AM accuracy in children with abnormal development of the hippocampus, a crucial brain region for AM retrieval. Thus, the present study investigated AM accuracy in 68 typically and atypically developing children using a staged autobiographical event, the Children's Autobiographical Interview, and structural magnetic resonance imaging. The atypically developing group consisted of 17 children (HYPO) exposed during gestation to insufficient maternal thyroid hormone (TH), a critical substrate for hippocampal development, and 25 children with congenital hypothyroidism (CH), who were compared to 26 controls. Groups differed significantly in the number of accurate episodic details recalled and proportion accuracy scores, with controls having more accurate recollections of the staged event than both TH-deficient groups. Total hippocampal volumes and anterior hippocampal volumes were positively correlated with proportion accuracy scores, but not total accurate episodic details, in HYPO and CH. In addition, greater severity of TH deficiency predicted lower proportion accuracy scores in both HYPO and CH. Overall, these results indicate that children with early TH deficiency have deficits in AM accuracy and that the anterior hippocampus may play a particularly important role in accurate AM retrieval. PMID:24462783

Willoughby, Karen A; McAndrews, Mary Pat; Rovet, Joanne F

2014-07-01

151

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

NASA Astrophysics Data System (ADS)

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.

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

1995-08-01

152

Early event-related brain potentials that reflect interest for content information in the media.  

PubMed

This study investigated the relationship between event-related brain potentials (ERPs) to abridged content information in the media and the subsequent decisions to view the full content. Student volunteers participated in a task that simulated information selection on the basis of the content information. Screenshots of television clips and headlines of news articles on the Web were used as content information for the image condition and the headline condition, respectively. Following presentation of a stimulus containing content information, participants decided whether or not they would view the full content by pressing a select or a reject button. When the select button was pressed, participants were presented with a television clip or a news article. When the reject button was pressed, participants continued on to the next trial, without viewing further. In comparison with rejected stimuli, selected stimuli elicited a larger negative component, with a peak latency of ?250 ms. The increase in the negative component was independent of the type of visual stimulus. These results suggest that interest toward content information is reflected in early-stage event-related brain potential responses. PMID:22336875

Adachi, Shinobu; Morikawa, Koji; Nittono, Hiroshi

2012-03-28

153

New Early Jurassic Tetrapod Assemblages Constrain Triassic-Jurassic Tetrapod Extinction Event  

NASA Astrophysics Data System (ADS)

The discovery of the first definitively correlated earliest Jurassic (200 million years before present) tetrapod assemblage (Fundy basin, Newark Supergroup, Nova Scotia) allows reevaluation of the duration of the Triassic-Jurassic tetrapod extinction event. Present are tritheledont and mammal-like reptiles, prosauropod, theropod, and ornithischian dinosaurs, protosuchian and sphenosuchian crocodylomorphs, sphenodontids, and hybodont, semionotid, and palaeonisciform fishes. All of the families are known from Late Triassic and Jurassic strata from elsewhere; however, pollen and spore, radiometric, and geochemical correlation indicate an early Hettangian age for these assemblages. Because all ``typical Triassic'' forms are absent from these assemblages, most Triassic-Jurassic tetrapod extinctions occurred before this time and without the introduction of new families. As was previously suggested by studies of marine invertebrates, this pattern is consistent with a global extinction event at the Triassic-Jurassic boundary. The Manicouagan impact structure of Quebec provides dates broadly compatible with the Triassic-Jurassic boundary and, following the impact theory of mass extinctions, may be implicated in the cause.

Olsen, P. E.; Shubin, N. H.; Anders, M. H.

1987-08-01

154

Replication and Control of Circular Bacterial Plasmids  

PubMed Central

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.

del Solar, Gloria; Giraldo, Rafael; Ruiz-Echevarria, Maria Jesus; Espinosa, Manuel; Diaz-Orejas, Ramon

1998-01-01

155

Brain Event-Related Potentials: Diagnosing Early-Stage Alzheimer's Disease  

PubMed Central

A pattern of components from brain Event-Related Potentials (ERP) (cognitive non-invasive electrical brain measures) performed well in separating early-stage Alzheimer’s disease (AD) subjects from normal-aging control subjects and shows promise for developing a clinical diagnostic for Probable AD. A Number-Letter task elicited brain activity related to cognitive processes. In response to the task stimuli, brain activity was recorded as ERPs, whose components were measured by Principal Components Analysis (PCA). The ERP component scores to relevant and irrelevant stimuli were used in Discriminant Analyses to develop functions that successfully classified individuals as belonging to an early-stage Alzheimer’s disease group or a like-aged Control group, with probabilities of an individual belonging to each group. Applying the discriminant function to the developmental half of the data showed 92% of the subjects were correctly classified into either the AD group or the Control group with a sensitivity of 1.00. The two crossvalidation results were good with sensitivities of 0.83 and classification accuracies of 0.75–0.79. P3 and CNV components, as well as other, earlier ERP components, e.g. C145 and the memory “Storage” component, were useful in the discriminant functions.

Chapman, Robert M.; Nowlis, Geoffrey H.; McCrary, John W.; Chapman, John A.; Sandoval, Tiffany C.; Guillily, Maria D.; Gardner, Margaret N.; Reilly, Lindsey A.

2009-01-01

156

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

SciTech Connect

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.

Tekpli, Xavier; Rissel, Mary; Huc, Laurence [EA 4427 SeRAIC, Equipe labellisee Ligue contre le Cancer, Universite de Rennes 1, IFR 140, 35043 Rennes cedex (France); Catheline, Daniel [Laboratoire de Biochimie, INRA-Agrocampus Rennes, 35042 Rennes (France); Sergent, Odile [EA 4427 SeRAIC, Equipe labellisee Ligue contre le Cancer, Universite de Rennes 1, IFR 140, 35043 Rennes cedex (France); Rioux, Vincent; Legrand, Philippe [Laboratoire de Biochimie, INRA-Agrocampus Rennes, 35042 Rennes (France); Holme, Jorn A. [Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 404 Torshov, N-4303 Oslo (Norway); Dimanche-Boitrel, Marie-Therese [EA 4427 SeRAIC, Equipe labellisee Ligue contre le Cancer, Universite de Rennes 1, IFR 140, 35043 Rennes cedex (France); Lagadic-Gossmann, Dominique, E-mail: dominique.lagadic@univ-rennes1.f [EA 4427 SeRAIC, Equipe labellisee Ligue contre le Cancer, Universite de Rennes 1, IFR 140, 35043 Rennes cedex (France)

2010-02-15

157

Apoptosis induced in an early step of African swine fever virus entry into vero cells does not require virus replication.  

PubMed

Permissive Vero cells develop apoptosis, as characterized by DNA fragmentation, caspases activation, cytosolic release of mitochondrial cytochrome c, and flow cytometric analysis of DNA content, upon infection with African swine fever virus (ASFV). To determine the step in virus replication that triggers apoptosis, we used UV-inactivated virus, inhibitors of protein and nucleic acid synthesis, and lysosomotropic drugs that block virus uncoating. ASFV-induced apoptosis was accompanied by caspase-3 activation, which was detected even in the presence of either cytosine arabinoside or cycloheximide, indicating that viral DNA replication and protein synthesis were not required to activate the apoptotic process. The activation of caspase-3 was released from chloroquine inhibition 2 h after virus absorption, while the infection with UV-inactivated ASFV did not induce the activation of the caspase cascade. We conclude that ASFV induces apoptosis in the infected cell by an intracellular pathway probably triggered during the process of virus uncoating. PMID:12009879

Carrascosa, Angel L; Bustos, María J; Nogal, María L; González de Buitrago, Gonzalo; Revilla, Yolanda

2002-03-15

158

Methylation of homeobox genes is a frequent and early epigenetic event in breast cancer  

PubMed Central

Introduction Aberrant methylation of CpG islands is a hallmark of cancer and occurs at an early stage in breast tumorigenesis. However, its impact on tumor development is not fully determined, and its potential as a diagnostic biomarker remains to be validated. Methylation profiling of invasive breast carcinoma has been largely explored. Conversely, very little and sparse information is available on early-stage breast cancer. To gain insight into the epigenetic switches that may promote and/or contribute to the initial neoplastic events during breast carcinogenesis, we have analyzed the DNA methylation profile of ductal carcinoma in situ, a premalignant breast lesion with a great potential to progress toward invasive carcinoma. Methods We have utilized a comprehensive and sensitive array-based DNA mapping technique, the methylated-CpG island recovery assay, to profile the DNA methylation pattern in ductal carcinoma in situ. Differential methylation of CpG islands was compared genome-wide in tumor DNA versus normal DNA utilizing a statistical linear model in the LIMMA software package. Results Using this approach, we have identified 108 significant CpG islands that undergo aberrant DNA methylation in ductal carcinoma in situ and stage I breast tumors, with methylation frequencies greater than or comparable with those of more advanced invasive carcinoma (50% to 93%). A substantial fraction of these hypermethylated CpG islands (32% of the annotated CpG islands) is associated with several homeobox genes, such as the TLX1, HOXB13, and HNF1B genes. Fifty-three percent of the genes hypermethylated in early-stage breast cancer overlap with known Polycomb targets and include homeobox genes and other developmental transcription factors. Conclusions We have identified a series of new potential methylation biomarkers that may help elucidate the underlying mechanisms of breast tumorigenesis. More specifically, our results are suggestive of a critical role of homeobox gene methylation in the insurgence and/or progression of breast cancer.

Tommasi, Stella; Karm, Deborah L; Wu, Xiwei; Yen, Yun; Pfeifer, Gerd P

2009-01-01

159

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

Microsoft Academic Search

Containment in cell membranes is essential for all contemporary life, and apparently even the earliest life forms had to be\\u000a somehow contained. It has been postulated that random enclosure of replicating molecules inside of spontaneously assembled\\u000a vesicles would have formed the initial cellular ancestors. However, completely random re-formation or division of such primitive\\u000a vesicles would have abolished the heritability of

Tiina Laiterä; Kirsi Lehto

2009-01-01

160

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

PubMed

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

Davies, M S

1996-01-01

161

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

SciTech Connect

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.

Davis, M.S. [Univ. of Sunderland (United Kingdom). Ecology Centre] [Univ. of Sunderland (United Kingdom). Ecology Centre

1996-05-01

162

Dating the end-Triassic and Early Jurassic mass extinctions, correlative large igneous provinces, and isotopic events  

Microsoft Academic Search

The end-Triassic marks one of the five biggest mass extinctions, and was followed by a well-known second-order extinction event in the Early Jurassic. Previously pub- lished geological time scales were inadequate for correlation of extinctions with other global events and to unravel their dynamics. Here we present a revised time scale based on high-precision U-Pb ages integrated with ammonoid biochronology

Jozsef Palfy; Paul L. Smith; James K. Mortensen

163

The impact of early-diagnosed new-onset post-transplantation diabetes mellitus on survival and major cardiac events  

Microsoft Academic Search

The impact of early-diagnosed new-onset post-transplantation diabetes mellitus (PTDM) on cardiovascular (CV) disease is not well described. The objectives of the present prospective single-center observational study were to assess the long-term effects of early-diagnosed new-onset PTDM on major cardiac events (MCE; cardiac death or nonfatal acute myocardial infarction) and patient survival. Diabetic status and CV risk factors were assessed in

J Hjelmesæth; A Hartmann; T Leivestad; H Holdaas; S Sagedal; M Olstad; T Jenssen

2006-01-01

164

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

PubMed

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

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

2014-01-01

165

A Time Scale for Major Events in Early Mars Crustal Evolution  

NASA Technical Reports Server (NTRS)

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.

Frey, Herbert V.

2004-01-01

166

Choline acetyltransferase expression does not identify early pathogenic events in fetal SMA spinal cord.  

PubMed

We investigated the expression of choline acetyltransferase, a specific marker for cholinergic neurons, in control and spinal muscular atrophy fetuses and newborns. By immunoblot we observed at 12 and 15 weeks a similar pattern of choline acetyltransferase expression in spinal muscular atrophy with respect to controls, although at 22 weeks this expression was reduced, probably due to a smaller number of motor neurons in the spinal muscular atrophy spinal cord. By immunohistochemistry, the counting of positive and negative motor neurons for choline acetyltransferase immunostaining in control and spinal muscular atrophy fetuses showed a similar proportion at all stages analyzed. The choline acetyltransferase-negative motor neurons were of similar appearance in both groups. After birth, chromatolytic motor neurons were detected in spinal muscular atrophy, all of which were choline acetyltransferase-negative. Our results in spinal muscular atrophy fetuses indicate that choline acetyltransferase immunostaining does not identify early events in neuronal pathogenesis and suggest that the spinal muscular atrophy surviving motor neurons may not be dysfunctional during this period. Furthermore, spinal muscular atrophy choline acetyltransferase-negative motor neurons showed detectable pathological changes only after birth, indicating that choline acetyltransferase is a late marker for motor neuron degeneration and not a primary contributing factor in this process. PMID:15725587

Soler-Botija, Carolina; Cuscó, Ivón; López, Eva; Clua, Agustín; Gich, Ignasi; Baiget, Montserrat; Ferrer, Isidre; Tizzano, Eduardo F

2005-03-01

167

Effect of metallic cations on the efficiency of DNA amplification. Implications for nucleic acid replication during early stages of life  

NASA Astrophysics Data System (ADS)

The process of catalysis of biochemical reactions has been essential since the first organic molecules appeared on Earth. As the complexity of the ensemble of primitive biomolecules was very low, primitive catalysts had necessarily to be very simple molecules or ions. The evolution of catalysts had to be in parallel with the evolution of the molecular species reacting. An example of this parallel evolution is nucleic acid polymerization. Synthesis of primitive short oligonucleotides could have been catalysed by metal ions either in solution or on the surface of minerals such as montmorillonite clays. Some oligonucleotides could start to function as templates for the synthesis of complementary copies and there is experimental evidence supporting the role also played by metal ions in this process. In later stages of evolution, a group of enzymatic proteins, nucleic acid polymerases, has been selected to catalyse nucleic acid replication. The presence of Mg2+ in the active centre of these enzymes suggests that evolution has preserved some of the primitive catalysts, including them as cofactors of more complex molecules. However, the reasons why Mg2+ was selected among other ions that possibly were present in primitive environments are unknown. In this paper we try to approach this question by analysing the amplification efficiency of the polymerase chain reaction of a DNA fragment in the presence of different metal ions. In some cases the conditions of the reaction have been displaced from optimum (by the presence of nucleotide imbalances and a suboptimal Mg2+concentration). The results obtained permit one to draw interesting conclusions about how some metallic cations can help replication to proceed in conditions of limited substrate availability, a circumstance that could have been frequent at prebiotic stages, when nucleic acid synthesis was dependent on the physico-chemical conditions of the environment.

Arribas, María; de Vicente, Aránzazu; Arias, Armando; Lázaro, Ester

2005-04-01

168

Paleoceanographic Implications of the Terrestrial Carbon-Isotope Record of the Early Toarcian (Jurassic) Oceanic Anoxic Event  

Microsoft Academic Search

Macrofossil wood in two European sections representing the Toarcian (Early Jurassic) Oceanic Anoxic Event (OAE) have previously been shown to exhibit a large (~ -6 to -7 %) shift in d13C values which has been interpreted as a massive and geologically short-lived perturbation to the global carbon cycle. This interpretation has recently been challenged on the basis of a compilation

S. Hesselbo; H. C. Jenkyns; L. V. Duarte

2005-01-01

169

Effects of musical expertise on the early right anterior negativity: An event-related brain potential study  

Microsoft Academic Search

Event-related brain potentials in response to harmonically inappropriate chords were compared for musical experts and novices. Similar to previous studies, these chords elicited an early right anterior negativity ~ERAN!. The amplitude of the ERAN was clearly larger for musical experts than for novices, presumably because experts had more specific musical expectancies than novices. Chords with a physically deviant timbre elicited

STEFAN KOELSCH; JULIA KANSOK

2002-01-01

170

Use of structured triacylglycerols containing predominantly stearic and oleic acids to probe early events in metabolic processing of dietary fat  

Microsoft Academic Search

Early events in the metabolic processing of dietary triacylglycerol may have an important impact on subsequent development of risk factors for coronary heart disease. We have used structured triacylglycerols containing predomi- nantly stearic or oleic acids at the sn -2 position to probe as- pects of the processing of dietary fatty acids presented to ad- ipose tissue in chylomicron-triacylglycerol. Studies

Lucinda K. M. Summers; Barbara A. Fielding; Sara L. Herd; Vera Ilic; Mo L. Clark; Paul T. Quinlan; Keith N. Frayn

171

Dipole source localization of event-related brain activity indicative of an early visual selective attention deficit in ADHD children  

Microsoft Academic Search

ObjectiveThis study was aimed at investigating whether attention-deficit hyperactivity disorder (ADHD) children suffer from specific early selective attention deficits in the visual modality with the aid of event-related brain potentials (ERPs). Furthermore, brain source localization was applied to identify brain areas underlying possible deficits in selective visual processing in ADHD children.

L. M Jonkman; J. L Kenemans; C Kemner; M. N Verbaten; H van Engeland

2004-01-01

172

Critical Role of the Rostral Ventromedial Medulla in Early Spinal Events Leading to Chronic Constriction Injury Neuropathy in Rats  

Microsoft Academic Search

Neuropathic pain is a major clinical problem, and several animal models have been developed to investigate its mechanisms and its treatment. In this report, the role of the rostral ventromedial medulla (RVM) in the early events of the chronic constriction injury (CCI) model was investigated in behavioral and electrophysiological experiments. Placing the 4 CCI ligatures around the sciatic nerve induced

Raul Sanoja; Horacio Vanegas; Victor Tortorici

2008-01-01

173

Cybernetic origins of replication  

NASA Astrophysics Data System (ADS)

An evolutionary progression leading toward replication is resolved into several phases; (a) the replication of RNA segments by self-priming and -templating, (b) the replication of single stranded molecules by elongation and controlled scission, (c) replication of complementary duplexes and (d) replication of DNA. The initial phase is suggested by evidence for the existence of tandem repeats in an early population of molecules presumed to be ancestral to today's structurl RNAs. Relics of these repeats are seen in the positioning of sequence matches between transfer and ribosomal RNAs. Conservation of the positions of the matches is indicated by persistence of a periodicity in their spacings along the molecules. Selection is viewed as a vector, with a source and a focus. The evolutionary progression entails shifts in the source of selection, from external catalysts to the replicating molecule itself, and in its focus, from substrate to replicator, to the products of the replicator's activity. When the source and focus of selection are the same selection becomes internalized, and replication and Darwinian evolution follow. Catalytic specificity is regarded as an antecedent to natural selection. Shifting of the source and focus of selection and switches in evolution's ‘vehicle’, the most fundamental thing that evolves, result in profound changes in the modes of evolution. Control provides a conceptual framwork within which entry into a Darwinian mode of evolution, and ultimately liberation from Darwinian evolution might be explained.

Bloch, David P.

1988-03-01

174

DNA replication  

NSDL National Science Digital Library

Matthew Meselson and Franklin Stahl hypothesized that DNA could replicate in any of three ways. They used isotopes of nitrogen to label DNA for their experiments to find which one of the methods was used for DNA replication. They came to the conclusion that DNA replicates via the semi-conservative method.

Mike Jones (None;)

2005-09-15

175

Reliability of demographic and socioeconomic variables in predicting early initiation of breastfeeding: a replication analysis using the Kenya Demographic and Health Survey data  

PubMed Central

Objectives Examine the reliability of sociodemographic variables in predicting initiation of breastfeeding within an hour of birth (EarlyBF), using data from 1998, 2003 and 2008–2009. Study design A replication analysis using the Kenya Demographic and Health Survey (KDHS) data collected in 1998, 2003 and 2008–2009. The candidate predictor variables were child's gender, home or health facility place of birth, vaginal or caesarean mode of birth, urban or rural setting, province of residence, Wealth Index and maternal education, occupation, literacy and media exposure. Setting Kenya. Participants 6375 dyads of mothers aged 15–49 and their children aged 0–23?months (2125 dyads in each of the survey years). Results Mode of birth and province were statistically significant predictors of EarlyBF in 1998, 2003 and 2008–2009. Children delivered through caesarean section were non-EarlyBF in 1998 (OR 2.63, 95% CI 1.72 to 4.04), 2003 (OR 3.36, 95% CI 1.83 to 6.16) and 2008 (OR 3.51, 95% CI 2.17 to 5.69). The same was true of those living in the Western province in 1998 (OR 2.67, 95% CI 1.61 to 4.43), 2003 (OR 4.92, 95% CI 3.01 to 8.04) and 2008 (OR 6.07, 95% CI 3.54 to 10.39). Conclusions The 1998 KDHS data do not provide the basis for reliable prediction of EarlyBF, with reliability conceptualised as replicability of findings using highly similar data sets from 2003 and 2008–2009. Most of the demographic and socioeconomic variables were unreliable predictors of EarlyBF. We speculate that activities in parts or all of Kenya changed the analysis context in the period between 1998 and 2008–2009, and these changes were of a sufficient magnitude to affect the relationships under investigation. The degree to which this is a general problem in child health research is not known, calling for further research to investigate this methodological issue with other health end points and other data.

Matanda, Dennis J; Mittelmark, Maurice B; Urke, Helga B; Amugsi, Dickson A

2014-01-01

176

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

PubMed Central

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.

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

2010-01-01

177

Impact of LIP formation on marine productivity during early Aptian and latest Cenomanian Oceanic Anoxic Events  

NASA Astrophysics Data System (ADS)

Of all the Cretaceous Oceanic Anoxic Events (OAEs), the Early Aptian OAE1a and latest Cenomanian OAE2 are truly global in nature and typically represented by carbonate crisis and Corg-rich black shales. They correlate with onset and climax of the mid-Cretaceous greenhouse, a time of exceptional warmth with accelerated burial of organic matter, carbon and strontium isotope excursions, and major biotic changes. Extraordinary rates of volcanism during the formation of Ontong Java and Caribbean Plateaus are proposed to have introduced excess CO_2 in the ocean/atmosphere system, turning the climate into a super-greenhouse state. High-resolution multidisciplinary investigations of well-dated sections indicate that marine ecosystems reacted to higher fertility and pCO2 by reducing biomineralization and increasing production of organic matter. In particular, rates of calcitization and evolutionary changes of micrite-forming calcareous nannoplankton (the biological and carbonate pump) affected the organic and inorganic carbon cycle as well as diffusion of atmospheric CO_2 in the Cretaceous ocean. Increasing geological evidence suggests that OAE1a and OAE2 were mainly oceanic productivity events, directly or indirectly controlled by submarine volcanic eruptions. High levels of volcanogenic CO_2 in the atmosphere accelerated continental weathering and increased nutrient content in oceanic surface waters via river run-off. However, only coastal eutrophication can be triggered by river input, and this mechanism cannot explain enhanced primary productivity in remote parts of large oceans like those recorded in wide-spread sediments of OAE1a and OAE2. Conversely, global productivity can be stimulated by hydrothermal megaplumes that introduce in the oceans high concentrations of dissolved and particulate metals that are biolimiting (and toxic) and, consequently, can trigger large blooms (and deaths) of primary producers. We speculate that during OAE1a and OAE2, higher productivity was essentially induced and maintained by hydrothermal inputs of biolimiting metals during the construction of Ontong Java and Caribbean Plateaus, respectively, that also affected the ocean stratification by warming deep and intermediate waters, causing more efficient nutrient cycling.

Erba, E.; Duncan, R.

2003-04-01

178

Discordant expression of the immediate-early 1 and 2 gene regions of human cytomegalovirus at early times after infection involves posttranscriptional processing events.  

PubMed Central

Expression of the immediate-early 1 and 2 (IE-1 and IE-2) gene region of human cytomegalovirus (HCMV) was studied during initial phases of the replicative cycle. Accumulation of RNA from IE-1 and -2 was found to be differential. Transcripts from IE-2 reached peak levels very early in infection between 3 and 5 h, whereas IE-1 RNA peak levels were detected later, between 6 and 8 h. A strong decrease in steady-state levels of a 2.2-kb IE-2 RNA was observed at a time when IE-1 transcripts showed a further increase in abundance. Northern (RNA) blot experiments revealed that expression of both the IE-1 RNA and the 2.2-kb IE-2 transcript is controlled by the IE-1 enhancer-promoter. Nuclear run-on experiments demonstrated equal rates of primary transcription for IE-1 and -2 at a time when different steady-state levels of RNA were observed. Concomitant with down-regulation of IE-2 RNAs, a decrease in the size of the IE-1 transcript was detected. At 2 to 5 h after infection the IE-1 transcript migrated at 1.95 kb, whereas later in the replicative cycle the RNA was found at 1.8 kb. RNase H blot analysis revealed that this size discrepancy is due to a shorter poly(A) tail of the IE-1 RNA at early times after infection. These experiments suggest that in addition to transcriptional regulation, specific posttranscriptional mechanisms are involved in controlling expression from the IE-1 and -2 gene region of HCMV. Images

Stamminger, T; Puchtler, E; Fleckenstein, B

1991-01-01

179

Centromere replication timing determines different forms of genomic instability in Saccharomyces cerevisiae checkpoint mutants during replication stress.  

PubMed

Yeast replication checkpoint mutants lose viability following transient exposure to hydroxyurea, a replication-impeding drug. In an effort to understand the basis for this lethality, we discovered that different events are responsible for inviability in checkpoint-deficient cells harboring mutations in the mec1 and rad53 genes. By monitoring genomewide replication dynamics of cells exposed to hydroxyurea, we show that cells with a checkpoint deficient allele of RAD53, rad53K227A, fail to duplicate centromeres. Following removal of the drug, however, rad53K227A cells recover substantial DNA replication, including replication through centromeres. Despite this recovery, the rad53K227A mutant fails to achieve biorientation of sister centromeres during recovery from hydroxyurea, leading to secondary activation of the spindle assembly checkpoint (SAC), aneuploidy, and lethal chromosome segregation errors. We demonstrate that cell lethality from this segregation defect could be partially remedied by reinforcing bipolar attachment. In contrast, cells with the mec1-1 sml1-1 mutations suffer from severely impaired replication resumption upon removal of hydroxyurea. mec1-1 sml1-1 cells can, however, duplicate at least some of their centromeres and achieve bipolar attachment, leading to abortive segregation and fragmentation of incompletely replicated chromosomes. Our results highlight the importance of replicating yeast centromeres early and reveal different mechanisms of cell death due to differences in replication fork progression. PMID:19805819

Feng, Wenyi; Bachant, Jeff; Collingwood, David; Raghuraman, M K; Brewer, Bonita J

2009-12-01

180

Association of early age at establishment of chronic hepatitis B infection with persistent viral replication, liver cirrhosis and hepatocellular carcinoma: a systematic review.  

PubMed

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

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

2013-01-01

181

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

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.

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

2013-01-01

182

Early aberrant DNA methylation events in a mouse model of acute myeloid leukemia  

PubMed Central

Background Aberrant DNA methylation is frequently found in human malignancies including acute myeloid leukemia (AML). While most studies focus on later disease stages, the onset of aberrant DNA methylation events and their dynamics during leukemic progression are largely unknown. Methods We screened genome-wide for aberrant CpG island methylation in three disease stages of a murine AML model that is driven by hypomorphic expression of the hematopoietic transcription factor PU.1. DNA methylation levels of selected genes were correlated with methylation levels of CD34+ cells and lineage negative, CD127-, c-Kit+, Sca-1+ cells; common myeloid progenitors; granulocyte-macrophage progenitors; and megakaryocyte-erythroid progenitors. Results We identified 1,184 hypermethylated array probes covering 762 associated genes in the preleukemic stage. During disease progression, the number of hypermethylated genes increased to 5,465 in the late leukemic disease stage. Using publicly available data, we found a significant enrichment of PU.1 binding sites in the preleukemic hypermethylated genes, suggesting that shortage of PU.1 makes PU.1 binding sites in the DNA accessible for aberrant methylation. Many known AML associated genes such as RUNX1 and HIC1 were found among the preleukemic hypermethylated genes. Nine novel hypermethylated genes, FZD5, FZD8, PRDM16, ROBO3, CXCL14, BCOR, ITPKA, HES6 and TAL1, the latter four being potential PU.1 targets, were confirmed to be hypermethylated in human normal karyotype AML patients, underscoring the relevance of the mouse model for human AML. Conclusions Our study identified early aberrantly methylated genes as potential contributors to onset and progression of AML.

2014-01-01

183

Phase noise reveals early category-specific modulation of the event-related potentials  

PubMed Central

Previous studies have found that the amplitude of the early event-related potential (ERP) components evoked by faces, such as N170 and P2, changes systematically as a function of noise added to the stimuli. This change has been linked to an increased perceptual processing demand and to enhanced difficulty in perceptual decision making about faces. However, to date it has not yet been tested whether noise manipulation affects the neural correlates of decisions about face and non-face stimuli similarly. To this end, we measured the ERPs for faces and cars at three different phase noise levels. Subjects performed the same two-alternative age-discrimination task on stimuli chosen from young–old morphing continua that were created from faces as well as cars and were calibrated to lead to similar performances at each noise-level. Adding phase noise to the stimuli reduced performance and enhanced response latency for the two categories to the same extent. Parallel to that, phase noise reduced the amplitude and prolonged the latency of the face-specific N170 component. The amplitude of the P1 showed category-specific noise dependence: it was enhanced over the right hemisphere for cars and over the left hemisphere for faces as a result of adding phase noise to the stimuli, but remained stable across noise levels for cars over the left and for faces over the right hemisphere. Moreover, noise modulation altered the category-selectivity of the N170, while the P2 ERP component, typically associated with task decision difficulty, was larger for the more noisy stimuli regardless of stimulus category. Our results suggest that the category-specificity of noise-induced modulations of ERP responses starts at around 100 ms post-stimulus.

Nemeth, Kornel; Kovacs, Petra; Vakli, Pal; Kovacs, Gyula; Zimmer, Marta

2014-01-01

184

The Nrf2 activator, tBHQ, differentially affects early events following stimulation of Jurkat cells.  

PubMed

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that is activated by cellular stresses, such as oxidative compounds. After activation, Nrf2 induces transcription of its target genes, many of which have cytoprotective functions. Previously, we have shown that activation of Nrf2 by tert-butylhydroquinone (tBHQ) skews murine CD4? T-cell differentiation. Although the role of Nrf2 in murine T cells is somewhat characterized, it is largely uncharacterized in human T cells. Therefore, the aim of the current studies was to characterize the effects of the Nrf2 activator, tBHQ, on the early events of human CD4? T-cell activation. Pretreatment of Jurkat T cells with tBHQ, prior to activation with anti-CD3/anti-CD28, diminished the production of interleukin-2 (IL-2) at both the transcript and protein levels. Similarly, the expression of CD25 also diminished, albeit to a lesser degree than IL-2, after pretreatment with tBHQ. The decrease in IL-2 production was not due to decreased nuclear translocation of c-fos or c-jun. Although tBHQ caused both a delay and a decrease in Ca²? influx in activated Jurkat cells, no decrease in nuclear factor of activated T cells (NFAT) DNA binding or transcriptional activity was observed. In contrast to NFAT, tBHQ significantly decreased NF?B transcriptional activity. Collectively, our studies show that the Nrf2 activator, tBHQ, inhibits IL-2 and CD25 expression, which correlates with decreased NF?B transcriptional activity in activated Jurkat cells. Overall, our studies suggest that Nrf2 represents a novel mechanism for the regulation of both human and mouse T cell function. PMID:23945499

Zagorski, Joseph W; Turley, Alexandra E; Dover, Heather E; VanDenBerg, Kelly R; Compton, Jacob R; Rockwell, Cheryl E

2013-11-01

185

Phase noise reveals early category-specific modulation of the event-related potentials.  

PubMed

Previous studies have found that the amplitude of the early event-related potential (ERP) components evoked by faces, such as N170 and P2, changes systematically as a function of noise added to the stimuli. This change has been linked to an increased perceptual processing demand and to enhanced difficulty in perceptual decision making about faces. However, to date it has not yet been tested whether noise manipulation affects the neural correlates of decisions about face and non-face stimuli similarly. To this end, we measured the ERPs for faces and cars at three different phase noise levels. Subjects performed the same two-alternative age-discrimination task on stimuli chosen from young-old morphing continua that were created from faces as well as cars and were calibrated to lead to similar performances at each noise-level. Adding phase noise to the stimuli reduced performance and enhanced response latency for the two categories to the same extent. Parallel to that, phase noise reduced the amplitude and prolonged the latency of the face-specific N170 component. The amplitude of the P1 showed category-specific noise dependence: it was enhanced over the right hemisphere for cars and over the left hemisphere for faces as a result of adding phase noise to the stimuli, but remained stable across noise levels for cars over the left and for faces over the right hemisphere. Moreover, noise modulation altered the category-selectivity of the N170, while the P2 ERP component, typically associated with task decision difficulty, was larger for the more noisy stimuli regardless of stimulus category. Our results suggest that the category-specificity of noise-induced modulations of ERP responses starts at around 100 ms post-stimulus. PMID:24795689

Németh, Kornél; Kovács, Petra; Vakli, Pál; Kovács, Gyula; Zimmer, Márta

2014-01-01

186

Suicidal Ideation and its Recurrence in Boys and Men From Early Adolescence to Early Adulthood: An Event History Analysis  

Microsoft Academic Search

Occurrence and recurrences of suicidal ideation (SI) were modeled among boys\\/men assessed annually from ages 12 to 29 years. Multiple-spell discrete-time event-history analyses permitted (a) determination of whether risk for SI escalates with prior experiences of SI (spell effects), while (b) accounting for changes in risk with time (period effects) and (c) controlling for vulnerability factors. Self-reported SI (presence\\/absence in

David C. R. Kerr; Lee D. Owen; Deborah M. Capaldi

2008-01-01

187

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

NASA Astrophysics Data System (ADS)

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.

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

2014-05-01

188

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

PubMed

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

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

2013-01-01

189

Late Pliensbachian (Early Jurassic) Cold Seep Carbonates: Methane Release Prior to the Toarcian Oceanic Anoxic Event  

NASA Astrophysics Data System (ADS)

We present evidence for methane seepage during the Early Jurassic (~ 185 Ma) in the form of newly discovered extensive occurrences of carbonate concretions that resemble the subsurface plumbing system of better known Cenozoic to Recent examples of cold seep carbonates. Columnar carbonate concretions of up to 1 m in length that are perpendicular to bedding, occur abundantly in the Upper Pliensbachian (upper Amaltheus margaritatus Zone, gibbosus Subzone) in outcrops in the vicinity of Riviere-sur-Tarn, southern France. Stable isotope analyses of these nodules show depleted ?13C values that decrease from the rim to the center from -18.8 to -25.7‰ (V-PDB), but normal marine ?18O values (-1.8‰). Computer tomographic (CT) scanning of the columnar concretions show one or more central canals that are lined or filled entirely with pyrite and late diagenetic minerals. Septarian cracks are also filled with secondary calcite and/or siderite. Based on our preliminary geochemical and sedimentological observations we suggest that these concretions formed as a combination of the anaerobic oxidation of methane (AOM) and sulfate reduction within the sediment. Previously, these concretions with one, two or more central tubes have been ascribed to the activity of an enigmatic organism, possibly with annelid or arthropod affinities, known as Tisoa siphonalis. Our results suggest tisoan structures are abiogenic. Interestingly, Tisoa siphonalis has been described from many locations in the Grands Causses Basin in southern France, and from northern France and Luxemburg, always occurring at the same stratigraphic level. Upper Pliensbachian cold seep carbonates thus possibly cover an area of several thousand square kilometers, largely distributed across the basin centres of the NW European epicontinental seaway. Our findings may have far reaching implications for understanding the Toarcian Oceanic Anoxic Event, which is interpreted to bear the hallmarks of catastrophic methane release from gas hydrates in the form of a pronounced negative C-isotope excursion. Carbon isotope analyses of Late Pliensbachian bulk carbonate (matrix) samples show clearly decreasing C-isotope values across the margaritatus Zone and reach -3‰ within the uppermost Pliensbachian spinatum Zone. We attribute this decrease to seeping fluids that led to induration and diagenesis. Isotope analyses of coeval belemnite rostra do not document such a negative C-isotope trend with values remaining stable around +2‰. Hence, if methane was seeping prior to the Toarcian OAE, it appears not to have imprinted global carbon reservoirs.

van de Schootbrugge, B.; Harazim, D.; Sorichter, K.; Fiebig, J.; Zanella, F.; Oschmann, W.; Rosenthal, Y.

2008-12-01

190

The early UL3 gene of equine herpesvirus-1 encodes a tegument protein not essential for replication or virulence in the mouse  

PubMed Central

The UL3 gene of equine herpesvirus-1 (EHV-1) is retained in the genome of defective interfering particles and encodes a ~33 kDa myristylated protein. Further characterization showed that the UL3 gene is trans-activated only by the sole immediate early (IE) protein and encodes an early protein that is dispensable for EHV-1 replication and localizes in the tegument of purified virions. UL3-deleted EHV-1 (vL11?UL3) exhibits properties of host cell tropism, plaque size, and growth kinetics similar to those of the parental virus. Expression levels of EHV-1 proteins representative of all three gene classes in vL11?UL3–infected cells were identical to those in cells infected with parental virus. Mice intranasally infected with vL11?UL3 and parental virus showed no significant difference in mortality or virus lung titers. These findings suggest that the UL3 protein does not play a major role in the biology of EHV-1 in cell culture or virulence in the mouse.

Ahn, Byung Chul; Kim, Seongman; Zhang, Yunfei; Charvat, Robert A.; O'Callaghan, Dennis J.

2011-01-01

191

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

NASA Technical Reports Server (NTRS)

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).

Stutte, Gary W.; Roberts, Michael

2012-01-01

192

Interrelationships between Yeast Ribosomal Protein Assembly Events and Transient Ribosome Biogenesis Factors Interactions in Early Pre-Ribosomes  

PubMed Central

Early steps of eukaryotic ribosome biogenesis require a large set of ribosome biogenesis factors which transiently interact with nascent rRNA precursors (pre-rRNA). Most likely, concomitant with that initial contacts between ribosomal proteins (r-proteins) and ribosome precursors (pre-ribosomes) are established which are converted into robust interactions between pre-rRNA and r-proteins during the course of ribosome maturation. Here we analysed the interrelationship between r-protein assembly events and the transient interactions of ribosome biogenesis factors with early pre-ribosomal intermediates termed 90S pre-ribosomes or small ribosomal subunit (SSU) processome in yeast cells. We observed that components of the SSU processome UTP-A and UTP-B sub-modules were recruited to early pre-ribosomes independently of all tested r-proteins. On the other hand, groups of SSU processome components were identified whose association with early pre-ribosomes was affected by specific r-protein assembly events in the head-platform interface of the SSU. One of these components, Noc4p, appeared to be itself required for robust incorporation of r-proteins into the SSU head domain. Altogether, the data reveal an emerging network of specific interrelationships between local r-protein assembly events and the functional interactions of SSU processome components with early pre-ribosomes. They point towards some of these components being transient primary pre-rRNA in vivo binders and towards a role for others in coordinating the assembly of major SSU domains.

Jakob, Steffen; Ohmayer, Uli; Neueder, Andreas; Hierlmeier, Thomas; Perez-Fernandez, Jorge; Hochmuth, Eduard; Deutzmann, Rainer; Griesenbeck, Joachim; Tschochner, Herbert; Milkereit, Philipp

2012-01-01

193

Huntingtin Aggregate-Associated Axonal Degeneration is an Early Pathological Event in Huntington's Disease Mice  

Microsoft Academic Search

Huntington's disease (HD) is characterized by the selective loss of striatal projection neurons. In early stages of HD, neurode- generation preferentially occurs in the lateral globus pallidus (LGP) and substantia nigra (SN), two regions in which the axons of striatal neurons terminate. Here we report that in mice ex- pressing full-length mutant huntingtin and modeling early stages of HD, neuropil

He Li; Shi-Hua Li; Zhao-Xue Yu; Peggy Shelbourne; Xiao-Jiang Li

2001-01-01

194

Events during Early Triassic recovery from the end-Permian extinction  

Microsoft Academic Search

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

Jinnan Tong; Suxin Zhang; Jingxun Zuo; Xinqi Xiong

2007-01-01

195

DNA Replication Timing Data Corroborate In Silico Human Replication Origin Predictions  

NASA Astrophysics Data System (ADS)

We develop a wavelet-based multiscale pattern recognition methodology to disentangle the replication- from the transcription-associated compositional strand asymmetries observed in the human genome. Comparing replication skew profiles to recent high-resolution replication timing data reveals that most of the putative replication origins that border the so-identified replication domains are replicated earlier than their surroundings whereas the central regions replicate late in the S phase. We discuss the implications of this first experimental confirmation of these replication origin predictions that are likely to be early replicating and active in most tissues.

Audit, B.; Nicolay, S.; Huvet, M.; Touchon, M.; D'Aubenton-Carafa, Y.; Thermes, C.; Arneodo, A.

2007-12-01

196

The African swine fever virus virion membrane protein pE248R is required for virus infectivity and an early postentry event.  

PubMed

The African swine fever virus (ASFV) protein pE248R, encoded by the gene E248R, is a late structural component of the virus particle. The protein contains intramolecular disulfide bonds and has been previously identified as a substrate of the ASFV-encoded redox system. Its amino acid sequence contains a putative myristoylation site and a hydrophobic transmembrane region near its carboxy terminus. We show here that the protein pE248R is myristoylated during infection and associates with the membrane fraction in infected cells, behaving as an integral membrane protein. Furthermore, the protein localizes at the inner envelope of the virus particles in the cytoplasmic factories. The function of the protein pE248R in ASFV replication was investigated by using a recombinant virus that inducibly expresses the gene E248R. Under repressive conditions, the ASFV polyproteins pp220 and pp62 are normally processed and virus particles with morphology indistinguishable from that of those produced in a wild-type infection or under permissive conditions are generated. Moreover, the mutant virus particles can exit the cell as does the parental virus. However, the infectivity of the pE248R-deficient virions was reduced at least 100-fold. An investigation of the defect of the mutant virus indicated that neither virus binding nor internalization was affected by the absence of the protein pE248R, but a cytopathic effect was not induced and early and late gene expression was impaired, indicating that the protein is required for some early postentry event. PMID:19793823

Rodríguez, Irene; Nogal, María L; Redrejo-Rodríguez, Modesto; Bustos, María J; Salas, María L

2009-12-01

197

The African Swine Fever Virus Virion Membrane Protein pE248R Is Required for Virus Infectivity and an Early Postentry Event ?  

PubMed Central

The African swine fever virus (ASFV) protein pE248R, encoded by the gene E248R, is a late structural component of the virus particle. The protein contains intramolecular disulfide bonds and has been previously identified as a substrate of the ASFV-encoded redox system. Its amino acid sequence contains a putative myristoylation site and a hydrophobic transmembrane region near its carboxy terminus. We show here that the protein pE248R is myristoylated during infection and associates with the membrane fraction in infected cells, behaving as an integral membrane protein. Furthermore, the protein localizes at the inner envelope of the virus particles in the cytoplasmic factories. The function of the protein pE248R in ASFV replication was investigated by using a recombinant virus that inducibly expresses the gene E248R. Under repressive conditions, the ASFV polyproteins pp220 and pp62 are normally processed and virus particles with morphology indistinguishable from that of those produced in a wild-type infection or under permissive conditions are generated. Moreover, the mutant virus particles can exit the cell as does the parental virus. However, the infectivity of the pE248R-deficient virions was reduced at least 100-fold. An investigation of the defect of the mutant virus indicated that neither virus binding nor internalization was affected by the absence of the protein pE248R, but a cytopathic effect was not induced and early and late gene expression was impaired, indicating that the protein is required for some early postentry event.

Rodriguez, Irene; Nogal, Maria L.; Redrejo-Rodriguez, Modesto; Bustos, Maria J.; Salas, Maria L.

2009-01-01

198

Variability in a dominant block to SIV early reverse transcription in rhesus monkey cells predicts in vivo viral replication and time to death.  

PubMed

While it has long been appreciated that there is considerable variability in host containment of HIV/SIV replication, the determinants of that variability are not fully understood. Previous studies demonstrated that the degree of permissivity of a macaque's peripheral blood mononuclear cells (PBMC) for infection with simian immunodeficiency virus (SIV) in vitro predicted that animal's peak plasma virus RNA levels following SIV infection in vivo. The present study was conducted to define the mechanisms underlying the variable intrinsic susceptibility of rhesus monkey PBMC to SIVsmE660 infection. In a cohort of 15 unrelated Indian-origin rhesus monkeys, infectability of PBMC of individual animals with SIVsmE660, as defined by tissue culture infectious dose (TCID50), varied by more than 3 logs and was a stable phenotype over time. Susceptibility of a monkey's PBMC to wild type SIVsmE660 infection correlated with the susceptibility of that monkey's PBMC to infection with VSV-G pseudotyped SIVsm543-GFP. Moreover, the permissivity of an individual monkey's PBMC for infection with this construct correlated with the permissivity of a B-lymphoblastoid cell line (B-LCL) generated from PBMC of the same animal. We found that the degree of intrinsic resistance of monkey B-LCL correlated with the copy number of early reverse transcription (ERT) SIV DNA. The resistance of monkey B-LCL to SIVsmE660 replication could be abrogated by preincubation of cells with the SIV virus-like particles (VLPs) and SIV resistance phenotype could be transferred to a SIV susceptible B-LCL through cell fusion. Finally, we observed a positive correlation between susceptibility of monkey B-LCL to SIV infection with a VSV-G pseudotyped SIV-GFP construct in vitro and both the peak plasma virus RNA levels in vivo and time to death following wild type SIV infection. These findings suggest that a dominant early RT restricting factor that can be saturated by SIV capsid may contribute to the variable resistance to SIV infection in rhesus monkey B-LCL and that this differential intrinsic susceptibility contributes to the clinical outcome of an SIV infection. PMID:20416115

Rogers, Thomas F; Lim, So-Yon; Sundsvold, T J; Chan, Tiffany; Hsu, Ariel; Letvin, Norman L

2010-01-01

199

Early Maastrichtian carbon cycle perturbation and cooling event: Implications from the South Atlantic Ocean  

Microsoft Academic Search

Published stable isotope records in marine carbonate are characterized by a positive ?18O excursion associated with a negative ?13C shift during the early Maastrichtian. However, the cause and even the precise timing of these excursions remain uncertain. We have generated high-resolution foraminiferal stable isotope and gray-scale records for the latest Campanian to early Maastrichtian (?73–68 Ma) at two Ocean Drilling

Oliver Friedrich; Jens O. Herrle; Paul A. Wilson; Matthew J. Cooper; Jochen Erbacher; Christoph Hemleben

2009-01-01

200

Early Decrease in Respiration and Uncoupling Event Independent of Cytochrome c Release in PC12 Cells Undergoing Apoptosis  

PubMed Central

Cytochrome c is a key molecule in mitochondria-mediated apoptosis. It also plays a pivotal role in cell respiration. The switch between these two functions occurs at the moment of its release from mitochondria. This process is therefore extremely relevant for the fate of the cell. Since cytochrome c mediates respiration, we studied the changes in respiratory chain activity during the early stages of apoptosis in order to contribute to unravel the mechanisms of cytochrome c release. We found that, during staurosporine (STS)- induced apoptosis in PC12 cells, respiration is affected before the release of cytochrome c, as shown by a decrease in the endogenous uncoupled respiration and an uncoupling event, both occurring independently of cytochrome c release. The decline in the uncoupled respiration occurs also upon Bcl-2 overexpression (which inhibits cytochrome c release), while the uncoupling event is inhibited by Bcl-2. We also observed that the first stage of nuclear condensation during STS-induced apoptosis does not depend on the release of cytochrome c into the cytosol and is a reversibile event. These findings may contribute to understand the mechanisms affecting mitochondria during the early stages of apoptosis and priming them for the release of apoptogenic factors.

Berghella, Libera; Ferraro, Elisabetta

2012-01-01

201

Integrating Sentence-Structural and Event Information in Early Verb Learning  

ERIC Educational Resources Information Center

Children use syntax as well as observations of events to learn verb meanings. This is known as syntactic bootstrapping. This dissertation investigated the origins and mechanisms of syntactic bootstrapping. Prior evidence suggested that two-year-olds, but not younger children, could use aspects of sentence structure to assign different…

Yuan, Sylvia Hsin Wei

2009-01-01

202

It's the Little Things: Exploring the Importance of Commonplace Events for Early-Career Teachers' Motivation  

ERIC Educational Resources Information Center

This paper seeks to provide a rationale for further researching the everyday events that keep teachers motivated or that discourage them. We put forward the idea that routine Affect Triggering Incidents (ATIs) are an important area for researchers to investigate in terms of how they impact teacher motivation and resilience. Two groups of…

Kitching, Karl; Morgan, Mark; O'Leary, Michael

2009-01-01

203

Relationships between the early Toarcian anoxic event and organic-walled phytoplankton in central Italy  

Microsoft Academic Search

The integration of palynological and geochemical data from three lower Toarcian successions in central Italy reveals that the composition of organic-walled phytoplankton assemblages were strongly affected by palaeoecological conditions related to bituminous sedimentation which accompanied the global anoxic event. The marked compositional variations of dinoflagellate cysts and prasinophytes, together with geochemical variations, have been linked to changes in surface water

Raffaella Bucefalo Palliani; James B. Riding

1999-01-01

204

AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis  

Microsoft Academic Search

The inhibition of apoptosis is a critical event in the develop- ment of colorectal malignancies, although the mechanism(s) remain incompletely understood. The anti-apoptotic proto- oncogene, AKT, has been implicated in the molecular patho- genesis of a variety of human malignancies; however, no data exist on the role of AKT in colon carcinogenesis. We therefore evaluated the presence of AKT in

Hemant K. Roy; Bola F. Olusola; Dahn L. Clemens; William J. Karolski; Anne Ratashak; Henry T. Lynch; Thomas C. Smyrk

2002-01-01

205

New Early Jurassic Tetrapod Assemblages Constrain Triassic-Jurassic Tetrapod Extinction Event  

Microsoft Academic Search

The discovery of the first definitively correlated earliest Jurassic (200 million years before present) tetrapod assemblage (Fundy basin, Newark Supergroup, Nova Scotia) allows reevaluation of the duration of the Triassic-Jurassic tetrapod extinction event. Present are tritheledont and mammal-like reptiles, prosauropod, theropod, and ornithischian dinosaurs, protosuchian and sphenosuchian crocodylomorphs, sphenodontids, and hybodont, semionotid, and palaeonisciform fishes. All of the families are

P. E. Olsen; N. H. Shubin; M. H. Anders

1987-01-01

206

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

ERIC Educational Resources Information Center

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).…

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

2011-01-01

207

DNA replication stress response involving PLK1, CDC6, POLQ, RAD51 and CLASPIN upregulation prognoses the outcome of early/mid-stage non-small cell lung cancer patients  

PubMed Central

Lung cancer is the leading cause of cancer deaths worldwide. Clinical staging classification is generally insufficient to provide a reliable prognosis, particularly for early stages. In addition, prognostic factors are therefore needed to better forecast life expectancy and optimize adjuvant therapeutic strategy. Recent evidence indicates that alterations of the DNA replication program contribute to neoplasia from its early stages and that cancer cells are frequently exposed to endogenous replication stress. We therefore hypothesized that genes involved in the replication stress response may represent an under-explored source of biomarkers. Expressions of 77 DNA replication-associated genes implicated in different aspects of chromosomal DNA replication, including licensing, firing of origins, elongation, replication fork maintenance and recovery, lesion bypass and post-replicative repair were determined in primary tumors and adjacent normal tissues from 93 patients suffering from early- or mid-stage non-small cell lung cancer (NSCLC). We then investigated a statistically significant interaction between gene expressions and survival of early-stage NSCLC patients.The expression of five genes, that is, POLQ, PLK1, RAD51, CLASPIN and CDC6 was associated with overall, disease-free and relapse-free survival. The expression levels are independent of treatment and stage classification. Except RAD51, their prognostic role on survival persists after adjustment on age, sex, treatment, stage classification and conventional proliferation markers, with a hazard ratio of 36.3 for POLQ (95%CI 2.6–517.4, P=0.008), 23.5 for PLK1 (95%CI 1.9–288.4, P=0.01), 20.7 for CLASPIN (95%CI 1.5–275.9, P=0.02) and 18.5 for CDC6 (95%CI 1.3–267.4, P=0.03). We also show that a five-gene signature including POLQ, PLK1, RAD51, CLASPIN and CDC6 separates patients into low- and high-risk groups, with a hazard ratio of 14.3 (95% CI 5.1–40.3, P<0.001). This ‘replication stress' metamarker may be a reliable predictor of survival for NSCLC, and may also help understand the molecular mechanisms underlying tumor progression.

Allera-Moreau, C; Rouquette, I; Lepage, B; Oumouhou, N; Walschaerts, M; Leconte, E; Schilling, V; Gordien, K; Brouchet, L; Delisle, M B; Mazieres, J; Hoffmann, J S; Pasero, P; Cazaux, C

2012-01-01

208

DNA replication stress response involving PLK1, CDC6, POLQ, RAD51 and CLASPIN upregulation prognoses the outcome of early/mid-stage non-small cell lung cancer patients.  

PubMed

Lung cancer is the leading cause of cancer deaths worldwide. Clinical staging classification is generally insufficient to provide a reliable prognosis, particularly for early stages. In addition, prognostic factors are therefore needed to better forecast life expectancy and optimize adjuvant therapeutic strategy. Recent evidence indicates that alterations of the DNA replication program contribute to neoplasia from its early stages and that cancer cells are frequently exposed to endogenous replication stress. We therefore hypothesized that genes involved in the replication stress response may represent an under-explored source of biomarkers. Expressions of 77 DNA replication-associated genes implicated in different aspects of chromosomal DNA replication, including licensing, firing of origins, elongation, replication fork maintenance and recovery, lesion bypass and post-replicative repair were determined in primary tumors and adjacent normal tissues from 93 patients suffering from early- or mid-stage non-small cell lung cancer (NSCLC). We then investigated a statistically significant interaction between gene expressions and survival of early-stage NSCLC patients.The expression of five genes, that is, POLQ, PLK1, RAD51, CLASPIN and CDC6 was associated with overall, disease-free and relapse-free survival. The expression levels are independent of treatment and stage classification. Except RAD51, their prognostic role on survival persists after adjustment on age, sex, treatment, stage classification and conventional proliferation markers, with a hazard ratio of 36.3 for POLQ (95%CI 2.6-517.4, P=0.008), 23.5 for PLK1 (95%CI 1.9-288.4, P=0.01), 20.7 for CLASPIN (95%CI 1.5-275.9, P=0.02) and 18.5 for CDC6 (95%CI 1.3-267.4, P=0.03). We also show that a five-gene signature including POLQ, PLK1, RAD51, CLASPIN and CDC6 separates patients into low- and high-risk groups, with a hazard ratio of 14.3 (95% CI 5.1-40.3, P<0.001). This 'replication stress' metamarker may be a reliable predictor of survival for NSCLC, and may also help understand the molecular mechanisms underlying tumor progression. PMID:23552402

Allera-Moreau, C; Rouquette, I; Lepage, B; Oumouhou, N; Walschaerts, M; Leconte, E; Schilling, V; Gordien, K; Brouchet, L; Delisle, M B; Mazieres, J; Hoffmann, J S; Pasero, P; Cazaux, C

2012-01-01

209

Is Epigenetics an Important Link between Early Life Events and Adult Disease?  

Microsoft Academic Search

Background: 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 complex chronic diseases, such as cardiovascular disease, type 2 diabetes and obesity, remains largely uncharacterized. Extensive work in animal models is

Robert A. Waterland

2009-01-01

210

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

ERIC Educational Resources Information Center

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…

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

2008-01-01

211

Family Support for Early Literacy and Numeracy: Examining Events in the Home and Community  

ERIC Educational Resources Information Center

Early childhood educators often make assumptions about the nature of families' understandings and what they do at home to support their young children's literacy and numeracy development and learning. Sometimes educator's have a limited understanding of children's every day experiences at home or in their community and the potential for these to…

Kennedy, Anne

2010-01-01

212

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

USGS Publications Warehouse

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.

Weems, R. E.

1992-01-01

213

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

PubMed Central

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

Te Brake, Hans

2013-01-01

214

End-binding protein 1 (EB1) up-regulation is an early event in colorectal carcinogenesis.  

PubMed

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

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

2014-03-01

215

Interactions of MCP1 with components of the replication machinery in mammalian cells.  

PubMed

Eukaryotic DNA replication starts with the assembly of a pre-replication complex (pre-RC) at replication origins. We have previously demonstrated that Metaphase Chromosome Protein 1 (MCP1) is involved in the early events of DNA replication. Here we show that MCP1 associates with proteins that are required for the establishment of the pre-replication complex. Reciprocal immunoprecipitation analysis showed that MCP1 interacted with Cdc6, ORC2, ORC4, MCM2, MCM3 and MCM7, with Cdc45 and PCNA. Immunofluorescence studies demonstrated the co-localization of MCP1 with some of those proteins. Moreover, biochemical studies utilizing chromatin-immunoprecipitation (ChIP) revealed that MCP1 preferentially binds replication initiation sites in human cells. Interestingly, although members of the pre-RC are known to interact with some hallmarks of heterochromatin, our co-immunoprecipitation and immunofluorescence analyses showed that MCP1 did not interact and did not co-localize with heterochromatic proteins including HP1? and MetH3K9. These observations suggest that MCP1 is associated with replication factors required for the initiation of DNA replication and binds to the initiation sites in loci that replicate early in S-phase. In addition, immunological assays revealed the association of MCP1 forms with histone H1 variants and mass spectrometry analysis confirmed that MCP1 peptides share common sequences with H1.2 and H1.5 subtypes. PMID:21383955

Bronze-da-Rocha, Elsa; Lin, Chii-Mei; Shimura, Tsutomu; Aladjem, Mirit I

2011-01-01

216

Interactions of MCP1 with Components of the Replication Machinery in Mammalian Cells  

PubMed Central

Eukaryotic DNA replication starts with the assembly of a pre-replication complex (pre-RC) at replication origins. We have previously demonstrated that Metaphase Chromosome Protein 1 (MCP1) is involved in the early events of DNA replication. Here we show that MCP1 associates with proteins that are required for the establishment of the pre-replication complex. Reciprocal immunoprecipitation analysis showed that MCP1 interacted with Cdc6, ORC2, ORC4, MCM2, MCM3 and MCM7, with Cdc45 and PCNA. Immunofluorescence studies demonstrated the co-localization of MCP1 with some of those proteins. Moreover, biochemical studies utilizing chromatin-immunoprecipitation (ChIP) revealed that MCP1 preferentially binds replication initiation sites in human cells. Interestingly, although members of the pre-RC are known to interact with some hallmarks of heterochromatin, our co-immunoprecipitation and immunofluorescence analyses showed that MCP1 did not interact and did not co-localize with heterochromatic proteins including HP1? and MetH3K9. These observations suggest that MCP1 is associated with replication factors required for the initiation of DNA replication and binds to the initiation sites in loci that replicate early in S-phase. In addition, immunological assays revealed the association of MCP1 forms with histone H1 variants and mass spectrometry analysis confirmed that MCP1 peptides share common sequences with H1.2 and H1.5 subtypes.

Bronze-da-Rocha, Elsa; Lin, Chii-Mei; Shimura, Tsutomu; Aladjem, Mirit I.

2011-01-01

217

Challenges and opportunities in research on early-life events/exposures and cancer development later in life.  

PubMed

It is becoming increasingly evident that early-life events and exposures have important consequences for cancer development later in life. However, epidemiological studies of early-life factors and cancer development later in life have had significant methodological challenges such as the long latency period, the distinctiveness of each cancer, and large number of subjects that must be studied, all likely to increase costs. These traditional hurdles might be mitigated by leveraging several existing large-scale prospective studies in the United States (US) and globally, as well as birth databases and birth cohorts, in order to launch both association and mechanistic studies of early-life exposures and cancer development later in life. Dedicated research funding will be needed to advance this paradigm shift in cancer research, and it seems justified by its potential to produce transformative understanding of how cancer develops over the life-course. This in turn has the potential to transform cancer prevention strategies through interventions in early-life rather than later in life, as is the current practice, where it is perhaps less effective. PMID:22527169

Mahabir, Somdat; Aagaard, Kjersti; Anderson, Lucy M; Herceg, Zdenko; Hiatt, Robert A; Hoover, Robert N; Linet, Martha S; Medina, Daniel; Potischman, Nancy; Tretli, Steinar; Trichopoulos, Dimitrios; Troisi, Rebecca

2012-06-01

218

Astronomical pacing of late Palaeocene to early Eocene global warming events  

Microsoft Academic Search

At the boundary between the Palaeocene and Eocene epochs, about 55million 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 2,800gigatonnes of methane from ocean clathrates, resulting in a large negative carbon isotope excursion and severe

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

2005-01-01

219

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

NASA Technical Reports Server (NTRS)

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.

Park, J.; Bogard, D. D.

2006-01-01

220

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

Microsoft Academic Search

To examine whether there are any characteristics of women or their initial tumors that might be useful for tailoring surveillance\\u000a recommendations to optimize outcomes. We followed 17,286 women for up to 5 years after an initial diagnosis of ductal carcinoma\\u000a in situ (DCIS) or early stage (I\\/II) invasive breast cancer diagnosed between 1996 and 2006. We calculated rates per 1,000\\u000a women

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

2010-01-01

221

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

NASA Technical Reports Server (NTRS)

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.

Bothun, G.

2005-01-01

222

Ar-39-Ar-40 Evidence for Early Impact Events on the LL Parent Body  

NASA Technical Reports Server (NTRS)

We determined Ar-39-Ar-40 ages of eight LL chondrites, and one igneous inclusion from an LL chondrite, with the object of understanding the thermal history of the LL-chondrite parent body. The meteorites in this study have a range of petrographic types from LL3.3 to LL6, and shock stages from S1 to S4. These meteorites reveal a range of K-Ar ages from 23.66 to 24.50 Ga, and peak ages from 23.74 to 24.55 Ga. Significantly, three of the eight chondrites (LL4, 5, 6) have K-Ar ages of -4.27 Ga. One of these (MIL99301) preserves an Ar-39-Ar-40 age of 4.23 +/- 0.03 Ga from low-temperature extractions, and an older age of 4.52 +/- 0.08 Ga from the highest temperature extractions. In addition, an igneous-textured impact melt DOM85505,22 has a peak Ar-39-Ar-40 age of >= 4.27 Ga. We interpret these results as evidence for impact events that occurred at about 4.27 Ga on the LL parent body that produced local impact melts, reset the Ar-39-Ar-40 ages of some meteorites, and exhumed (or interred) others, resulting in a range of cooling ages. The somewhat younger peak age of 3.74 Ga from GR095658 (LL3.3) suggests an additional impact event close to timing of impact-reset ages of some other ordinary chondrites between 3.6-3.8 Ga. The results from MIL99301 suggest that some apparently unshocked (Sl) chondrites may have substantially reset Ar-39-Ar-40 ages. A previous petrographic investigation of MIL99301 suggested that reheating to temperatures less than or equal to type 4 petrographic conditions (600C) caused fractures in olivine to anneal, resulting in a low apparent shock stage of S1 (unshocked). The Ar-39-Ar-40 age spectrum of MIL99301 is consistent with this interpretation. Older ages from high-T extractions may date an earlier impact event at 4.52 +/- 0.08 Ga, whereas younger ages from lower-T extractions date a later impact event at 4.23 Ar-39-Ar-40 0.03 Ga that may have caused annealing of feldspar and olivine

Dixon, E. T.; Bogard, D. D.; Garrison, D. H.; Rubin, A. E.

2006-01-01

223

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

PubMed

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

Boudjeko, Thaddée; Andème-Onzighi, Christine; Vicré, Maïté; Balangé, Alain-Pierre; Ndoumou, Denis Omokolo; Driouich, Azeddine

2006-01-01

224

A new reporter mouse cytomegalovirus reveals maintained immediate-early gene expression but poor virus replication in cycling liver sinusoidal endothelial cells  

PubMed Central

Background The MCMV major immediate early promoter/enhancer (MIEP) is a bidirectional promoter that drives the expression of the three immediate early viral genes, namely ie1, ie2 and ie3. The regulation of their expression is intensively studied, but still incompletely understood. Methods We constructed a reporter MCMV, (MCMV-MIEPr) expressing YFP and tdTomato under the control of the MIEP as proxies of ie1 and ie2, respectively. Moreover, we generated a liver sinusoidal endothelial cell line (LSEC-uniLT) where cycling is dependent on doxycycline. We used these novel tools to study the kinetics of MIEP-driven gene expression in the context of infection and at the single cell level by flow cytometry and by live imaging of proliferating and G0-arrested cells. Results MCMV replicated to higher titers in G0-arrested LSEC, and cycling cells showed less cytopathic effect or YFP and tdTomato expression at 5 days post infection. In the first 24 h post infection, however, there was no difference in MIEP activity in cycling or G0-arrested cells, although we could observe different profiles of MIEP gene expression in different cell types, like LSECs, fibroblasts or macrophages. We monitored infected LSEC-uniLT in G0 by time lapse microscopy over five days and noticed that most cells survived infection for at least 96 h, arguing that quick lysis of infected cells could not account for the spread of the virus. Interestingly, we noticed a strong correlation between the ratio of median YFP and tdTomato expression and length of survival of infected cells. Conclusion By means of our newly developed genetic tools, we showed that the expression pattern of MCMV IE1 and IE2 genes differs between macrophages, endothelial cells and fibroblasts. Substantial and cell-cycle independent differences in the ie1 and ie2 transcription could also be observed within individual cells of the same population, and marked ie2 gene expression was associated with longer survival of the infected cells.

2013-01-01

225

An in vitro tissue culture bilayer model to examine early events in Mycobacterium tuberculosis infection.  

PubMed

A tissue culture bilayer system that mimics some aspects of early alveolar infection by Mycobacterium tuberculosis was developed. This model incorporates human lung epithelial type II pneumocyte (A549) (upper chamber) and endothelial cell (lower chamber) layers separated by a microporous membrane. This construction makes it possible to observe and quantify the passage of bacteria through the two layers, to observe the interaction of the bacteria with the various cell types, and to examine the basic mechanisms of immune cell recruitment to the site of infection. After 10(7) organisms were added to the upper chamber we microscopically observed large numbers of bacteria attached to and within the pneumocytes and we determined by viable-cell counting that a small percentage of the inoculum (0.02 to 0.43%) passed through the bilayer into the lower chamber. When peripheral blood mononuclear cells were added to the lower chamber, microscopic examination indicated a migration of the mononuclear cells through the bilayer to the apical surface, where they were seen associated with the mycobacteria on the pneumocytes. The added complexity of the bilayer system offers an opportunity to define more precisely the roles of the various lung cell types in the pathogenesis of early tuberculosis. PMID:9916072

Birkness, K A; Deslauriers, M; Bartlett, J H; White, E H; King, C H; Quinn, F D

1999-02-01

226

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

NASA Astrophysics Data System (ADS)

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.

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

1988-02-01

227

Toward a Molecular Theory of Early and Late Events in Monomer to Amyloid Fibril Formation  

NASA Astrophysics Data System (ADS)

Quantitative understanding of the kinetics of fibril formation and the molecular mechanism of transition from monomers to fibrils is needed to obtain insights into the growth of amyloid fibrils and more generally self-assembly multisubunit protein complexes. Significant advances using computations of protein aggregation in a number of systems have established generic and sequence-specific aspects of the early steps in oligomer formation. Theoretical considerations, which view oligomer and fibril growth as diffusion in a complex energy landscape, and computational studies, involving minimal lattice and coarse-grained models, have revealed general principles governing the transition from monomeric protein to ordered fibrillar aggregates. Detailed atomistic calculations have explored the early stages of the protein aggregation pathway for a number of amyloidogenic proteins, most notably amyloid ?- (A?-) protein and fragments from proteins linked to various diseases. These computational studies have provided insights into the role of sequence, role of water, and specific interatomic interactions underlying the thermodynamics and dynamics of elementary kinetic steps in the aggregation pathway. Novel methods are beginning to illustrate the structural basis for the production of A?-peptides through interactions with secretases in the presence of membranes. We show that a variety of theoretical approaches, ranging from scaling arguments to minimal models to atomistic simulations, are needed as a complement to experimental studies probing the principles governing protein aggregation.

Straub, John E.; Thirumalai, D.

2011-05-01

228

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

SciTech Connect

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. The authors 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.

Wallin, E.T.; Mattinson, J.M.; Potter, A.W.

1988-02-01

229

Visualizing lipid raft dynamics and early signaling events during antigen receptor-mediated B-lymphocyte activation.  

PubMed

Recent biochemical evidence indicates that an early event in signal transduction by the B-cell antigen receptor (BCR) is its translocation to specialized membrane subdomains known as lipid rafts. We have taken a microscopic approach to image lipid rafts and early events associated with BCR signal transduction. Lipid rafts were visualized on primary splenic B lymphocytes from wild-type or anti-hen egg lysozyme BCR transgenic mice, and on a mature mouse B-cell line Bal 17 by using fluorescent conjugates of cholera toxin B subunit or a Lyn-based chimeric protein, which targets green fluorescent protein to the lipid raft compartment. Time-lapse imaging of B cells stimulated via the BCR with the antigen hen egg lysozyme, or surrogate for antigen anti-IgM, demonstrated that lipid rafts are highly dynamic entities, which move laterally on the surface of these cells and coalesce into large regions. These regions of aggregated lipid rafts colocalized with the BCR and tyrosine-phosphorylated proteins. Microscopic imaging of live B cells also revealed an inducible colocalization of lipid rafts with the tyrosine kinase Syk and the receptor tyrosine phosphatase CD45. These two proteins play indispensable roles in BCR-mediated signaling but are not detectable in biochemically purified lipid raft fractions. Strikingly, BCR stimulation also induced the formation of long, thread-like filopodial projections, similar to previously described structures called cytonemes. These B-cell cytonemes are rich in lipid rafts and actin filaments, suggesting that they might play a role in long-range communication and/or transportation of signaling molecules during an immune response. These results provide a window into the morphological and molecular organization of the B-cell membrane during the early phase of BCR signaling. PMID:12589045

Gupta, Neetu; DeFranco, Anthony L

2003-02-01

230

HIV-1 transmission during early antiretroviral therapy: evaluation of two HIV-1 transmission events in the HPTN 052 prevention study.  

PubMed

In the HPTN 052 study, transmission between HIV-discordant couples was reduced by 96% when the HIV-infected partner received suppressive antiretroviral therapy (ART). We examined two transmission events where the newly infected partner was diagnosed after the HIV-infected partner (index) initiated therapy. We evaluated the sequence complexity of the viral populations and antibody reactivity in the newly infected partner to estimate the dates of transmission to the newly infected partners. In both cases, transmission most likely occurred significantly before HIV-1 diagnosis of the newly infected partner, and either just before the initiation of therapy or before viral replication was adequately suppressed by therapy of the index. This study further strengthens the conclusion about the efficacy of blocking transmission by treating the infected partner of discordant couples. However, this study does not rule out the potential for HIV-1 transmission to occur shortly after initiation of ART, and this should be recognized when antiretroviral therapy is used for HIV-1 prevention. PMID:24086252

Ping, Li-Hua; Jabara, Cassandra B; Rodrigo, Allen G; Hudelson, Sarah E; Piwowar-Manning, Estelle; Wang, Lei; Eshleman, Susan H; Cohen, Myron S; Swanstrom, Ronald

2013-01-01

231

HIV-1 Transmission during Early Antiretroviral Therapy: Evaluation of Two HIV-1 Transmission Events in the HPTN 052 Prevention Study  

PubMed Central

In the HPTN 052 study, transmission between HIV-discordant couples was reduced by 96% when the HIV-infected partner received suppressive antiretroviral therapy (ART). We examined two transmission events where the newly infected partner was diagnosed after the HIV-infected partner (index) initiated therapy. We evaluated the sequence complexity of the viral populations and antibody reactivity in the newly infected partner to estimate the dates of transmission to the newly infected partners. In both cases, transmission most likely occurred significantly before HIV-1 diagnosis of the newly infected partner, and either just before the initiation of therapy or before viral replication was adequately suppressed by therapy of the index. This study further strengthens the conclusion about the efficacy of blocking transmission by treating the infected partner of discordant couples. However, this study does not rule out the potential for HIV-1 transmission to occur shortly after initiation of ART, and this should be recognized when antiretroviral therapy is used for HIV-1 prevention.

Rodrigo, Allen G.; Hudelson, Sarah E.; Piwowar-Manning, Estelle; Wang, Lei; Eshleman, Susan H.; Cohen, Myron S.; Swanstrom, Ronald

2013-01-01

232

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

PubMed

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

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

233

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

PubMed Central

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.

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

2014-01-01

234

Structural insights into early folding events using continuous-flow time-resolved SAXS  

PubMed Central

Small-angle x-ray scattering (SAXS) is a powerful method for obtaining quantitative structural information on the size and shape of proteins, and it is increasingly used in kinetic studies of folding and association reactions. In this mini-review, we discuss recent developments in using SAXS to obtain structural information on the unfolded ensemble and early folding intermediates of proteins using continuous-flow mixing devices. Interfacing of these micromachined devices to SAXS beamlines has allowed access to the microsecond time regime. The experimental constraints in implementation of turbulence and laminar flow based mixers with SAXS detection and a comparison of the two approaches are presented. Current improvements and future prospects of microsecond time-resolved SAXS and the synergy with ab initio structure prediction and molecular dynamics simulations are discussed.

Kathuria, Sagar V.; Guo, Liang; Graceffa, Rita; Barrea, Raul; Nobrega, R. Paul; Matthews, C. Robert; Irving, Tom; Bilsel, Osman

2012-01-01

235

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

PubMed Central

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

Giraldez, Maria Dolores; Balaguer, Francesc; Bujanda, Luis; Cuatrecasas, Miriam; Munoz, Jenifer; Alonso-Espinaco, Virginia; Larzabal, Mikel; Petit, Anna; Gonzalo, Victoria; Ocana, Teresa; Moreira, Leticia; Enriquez-Navascues, Jose Maria; Boland, C. Richard; Goel, Ajay; Castells, Antoni; Castellvi-Bel, Sergi

2011-01-01

236

Senescent Fibroblasts Enhance Early Skin Carcinogenic Events via a Paracrine MMP-PAR-1 Axis  

PubMed Central

The incidence of carcinoma increases greatly with aging, but the cellular and molecular mechanisms underlying this correlation are only partly known. It is established that senescent fibroblasts promote the malignant progression of already-transformed cells through secretion of inflammatory mediators. We investigated here whether the senescent fibroblast secretome might have an impact on the very first stages of carcinogenesis. We chose the cultured normal primary human epidermal keratinocyte model, because after these cells reach the senescence plateau, cells with transformed and tumorigenic properties systematically and spontaneously emerge from the plateau. In the presence of medium conditioned by autologous senescent dermal fibroblasts, a higher frequency of post-senescence emergence was observed and the post-senescence emergent cells showed enhanced migratory properties and a more marked epithelial-mesenchymal transition. Using pharmacological inhibitors, siRNAs, and blocking antibodies, we demonstrated that the MMP-1 and MMP-2 matrix metalloproteinases, known to participate in late stages of cancer invasion and metastasis, are responsible for this enhancement of early migratory capacity. We present evidence that MMPs act by activating the protease-activated receptor 1 (PAR-1), whose expression is specifically increased in post-senescence emergent keratinocytes. The physiopathological relevance of these results was tested by analyzing MMP activity and PAR-1 expression in skin sections. Both were higher in skin sections from aged subjects than in ones from young subjects. Altogether, our results suggest that during aging, the dermal and epidermal skin compartments might be activated coordinately for initiation of skin carcinoma, via a paracrine axis in which MMPs secreted by senescent fibroblasts promote very early epithelial-mesenchymal transition of keratinocytes undergoing transformation and oversynthesizing the MMP-activatable receptor PAR-1.

Malaquin, Nicolas; Vercamer, Chantal; Bouali, Fatima; Martien, Sebastien; Deruy, Emeric; Wernert, Nicolas; Chwastyniak, Maggy; Pinet, Florence; Abbadie, Corinne; Pourtier, Albin

2013-01-01

237

Deletion at fragile sites is a common and early event in Barrett's esophagus.  

PubMed

Barrett's esophagus (BE) is a premalignant intermediate to esophageal adenocarcinoma, which develops in the context of chronic inflammation and exposure to bile and acid. We asked whether there might be common genomic alterations that could be identified as potential clinical biomarker(s) for BE by whole genome profiling. We detected copy number alterations and/or loss of heterozygosity at 56 fragile sites in 20 patients with premalignant BE. Chromosomal fragile sites are particularly sensitive to DNA breaks and are frequent sites of rearrangement or loss in many human cancers. Seventy-eight percent of all genomic alterations detected by array-CGH were associated with fragile sites. Copy number losses in early BE were observed at particularly high frequency at FRA3B (81%), FRA9A/C (71.4%), FRA5E (52.4%), and FRA 4D (52.4%), and at lower frequencies in other fragile sites, including FRA1K (42.9%), FRAXC (42.9%), FRA 12B (33.3%), and FRA16D (33.3%). Due to the consistency of the region of copy number loss, we were able to verify these results by quantitative PCR, which detected the loss of FRA3B and FRA16D, in 83% and 40% of early molecular stage BE patients, respectively. Loss of heterozygosity in these cases was confirmed through pyrosequencing at FRA3B and FRA16D (75% and 70%, respectively). Deletion and genomic instability at FRA3B and other fragile sites could thus be a biomarker of genetic damage in BE patients and a potential biomarker of cancer risk. PMID:20647332

Lai, Lisa A; Kostadinov, Rumen; Barrett, Michael T; Peiffer, Daniel A; Pokholok, Dimitry; Odze, Robert; Sanchez, Carissa A; Maley, Carlo C; Reid, Brian J; Gunderson, Kevin L; Rabinovitch, Peter S

2010-08-01

238

Deletion at Fragile Sites is a Common and Early Event in Barrett's Esophagus  

PubMed Central

Barrett’s esophagus is a premalignant intermediate to esophageal adenocarcinoma, which develops in the context of chronic inflammation and exposure to bile and acid. We asked whether there might be common genomic alterations that could be identified as potential clinical biomarker(s) for Barrett’s esophagus by whole genome profiling. We detected copy number alterations and/or loss of heterozygosity (LOH) at fifty-six fragile sites in 20 patients with premalignant Barrett’s esophagus (BE). Chromosomal fragile sites are particularly sensitive to DNA breaks and have been shown to be frequent sites of rearrangement or loss in many human cancers. 78% of all genomic alterations detected by array-CGH were associated with fragile sites. Copy number losses in early BE were observed at particularly high frequency at FRA3B (81%), FRA9A/C (71.4%), FRA5E (52.4%) and FRA 4D (52.4%), and at lower frequencies in other fragile sites, including FRA1K (42.9%), FRAXC (42.9%), FRA 12B (33.3%) and FRA16D (33.3%). Due to the consistency of the region of copy number loss, we were able to verify these results by quantitative PCR which detected loss of FRA3B and FRA16D, in 83% and 40% of early molecular stage BE patients respectively. LOH in these cases was confirmed via pyrosequencing at FRA3B and FRA16D (75% and 70% respectively). Deletion and genomic instability at FRA3B and other fragile sites could thus be a biomarker of genetic damage in BE patients and a potential biomarker of cancer risk.

Lai, Lisa A.; Kostadinov, Rumen; Barrett, Michael T.; Peiffer, Daniel A.; Pokholok, Dimitry; Odze, Robert; Sanchez, Carissa A.; Maley, Carlo C.; Reid, Brian J.; Gunderson, Kevin L.; Rabinovitch, Peter S.

2011-01-01

239

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

PubMed

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

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

2013-12-23

240

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

PubMed Central

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

Swanson, Eric C.; Manning, Benjamin; Zhang, Hong

2013-01-01

241

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

PubMed

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

Babé, Aurélie; Lavigne, Tristan; Séverin, Jean-Philippe; Nagel, Kerstin A; Walter, Achim; Chaumont, François; Batoko, Henri; Beeckman, Tom; Draye, Xavier

2012-06-01

242

Early signaling events in grapevine cells elicited with cyclodextrins and methyl jasmonate.  

PubMed

The use of cyclic oligosaccharides like cyclodextrins (CDs), alone or combined with methyl jasmonate (MJ), as elicitors has proved very effective in stimulating the production of trans-resveratrol (trans-R) in Vitis vinifera suspension-cultured cells (SCC). Since elicitors can be used to increase trans-R production, understanding the molecular mechanisms involved would improve the management of grapevine cells as factories of this compound. The results obtained in this study provide evidence for a role of Ca(2+) in mediating elicitor-induced trans-R production in grapevine SCC. The Ca(2+) elevation was promoted by an uptake of Ca(2+) from the extracellular medium, and by Ca(2+) mobilization from intracellular organelles. Moreover, protein phosphorylation/dephosphorylation events seem to be involved in the signal transduction pathways triggered by CDs separately or in combination with MJ since trans-R production is dependent on both, the phosphorylation status of several proteins through mitogen-activated kinase pathway and the activity of tyrosine phosphatases. Our results also suggest that H(2)O(2) and NO participated in the production of trans-R triggered by both elicitors in grapevine SCC. Finally, a fast alkalinization of the extracellular medium is induced in the presence of CDs and/or MJ. PMID:23208304

Belchí-Navarro, Sarai; Almagro, Lorena; Sabater-Jara, Ana Belén; Fernández-Pérez, Francisco; Bru, Roque; Pedreño, Maria A

2013-01-01

243

Early sequence of events triggered by the interaction of Neisseria meningitidis with endothelial cells.  

PubMed

Neisseria meningitidis is a bacterium responsible for severe sepsis and meningitis. Following type IV pilus-mediated adhesion to endothelial cells, bacteria proliferating on the cellular surface trigger a potent cellular response that enhances the ability of adhering bacteria to resist the mechanical forces generated by the blood flow. This response is characterized by the formation of numerous 100?nm wide membrane protrusions morphologically related to filopodia. Here, a high-resolution quantitative live-cell fluorescence microscopy procedure was designed and used to study this process. A farnesylated plasma membrane marker was first detected only a few seconds after bacterial contact, rapidly followed by actin cytoskeleton reorganization and bulk cytoplasm accumulation. The bacterial type IV pili-associated minor pilin PilV is necessary for the initiation of this cascade. Plasma membrane composition is a key factor as cholesterol depletion with methyl-?-cyclodextrin completely blocks the initiation of the cellular response. In contrast membrane deformation does not require the actin cytoskeleton. Strikingly, plasma membrane remodelling undermicrocolonies is also independent of common intracellular signalling pathways as cellular ATP depletion is not inhibitory. This study shows that bacteria-induced plasma membrane reorganization is a rapid event driven by a direct cross-talk between type IV pili and the plasma membrane rather than by the activation of an intracellular signalling pathway that would lead to actin remodelling. PMID:24320113

Soyer, Magali; Charles-Orszag, Arthur; Lagache, Thibault; Machata, Silke; Imhaus, Anne-Flore; Dumont, Audrey; Millien, Corinne; Olivo-Marin, Jean-Christophe; Duménil, Guillaume

2014-06-01

244

How Cells feel their environment: a focus on early dynamic events  

PubMed Central

It is now well demonstrated that cell adhesion to a foreign surface strongly influences prominent functions such as survival, proliferation, differentiation, migration or mediator release. Thus, a current challenge of major practical and theoretical interest is to understand how cells process and integrate environmental cues to determine future behaviour. The purpose of this review is to summarize some pieces of information that might serve this task. Three sequential points are discussed. First, selected examples are presented to illustrate the influence of substratum chemistry, topography and mechanical properties on nearly all aspects of cell behaviour observed during the days following adhesion. Second, we review reported evidence that long term cell behaviour is highly dependent on the alterations of cell shape and cytoskeletal organization that are often initiated during the minutes to hours following adhesion. Third, we review recently obtained information on cell membrane roughness and dynamics, as well as kinetics and mechanics of molecular interactions. This knowledge is required to understand the influence of substratum structure on cell signaling during the first minute following contact, before the appearance of detectable structural changes. It is suggested that unraveling the earliest phenomena following cell-to-substratum encounter might provide a tractable way of better understanding subsequent events.

Cretel, Elodie; Pierres, Anne; Benoliel, Anne-Marie; Bongrand, Pierre

2008-01-01

245

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

NASA Astrophysics Data System (ADS)

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).

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

2014-05-01

246

CD6 attenuates early and late signaling events, setting thresholds for T-cell activation  

PubMed Central

The T lineage glycoprotein CD6 is generally considered to be a costimulator of T-cell activation. Here, we demonstrate that CD6 significantly reduces early and late T-cell responses upon superantigen stimulation or TCR triggering by Abs. Measuring calcium mobilization in single cells responding to superantigen, we found that human T cells expressing rat CD6 react significantly less well compared with T cells not expressing the exogenous receptor. When the cytoplasmic domain of rat CD6 was removed, calcium responses were recovered, indicating that the inhibitory properties of CD6 are attributable to its cytoplasmic domain. Calcium responses, and also late indicators of T-cell activation such as IL-2 release, were also diminished in TCR-activated Jurkat cells expressing human CD6, compared with CD6-deficient cells or cells expressing a cytoplasmic deletion mutant of human CD6. Similarly, calcium signals triggered by anti-CD3 were enhanced in human T lymphocytes following morpholino-mediated suppression of CD6 expression. Finally, the proliferation of T lymphocytes was increased when the CD6–CD166 interaction was blocked with anti-CD166 Abs, but inhibited when anti-CD6 Abs were used. Our data suggest that CD6 is a signaling attenuator whose expression alone, i.e. in the absence of ligand engagement, is sufficient to restrain signaling in T cells.

Oliveira, Marta I; Goncalves, Carine M; Pinto, Mafalda; Fabre, Stephanie; Santos, Ana Mafalda; Lee, Simon F; Castro, Monica A A; Nunes, Raquel J; Barbosa, Rita R; Parnes, Jane R; Yu, Chao; Davis, Simon J; Moreira, Alexandra; Bismuth, Georges; Carmo, Alexandre M

2012-01-01

247

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

NASA Technical Reports Server (NTRS)

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.

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

1987-01-01

248

CD8 T cell competition for dendritic cells in vivo is an early event in activation  

PubMed Central

T cell responses against an antigen are often focused on a small fraction of potentially immunogenic determinants, a phenomenon known as immunodominance. Immunodominance can be established at several stages of antigen presentation, including antigen processing, binding of peptides to MHC, and competition between T cells for dendritic cells (DCs). The mechanism of this T cell competition is unclear, but may include competition for physical access to DCs, competition for limiting soluble DC-derived factors, or a suppressive effect of one T cell population on the other(s). To model DC-specific T cell competition, normal mice were injected with one or two T cell receptor transgenic CD8 T cell populations, each with high affinity for different peptides presented by different class I MHC complexes. These mice were immunized with DCs pulsed with peptides that are recognized by the transferred T cells. Competition was detectable when both T cell populations were transferred and their target peptides were present on the same DCs. The competition resulted in fewer cells entering the response, but had no effect on the level of activation of the cells that did respond. The effect was evident very early in the response, and in fact the competing T cells needed to be present in the first 5 h of the response for competition to occur. Thus, some aspect of DCs other than peptide/MHC complexes is limiting in the earliest stages of the CD8 T cell response. These results have implications for the design of multivalent vaccines.

Willis, Richard A.; Kappler, John W.; Marrack, Philippa C.

2006-01-01

249

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

PubMed

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 1 week 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

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

2013-06-01

250

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

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…

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

2014-01-01

251

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

NASA Astrophysics Data System (ADS)

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 ~10°C, 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.

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

2005-12-01

252

Zinc accumulation after target loss: an early event in retrograde degeneration of thalamic neurons  

PubMed Central

Accumulation of cytoplasmic zinc is linked with a cascade of events leading to neuronal death. In many in vivo models of zinc-induced cell death, toxic concentrations of synaptically released zinc enter vulnerable neurons via neurotransmitter- or voltage-gated ion channels. In vitro studies demonstrate, in addition, that zinc can be liberated from intracellular stores following oxidative stress and contribute to cell death processes, including apoptosis. Here we describe accumulation of intracellular zinc in an in vivo model of cell death in the absence of presynaptic zinc release. We focused on the lateral geniculate nucleus (LGN) because LGN neurons undergo apoptosis when separated from their target, the primary visual cortex (V1), and the LGN is mostly devoid of zinc-containing presynaptic terminals. Infant and adult rats and adult mice received unilateral ablation of V1, either by aspiration or kainate injection. One to 14 days later, brain sections were stained with selenium autometallography or fluorescently labeled to localize zinc, or stained immunochemically for activated caspase-3. V1 lesions led to zinc accumulation in LGN neurons in infant and adult subjects. Zinc-containing neurons were evident 1–3 days after aspiration lesions, depending on age, but not until 14 days after kainate injection. Zinc accumulation was followed rapidly by immunostaining for activated caspase-3. Our data indicate that like neurotrauma and excitotoxicity, target deprivation leads to accumulation of zinc in apoptotic neurons. Moreover, zinc accumulation in vivo can occur in the absence of presynaptic zinc release. Together these findings suggest that accumulation of intracellular zinc is a ubiquitous component of the cell death cascade in neurons.

Land, Peter W.; Aizenman, Elias

2010-01-01

253

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

PubMed Central

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 child’s 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 child’s treatment may be particularly effective in the treatment of young children exposed to multiple risks.

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

2011-01-01

254

The actin cytoskeleton participates in the early events of autophagosome formation upon starvation induced autophagy  

PubMed Central

Autophagy is a process by which cytoplasmic material is sequestered in a double-membrane vesicle destined for degradation. Nutrient deprivation stimulates the pathway and the number of autophagosomes in the cell increases in response to such stimulus. In the current report we have demonstrated that actin is necessary for starvation-mediated autophagy. When the actin cytoskeleton is depolymerized, the increase in autophagic vacuoles in response to the starvation stimulus was abolished without affecting maturation of remaining autophagosomes. In addition, actin filaments colocalized with ATG14, BECN1/Beclin1 and PtdIns3P-rich structures, and some of them have a typical omegasome shape stained with the double FYVE domain or ZFYVE1/DFCP1. In contrast, no major colocalization between actin and ULK1, ULK2, ATG5 or MAP1LC3/LC3 was observed. Taken together, our data indicate that actin has a role at very early stages of autophagosome formation linked to the PtdIns3P generation step. In addition, we have found that two members of the Rho family of proteins, RHOA and RAC1 have a regulatory function on starvation-mediated autophagy, but with opposite roles. Indeed, RHOA has an activatory role whereas Rac has an inhibitory one. We have also found that inhibition of the RHOA effector ROCK impaired the starvation-mediated autophagic response. We propose that actin participates in the initial membrane remodeling stage when cells require an enhanced rate of autophagosome formation, and this actin function would be tightly regulated by different members of the Rho family.

Aguilera, Milton Osmar; Beron, Walter; Colombo, Maria Isabel

2012-01-01

255

The effects of early experience on face recognition: an event-related potential study of institutionalized children in Romania.  

PubMed

Data are reported from 3 groups of children residing in Bucharest, Romania. Face recognition in currently institutionalized, previously institutionalized, and never-institutionalized children was assessed at 3 time points: preintervention (n = 121), 30 months of age (n = 99), and 42 months of age (n = 77). Children watched photographs of caregiver and stranger faces while event-related potentials were recorded. Results demonstrate that institutionalized children show pervasive cortical hypoarousal in response to faces and that foster care is somewhat effective in remediating this deficit by 42 months of age. All 3 groups of children distinguished between the familiar and unfamiliar faces. These results have the potential to inform an understanding of the role of early experience in the development of the neural systems that subserve face recognition. PMID:19630892

Moulson, Margaret C; Westerlund, Alissa; Fox, Nathan A; Zeanah, Charles H; Nelson, Charles A

2009-01-01

256

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

PubMed Central

A major neuropathological hallmark of Alzheimer’s disease (AD) is the deposition of aggregated ? amyloid (A?) peptide in the senile plaques. A? 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 ? 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 A? 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 A? peptides in Alzheimer’s disease.

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

2012-01-01

257

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

NASA Astrophysics Data System (ADS)

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 ? 13C values suggesting a contribution of isotopically light biogenic CO 2 during the carbonate precipitation. As to ? 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.

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

2011-03-01

258

Quantifying the differential effects of DHA and DPA on the early events in visual signal transduction.  

PubMed

A range of evidence from animal, clinical and epidemiological studies indicates that highly polyunsaturated acyl chains play important roles in development, cognition, vision and other aspects of neurological function. In a number of these studies n3 polyunsaturated fatty acids (PUFAs) appear to be more efficacious than n6 PUFAs. In a previous study of retinal rod outer segments obtained from rats raised on either an n3 adequate or deficient diet, we demonstrated that the replacement of 22:6n3 by 22:5n6 in the n3 deficient rats led to functional deficits in each step in the visual signaling process (Niu et al., 2004). In this study, we examined rhodopsin and phosphodiesterase function and acyl chain packing properties in membranes consisting of phosphatidylcholines with sn-1=18:0, and sn-2=22:6n3, 22:5n6, or 22:5n3 in order to determine if differences in function are due to the loss of one double bond or due to differences in double bond location. At 37 °C the n6 lipid shifted the equilibrium between the active metarhodopsin II (MII) state and inactive metarhodopsin I (MI) state towards MI. In addition, 22:5n6 reduced the rates of MII formation and MII-transducin complex formation by 2- and 6-fold, respectively. At a physiologically relevant level of rhodopsin light stimulation, the activity of phosphodiesterase was reduced by 50% in the 22:5n6 membrane, relative to either of the n3 membranes. Activity levels in the two n3 membranes were essentially identical. Ensemble acyl chain order was assessed with time-resolved fluorescence measurements of the membrane probe diphenylhexatriene (DPH). Analysis in terms of the orientational distribution of DPH showed that acyl chain packing in the two n3 membranes is quite similar, while in the 22:5n6 membrane there was considerably less packing disorder in the bilayer midplane. These results demonstrate that the n3 bond configuration uniquely optimizes the early steps in signaling via a mechanism which may involve acyl chain packing deep in the bilayer. PMID:22405878

Mitchell, Drake C; Niu, Shui-Lin; Litman, Burton J

2012-05-01

259

Perillyl Alcohol Protects Against Fe-NTA-Induced Nephrotoxicity and Early Tumor Promotional Events in Rat Experimental Model  

PubMed Central

Plants have been widely used as protective agents against a wide variety of processes and compounds that damage tissues via free radical mechanisms. Perillyl alcohol (PA) is a naturally occurring monoterpene found in the essential oils of numerous species of plants including mints, cherries and celery seeds. This monocyclic monoterpene has shown antioxidant and therapeutic activity in various studies against various xenobiotics. In this study, we have analyzed the effects of PA against single intraperitoneal dose of ferric nitrilotriacetate (Fe-NTA) (9 mg iron per kg body weight)-induced nephrotoxicity and early tumor promotional events. The pretreatment of Fe-NTA-treated rats with 0.5% per kg body weight dose and 1% per kg body weight dose of PA for seven consecutive days significantly reversed the Fe-NTA-induced malondialdehyde formation, xanthine oxidase activity (P < 0.001), ornithine decarboxylase activity (P < 0.001) and 3[H]thymidine incorporation in renal DNA (P < 0.001) with simultaneous significant depletion in serum toxicity markers blood urea nitrogen and creatinine (P < 0.001). Significant restoration at both the doses was recorded in depleted renal glutathione content, and its dependent enzymes with prophylactic treatment of PA. Present results suggest that PA potentially attenuates against Fe-NTA-induced oxidative damage and tumor promotional events that preclude its development as a future drug to avert the free radical-induced toxicity.

Jahangir, Tamanna

2007-01-01

260

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

PubMed Central

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.

Vakli, Pal; Nemeth, Kornel; Zimmer, Marta; Schweinberger, Stefan R.; Kovacs, Gyula

2014-01-01

261

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

PubMed

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 microl 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 microl 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

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

2009-01-01

262

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

NASA Astrophysics Data System (ADS)

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, Neuquén (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.

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

2012-12-01

263

Timing and Paleoceanography of Early Cretaceous Oceanic Anoxic Events in the Pacific Ocean as Determined From Wireline Logs  

NASA Astrophysics Data System (ADS)

DSDP and ODP core recovery of Early Cretaceous pelagic sediments in the Pacific Ocean has been limited by the widespread occurrence of chert. Remarkably, Leg 198 of the Ocean Drilling Program (Shatsky Rise, north west Pacific) was very successful in recovering shales rich in organic-carbon, dated as being equivalent to the Early Aptian "Selli Level", thus confirming the truly global nature of Oceanic Anoxic Event 1a. However, recovery of contiguous deposits of late Aptian and Albian age was generally poor. Two of three sites at which OAE1a was recovered (1207 and 1213) were logged using standard downhole geophysical tools, which provide us with an alternative method for investigating the sedimentary and paleoceanographic history of these sites. Using the downhole logs we present an interpretation of the Aptian-Albian sedimentary history of Shatsky Rise and discuss the paleoceanographic implications of changing abundances of clay, carbonate and biosiliceous sediments. Plotting the geophysical logging data against time yields interesting information about the onset, duration and termination of organic-carbon burial. Comparison with logging and biostratigraphic data from other sites in the Pacific and Tethys allows us to assess whether OAE1a was truly synchronous and to evaluate differences in paleoceanography in different ocean basins during OAE1a.

Robinson, S. A.; Williams, T.; Bown, P. R.

2003-12-01

264

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

NASA Astrophysics Data System (ADS)

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

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

2013-12-01

265

Parvovirus Minute Virus of Mice Induces a DNA Damage Response That Facilitates Viral Replication  

PubMed Central

Infection by DNA viruses can elicit DNA damage responses (DDRs) in host cells. In some cases the DDR presents a block to viral replication that must be overcome, and in other cases the infecting agent exploits the DDR to facilitate replication. We find that low multiplicity infection with the autonomous parvovirus minute virus of mice (MVM) results in the activation of a DDR, characterized by the phosphorylation of H2AX, Nbs1, RPA32, Chk2 and p53. These proteins are recruited to MVM replication centers, where they co-localize with the main viral replication protein, NS1. The response is seen in both human and murine cell lines following infection with either the MVMp or MVMi strains. Replication of the virus is required for DNA damage signaling. Damage response proteins, including the ATM kinase, accumulate in viral-induced replication centers. Using mutant cell lines and specific kinase inhibitors, we show that ATM is the main transducer of the signaling events in the normal murine host. ATM inhibitors restrict MVM replication and ameliorate virus-induced cell cycle arrest, suggesting that DNA damage signaling facilitates virus replication, perhaps in part by promoting cell cycle arrest. Thus it appears that MVM exploits the cellular DNA damage response machinery early in infection to enhance its replication in host cells.

Adeyemi, Richard O.; Landry, Sebastien; Davis, Meredith E.; Weitzman, Matthew D.; Pintel, David J.

2010-01-01

266

Coxsackievirus B3-induced calpain activation facilitates the progeny virus replication via a likely mechanism related with both autophagy enhancement and apoptosis inhibition in the early phase of infection: an in vitro study in H9c2 cells.  

PubMed

Calpain is a family of neutral cysteine proteinase involved in many physiological and pathological processes including virus replication, autophagy and apoptosis. Previous study has indicated the involvement of calpain in pathogenesis of coxsackievirus B3 (CVB3)-induced myocarditis. Besides, many studies demonstrated that host cell autophagy and apoptosis mechanisms participate in virus life cycle. However, role of calpain in CVB3 replication via autophagy/apoptosis mechanisms has not been reported, which was discussed here in H9c2 cardiomyocytes. The data demonstrated that calpain was activated following CVB3 infection. Calpain inhibition decreased autophagy, indicating role of calpain in enhancing autophagy during CVB3 infection. Both calpain activity and autophagy were involved in facilitating CVB3 replication demonstrated by virus titer and CVB3 capsid protein VP1 expression alterations resulting from calpain inhibitor ALLN and autophagy inhibitor 3MA intervention. We also found that both calpain activity and autophagy suppressed caspase3 activity and host cell apoptosis 5-10h post-infection (p.i.). In summary, the present study shows that CVB3 infection of H9c2 cells hinders caspase3 activity provocation and cell apoptosis at least in the early phase of infection (5-10h p.i.) via calpain-induced autophagy enhancement, which might be a mechanism facilitating CVB3 replication in host cells. PMID:24177271

Li, Minghui; Wang, Xinggang; Yu, Yong; Yu, Ying; Xie, Yeqing; Zou, Yunzeng; Ge, Junbo; Peng, Tianqing; Chen, Ruizhen

2014-01-22

267

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

NASA Astrophysics Data System (ADS)

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

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

2014-05-01

268

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

NASA Astrophysics Data System (ADS)

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.

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

2014-05-01

269

Cardiovascular events in early RA are a result of inflammatory burden and traditional risk factors: a five year prospective study  

PubMed Central

Introduction Co-morbidity and mortality due to cardiovascular disease (CVD) are increased in patients with rheumatoid arthritis (RA). Most published studies in this field are retrospective or cross sectional. We investigated the presence of traditional and disease related risk factors for CVD at the onset of RA and during the first five years following diagnosis. We also evaluated their potential for predicting a new cardiovascular event (CVE) during the five-year follow-up period and the modulatory effect of pharmacological treatment. Methods All patients from the four northern-most counties of Sweden with early RA are, since December 1995, consecutively recruited at diagnosis (T0) into a large survey on the progress of the disease. Information regarding cardiovascular co-morbidity and related predictors was collected from clinical records and supplemented with questionnaires. By April 2008, 700 patients had been included of whom 442 patients had reached the five-year follow-up (T5). Results Among the 442 patients who reached T5 during the follow-up period, treatment for hypertension increased from 24.5 to 37.4% (P < 0.001)), diagnosis of diabetes mellitus (DM) from 7.1 to 9.5% (P < 0.01) whilst smoking decreased from 29.8 to 22.4% (P < 0.001) and the BMI from 26.3 to 25.8 (P < 0.05), respectively. By T5, 48 patients had suffered a new CVE of which 12 were fatal. A total of 23 patients died during the follow-up period. Age at disease onset, male sex, a previous CVE, DM, treatment for hypertension, triglyceride level, cumulative disease activity (area under the curve (AUC) disease activity score (DAS28)), extra-articular disease, corticosteroid use, shorter duration of treatment with disease modifying anti-rheumatic drugs (DMARDs) and use of COX-2 inhibitors increased the hazard rate for a new CVE. A raised erythrocyte sedimentation rate (ESR) at inclusion and AUC DAS28 at six months increased the hazard rate of CVE independently whilst DMARD treatment was protective in multiple Cox extended models adjusted for sex and CV risk factors. The risk of a CVE due to inflammation was potentiated by traditional CV risk factors. Conclusions The occurrence of new CV events in very early RA was explained by traditional CV risk factors and was potentiated by high disease activity. Treatment with DMARDs decreased the risk. The results may have implications for cardio-protective strategies in RA.

2011-01-01

270

Effects of Phenylethyl Isothiocyanate on Early Molecular Events in N-Nitrosomethylbenzylamine-Induced Cytotoxicity in Rat Esophagus  

PubMed Central

There is little information on early molecular events in the development of N-nitrosomethylbenzylamine (NMBA)–induced rat esophageal tumorigenesis and of the effects of chemopreventive agents on these events. In this study, we identified genes in rat esophagus that were differentially expressed in response to short-term NMBA treatment and modulated by cotreatment with phenylethyl isothiocyanate (PEITC). Rats were fed AIN-76A diet or AIN-76A diet containing PEITC for 3 weeks. During the 3rd week of dietary treatment, they were administered three s.c. doses of NMBA (0.5 mg/kg body weight). Rats were sacrificed 24 h after the last treatment; esophagi were excised and processed for histologic grading, microarray and real-time PCR analysis. Histopathologic analysis showed that treatment of rats with PEITC had a protective effect on NMBA-induced preneoplastic lesions in the rat esophagus. We identified 2,261 genes that were differentially expressed in the NMBA-treated versus control esophagi and 1,936 genes in the PEITC + NMBA versus NMBA-treated esophagi. The intersection of these two sets resulted in the identification of 1,323 genes in NMBA-treated esophagus, the vast majority of which were modulated by PEITC to near-normal levels of expression. Measured changes in the expression levels of eight selected genes were validated using real-time PCR. Results from 12 microarrays indicated that PEITC treatment had a genome-wide modulating effect on NMBA-induced gene expression. Samples obtained from animals treated with PEITC alone or cotreated with PEITC + NMBA were more similar to controls than to samples treated with NMBA alone.

Reen, Rashmeet K.; Dombkowski, Alan A.; Kresty, Laura A.; Cukovic, Daniela; Mele, Jennifer M.; Salagrama, Sridevi; Nines, Ronald; Stoner, Gary D.

2010-01-01

271

Receptor-linked early events induced by vasoactive intestinal contractor (VIC) on neuroblastoma and vascular smooth-muscle cells.  

PubMed Central

Vasoactive intestinal contractor (VIC) caused a series of biochemical events, including the temporal biphasic accumulation of 1,2-diacylglycerol (DAG), transient formation of Ins(1,4,5)P3, and increase in intracellular free Ca2+ [( Ca2+]i) in neuroblastoma NG108-15 cells. In these cellular responses, VIC was found to be much more potent in NG108-15 cells than in cultured rat vascular smooth-muscle cells. The single cell [Ca2+]i assay revealed that in the presence of nifedipine (1 microM) or EGTA (1 mM), the peak [Ca2+]i declined more rapidly to the resting level in VIC-stimulated NG108-15 cells, indicating that the receptor-mediated intracellular Ca2+ mobilization is followed by Ca2+ influx through the nifedipine-sensitive Ca2+ channel. Pretreatment with pertussis toxin only partially decreased Ins(1,4,5)P3 generation as well as the [Ca2+]i transient induced by VIC, whereas these events induced by endothelin-1 were not affected by the toxin, suggesting involvement of distinct GTP-binding proteins. The VIC-induced transient Ins(1,4,5)P3 formation coincident with the first early peak of DAG formation suggested that PtdIns(4,5)P2 is a principal source of the first DAG increase. Labelling studies with [3H]myristate, [14C]palmitate and [3H]choline indicated that in neuroblastoma cells phosphatidylcholine (PtdCho) was hydrolysed by a phospholipase C to cause the second sustained DAG increase. Down-regulation of protein kinase C (PKC) by prolonged pretreatment with phorbol ester markedly prevented the VIC-induced delayed DAG accumulation. Furthermore, chelation of intracellular CA2+ completely abolished the second sustained phase of DAG production. These findings suggest that PtdCho hydrolysis is responsible for the sustained production of DAG and is dependent on both Ca2+ and PKC.

Fu, T; Okano, Y; Zhang, W; Ozeki, T; Mitsui, Y; Nozawa, Y

1990-01-01

272

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

PubMed Central

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

Ye, Xiaoqin

2013-01-01

273

Nuclear Position Leaves its Mark on Replication Timing  

Microsoft Academic Search

The multiple replication origins of eukaryotic chromo- somes are programmed to replicate at specific times throughout S phase of the cell cycle. The functional sig- nificance of this program is not understood, but, in gen- eral, transcriptionally active chromatin replicates early in S phase, whereas hypoacetylated, transcriptionally in- active chromatin replicates later. During metazoan de- velopment, multiple origins, encompassing megabase

David M. Gilbert

2001-01-01

274

Modified allelic replication in lymphocytes of patients with neurofibromatosis type 1  

Microsoft Academic Search

Transcription activity of genes is related to their replication timing, accordingly gene activation is coupled with a shift from late replication to early replication and vice versa. The relationship between replication timing and gene expression is best manifested by monoallelically expressed genes which show an asynchronous pattern of allelic replication, with the active allele replicating earlier than the inactive counterpart.

Orit Reish; Ana Orlovski; Maya Mashevitz; Carron Sher; Vitalia Libman; Malka Rosenblat; Lydia Avivi

2003-01-01

275

Early and late HIV-1 membrane fusion events are impaired by sphinganine lipidated peptides that target the fusion site.  

PubMed

Lipid-conjugated peptides have advanced the understanding of membrane protein functions and the roles of lipids in the membrane milieu. These lipopeptides modulate various biological systems such as viral fusion. A single function has been suggested for the lipid, binding to the membrane and thus elevating the local concentration of the peptide at the target site. In the present paper, we challenged this argument by exploring in-depth the antiviral mechanism of lipopeptides, which comprise sphinganine, the lipid backbone of DHSM (dihydrosphingomyelin), and an HIV-1 envelope-derived peptide. Surprisingly, we discovered a partnership between the lipid and the peptide that impaired early membrane fusion events by reducing CD4 receptor lateral diffusion and HIV-1 fusion peptide-mediated lipid mixing. Moreover, only the joint function of sphinganine and its conjugate peptide disrupted HIV-1 fusion protein assembly and folding at the later fusion steps. Via imaging techniques we revealed for the first time the direct localization of these lipopeptides to the virus-cell and cell-cell contact sites. Overall, the findings of the present study may suggest lipid-protein interactions in various biological systems and may help uncover a role for elevated DHSM in HIV-1 and its target cell membranes. PMID:24766462

Klug, Yoel A; Ashkenazi, Avraham; Viard, Mathias; Porat, Ziv; Blumenthal, Robert; Shai, Yechiel

2014-07-15

276

Indirect comparisons of adverse events and dropout rates in early Parkinson's disease trials of pramipexole, ropinirole, and rasagiline.  

PubMed

The comparative safety profiles of monotherapeutic treatments for Parkinson's disease (PD) can provide valuable therapeutic information. The objective of this study was to perform an indirect comparison of Adverse Events (AEs) and Dropout Rates (DRs) among clinical trials of pramipexole, ropinirole, and rasagiline. Outcomes analyzed included DRs, total AEs, and AE categories: Cognitive (CG), Gastrointestinal (GI), and Sleep/Fatigue (SF). The odds-ratio (OR) and Credible Interval (CrI) of outcomes between products using placebo as common comparator was calculated using indirect meta-analytical methods. AEs incidences for subjects receiving rasagiline were not significantly different from placebo, whereas DRs were significantly lower than for placebo (OR = 0.55; 95% CrI = 0.34-0.88). Patients receiving pramipexole or ropinirole had higher incidence of all AEs and DRs than patients taking rasagiline, except for the nonsignificant incidence of CG for ropinirole vs. rasagiline (1.76; 0.69-4.70). The incidence of GI (2.11; 1.13-4.06) and SF (2.75; 1.42-5.47) was significantly higher for ropinirole than for pramipexole, whereas the incidence of CG was significantly lower for ropinirole than for pramipexole (0.22; 0.07-0.69). Findings suggest that subjects with early PD treated with rasagiline have fewer AEs and DRs than those treated with pramipexole or ropinirole. GI and SF AEs were highest for subjects treated with ropinirole, while individuals treated with pramipexole exhibited the highest incidence of cognitive AEs. PMID:22304415

Zagmutt, Francisco J; Tarrants, Marcy L

2012-07-01

277

Early Events in the Fusarium verticillioides-Maize Interaction Characterized by Using a Green Fluorescent Protein-Expressing Transgenic Isolate  

PubMed Central

The infection of maize by Fusarium verticillioides can result in highly variable disease symptoms ranging from asymptomatic plants to severe rotting and wilting. We produced F. verticillioides green fluorescent protein-expressing transgenic isolates and used them to characterize early events in the F. verticillioides-maize interaction that may affect later symptom appearance. Plants grown in F. verticillioides-infested soil were smaller and chlorotic. The fungus colonized all of the underground parts of a plant but was found primarily in lateral roots and mesocotyl tissue. In some mesocotyl cells, conidia were produced within 14 to 21 days after infection. Intercellular mycelium was detected, but additional cells were not infected until 21 days after planting. At 25 to 30 days after planting, the mesocotyl and main roots were heavily infected, and rotting developed in these tissues. Other tissues, including the adventitious roots and the stem, appeared to be healthy and contained only a small number of hyphae. These results imply that asymptomatic systemic infection is characterized by a mode of fungal development that includes infection of certain tissues, intercellular growth of a limited number of fungal hyphae, and reproduction of the fungus in a few cells without invasion of other cells. Development of visibly rotted tissue is associated with massive production of fungal mycelium and much less organized growth.

Oren, Liat; Ezrati, Smadar; Cohen, David; Sharon, Amir

2003-01-01

278

Upregulation of the insulin receptor and type I insulin-like growth factor receptor are early events in hepatocarcinogenesis.  

PubMed

The molecular mechanisms underlying the development of hepatocellular carcinoma (HCC) are not yet fully understood. Preneoplastic foci of altered hepatocytes regularly precede HCC in various species. The predominant earliest type of foci of altered hepatocytes, the glycogen storage focus (GSF), shows an excess of glycogen (glycogenosis) in the cytoplasm. During progression from GSF to HCC, the stored glycogen is gradually reduced, resulting in complete loss in basophilic HCC. We have previously shown that in N-nitrosomorpholine-induced hepatocarcinogenesis, insulin receptor substrate (IRS-1) is strongly expressed in GSF and reduced during progression to HCC, thus correlating with the glycogen content. In the present study, we observed increased levels of insulin receptor, IGF-I receptor (IGF-IR), IRS-2, and mitogen-activated kinase/extracellular regulated kinase-1 in GSF, following the same pattern of expression as IRS-1. We conclude that the abundance of IRS-1, IRS-2, and mitogen-activated kinase/extracellular regulated kinase-1 coincides with a concerted upregulation of both IR and IGF-IR induced by the hepatocarcinogen. Our data suggest that in early hepatocellular preneoplasia, the upregulation of IR elicits glycogenosis through IRS-1 and/or IRS-2, whereas the increased level of the IGF-IR may lead to the increased cell proliferation previously reported in GSF. Therefore, the concerted upregulation of both IR and IGF-IR may represent initial events in hepatocarcinogenesis. PMID:21411721

Aleem, Eiman; Nehrbass, Dirk; Klimek, Fritz; Mayer, Doris; Bannasch, Peter

2011-04-01

279

PIK3CA mutation is an early event in the development of endometriosis-associated ovarian clear cell adenocarcinoma.  

PubMed

Clear cell adenocarcinoma (CCA), a highly lethal histological subtype of ovarian carcinoma, is a type of human cancer with a high frequency of activating mutations in the PIK3CA gene. In this study, we aimed to determine how these mutations contribute to tumour development of CCAs. Exons 9 and 20 of the PIK3CA gene were analysed by direct genomic DNA sequencing of 23 CCAs with synchronous putative precursor lesions (ie endometriosis adjacent to carcinoma, with or without cytological atypia) and their mutational statuses were compared. Somatic mutations of the PIK3CA gene were detected in 10/23 (43%) carcinomas and in all cases the type of mutation was H1047R in the kinase domain. The identical H1047R mutation was also detected in the coexisting endometriotic epithelium, adjacent to the CCAs, in nine of ten (90%) cases. Moreover, in six of the nine lesions, the H1047R mutation was identified even in the endometrioses lacking cytological atypia. These findings provide evidence that mutations of the PIK3CA gene occur in the putative precursor lesions of CCA, strongly suggesting that they are very early events in tumourigenesis, probably initiating the malignant transformation of endometriosis. A specific kinase inhibitor to mutated PIK3CA may potentially be an effective therapeutic reagent against these carcinomas. PMID:21735444

Yamamoto, Sohei; Tsuda, Hitoshi; Takano, Masashi; Iwaya, Keichi; Tamai, Seiichi; Matsubara, Osamu

2011-10-01

280

First histopathological and immunophenotypic analysis of early dynamic events in a patient with segmental vitiligo associated with halo nevi.  

PubMed

Segmental vitiligo is often ascribed to the neurogenic theory of melanocyte destruction, although data about the initial etiopathological events are scarce. Clinical, histopathological and T-cell phenotypic analyses were performed during the early onset of a segmental vitiligo lesion in a patient with associated halo nevi. Histopathological analysis revealed a lymphocytic infiltrate, mainly composed of CD8+ T-cells and some CD4(+) T-cells around the dermo-epidermal junction. Flow cytometry analysis of resident T-cells revealed a clear enrichment of pro-inflammatory IFN-gamma producing CD8+ T-cells in lesional skin compared to the non-lesional skin. Using human leukocyte antigen-peptide tetramers (MART-1, tyrosinase, gp100), increased numbers of T cells, recognizing melanocyte antigens were found in segmental vitiligo lesional skin, as compared with the non-lesional skin and the blood. Our findings indicate that a CD8+ melanocyte specific T cell-mediated immune response, as observed in generalized vitiligo, also plays a role in segmental vitiligo with associated halo nevi. PMID:20370855

van Geel, Nanja A C; Mollet, Ilse G; De Schepper, Sofie; Tjin, Esther P M; Vermaelen, Karim; Clark, Rachael A; Kupper, Thomas S; Luiten, Rosalie M; Lambert, Jo

2010-06-01

281

MGMT promoter hypermethylation is a frequent, early, and consistent event in astrocytoma progression, and not correlated with TP53 mutation  

PubMed Central

Hypermethylation of the MGMT gene promoter and mutation of the TP53 tumor-suppressor gene are frequently present in diffuse astrocytomas. However, there is only anecdotal information about MGMT methylation status and TP53 mutations during progression of low-grade diffuse astrocytoma (AII) to anaplastic astrocytoma (AIII) and secondary glioblastoma (sGB). In this study biopsy specimens from 51 patients with astrocytic tumors with radiologically proved progression from low to high-grade malignancy were investigated for the presence and consistency of MGMT promoter hypermethylation and TP53 mutations. For 27 patients biopsy samples both of primary tumors and their recurrences were available. For the other 24 patients histology of either the low-grade lesion or the high-grade recurrence was available. It was found that MGMT promoter hypermethylation and TP53 mutations are both frequent and early events in the progression of astrocytomas and that their status is consistent over time. No correlation was found between MGMT methylation status and the presence of TP53 mutations. In addition, no correlation was found between MGMT promoter hypermethylation and the type of TP53 mutations. These results argue against the putative TP53 G:C>A:T transition mutations suggested to occur preferentially in MGMT hypermethylated tumors.

Groenendijk, Floris H.; Taal, Walter; Dubbink, Hendrikus J.; Haarloo, Cathleen R.; Kouwenhoven, Mathilde C.; van den Bent, Martin J.; Kros, Johan M.

2010-01-01

282

Membrane Proteome Analysis of Cerulein-Stimulated Pancreatic Acinar Cells: Implication for Early Event of Acute Pancreatitis  

PubMed Central

Background/Aims Cerulein pancreatitis is similar to human edematous pancreatitis with dysregulation of the production and secretion of digestive enzymes, edema formation, cytoplasmic vacuolization and the death of acinar cells. We hypothesized that membrane proteins may be altered as the early event during the induction of acute pancreatitis. Present study aims to determine the differentially expressed proteins in the membranes of cerulein-treated pancreatic acinar cells. Methods Pancreatic acinar AR42J cells were treated with 10-8 M cerulein for 1 hour. Membrane proteins were isolated from the cells and separated by two-dimensional electrophoresis using pH gradients of 5-8. Membrane proteins were identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis of the peptide digests. The differentially expressed proteins, whose expression levels were more or less than three-fold in cerulein-treated cells, were analyzed. Results Two differentially expressed proteins (mannan-binding lectin-associated serine protease-2, heat shock protein 60) were up-regulated while four proteins (protein disulfide isomerase, ?-actin, isocitrate dehydrogenase 3, seven in absentia homolog 1A) were down-regulated by cerulein treatment in pancreatic acinar cells. These proteins are related to cell signaling, oxidative stress, and cytoskeleton arrangement. Conclusions Oxidative stress may induce cerulein-induced cell injury and disturbances in defense mechanism in pancreatic acinar cells.

Lee, Jangwon; Seo, Ji Hye; Lim, Joo Weon

2010-01-01

283

Abnormal Mitochondrial Dynamics and Synaptic Degeneration as Early Events in Alzheimer's Disease: Implications to Mitochondria-Targeted Antioxidant Therapeutics  

PubMed Central

Synaptic pathology and mitochondrial oxidative damage are early events in Alzheimer’s disease (AD) progression. Loss of synapses and synaptic damage are the best correlate of cognitive deficits found in AD patients. Recent research on amyloid bet (A?) and mitochondria in AD revealed that A? accumulates in synapses and synaptic mitochondria, leading to abnormal mitochondrial dynamics and synaptic degeneration in AD neurons. Further, recent studies using live-cell imaging and primary neurons from amyloid beta precursor protein (A?PP) transgenic mice revealed that reduced mitochondrial mass, defective axonal transport of mitochondria and synaptic degeneration, indicating that A? is responsible for mitochondrial and synaptic deficiencies. Tremendous progress has been made in studying antioxidant approaches in mouse models of AD and clinical trials of AD patients. This article highlights the recent developments made in A?-induced abnormal mitochondrial dynamics, defective mitochondrial biogenesis, impaired axonal transport and synaptic deficiencies in AD. This article also focuses on mitochondrial approaches in treating AD, and also discusses latest research on mitochondria-targeted antioxidants in AD.

Reddy, P. Hemachandra; Tripathy, Raghav; Troung, Quang; Thirumala, Karuna; Reddy, Tejaswini P.; Anekonda, Vishwanath; Shirendeb, Ulziibat P.; Calkins, Marcus J.; Reddy, Arubala P.; Mao, Peizhong; Manczak, Maria

2011-01-01

284

Abnormal mitochondrial dynamics and synaptic degeneration as early events in Alzheimer's disease: implications to mitochondria-targeted antioxidant therapeutics.  

PubMed

Synaptic pathology and mitochondrial oxidative damage are early events in Alzheimer's disease (AD) progression. Loss of synapses and synaptic damage are the best correlates of cognitive deficits found in AD patients. Recent research on amyloid beta (A?) and mitochondria in AD revealed that A? accumulates in synapses and synaptic mitochondria, leading to abnormal mitochondrial dynamics and synaptic degeneration in AD neurons. Further, recent studies using live-cell imaging and primary neurons from amyloid beta precursor protein (A?PP) transgenic mice revealed reduced mitochondrial mass, defective axonal transport of mitochondria and synaptic degeneration, indicating that A? is responsible for mitochondrial and synaptic deficiencies. Tremendous progress has been made in studying antioxidant approaches in mouse models of AD and clinical trials of AD patients. This article highlights the recent developments made in A?-induced abnormal mitochondrial dynamics, defective mitochondrial biogenesis, impaired axonal transport and synaptic deficiencies in AD. This article also focuses on mitochondrial approaches in treating AD, and also discusses latest research on mitochondria-targeted antioxidants in AD. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease. PMID:22037588

Reddy, P Hemachandra; Tripathi, Raghav; Troung, Quang; Tirumala, Karuna; Reddy, Tejaswini P; Anekonda, Vishwanath; Shirendeb, Ulziibat P; Calkins, Marcus J; Reddy, Arubala P; Mao, Peizhong; Manczak, Maria

2012-05-01

285

Early and late HIV-1 membrane fusion events are impaired by sphinganine lipidated peptides that target the fusion site  

PubMed Central

Lipid-conjugated peptides have advanced the understanding of membrane protein functions and the roles of lipids in the membrane milieu. These lipopeptides modulate various biological systems such as viral fusion. A single function has been suggested for the lipid, binding to the membrane and thus elevating the local concentration of the peptide at the target site. In the present paper, we challenged this argument by exploring in-depth the antiviral mechanism of lipopeptides, which comprise sphinganine, the lipid backbone of DHSM (dihydrosphingomyelin), and an HIV-1 envelope-derived peptide. Surprisingly, we discovered a partnership between the lipid and the peptide that impaired early membrane fusion events by reducing CD4 receptor lateral diffusion and HIV-1 fusion peptide-mediated lipid mixing. Moreover, only the joint function of sphinganine and its conjugate peptide disrupted HIV-1 fusion protein assembly and folding at the later fusion steps. Via imaging techniques we revealed for the first time the direct localization of these lipopeptides to the virus–cell and cell–cell contact sites. Overall, the findings of the present study may suggest lipid–protein interactions in various biological systems and may help uncover a role for elevated DHSM in HIV-1 and its target cell membranes.

Klug, Yoel A.; Ashkenazi, Avraham; Viard, Mathias; Porat, Ziv; Blumenthal, Robert; Shai, Yechiel

2014-01-01

286

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

PubMed Central

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.

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

2014-01-01

287

Upregulation of focal adhesion kinase (FAK) expression in ductal carcinoma in situ (DCIS) is an early event in breast tumorigenesis.  

PubMed

Focal adhesion kinase (FAK) is a protein tyrosine kinase that is overexpressed in a subset of invasive breast cancers. FAK transmits signals that mediate several functions including tumor cell proliferation, migration, adhesion and survival. We used immunohistochemical techniques to assess FAK expression in patients with fibrocystic disease (FCD), atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDC). Formalin-fixed, paraffin-embedded (FFPE) tissue sections were obtained from 119 patients (12 FCD, 38 ADH, 51 DCIS and 18 IDC). The anti-FAK 4.47 monoclonal antibody was used to detect FAK expression. FAK expression was scored as high (3 or 4 intensity and > or =90% positive cells) or low. The DCIS tissue sections demonstrated high FAK expression in 34/51 (66%) of the sections. High FAK expression was demonstrated in 6/18 (33%) of the IDC tissue sections and 8/38 (21%) of the ADH tissue sections. None (0/12) of the FCD tissues sections stained high for FAK. The pattern of FAK expression in DCIS was significantly higher than ADH (p < 0.0001) and IDC (p = 0.02). We conclude that FAK overexpression in preinvasive, DCIS tumors precedes tumor cell invasion or metastasis, suggesting that FAK may function as a survival signal and be an early event in breast tumorigenesis. PMID:15564794

Lightfoot, Harry M; Lark, Amy; Livasy, Chad A; Moore, Dominic T; Cowan, David; Dressler, Lynn; Craven, Rolf J; Cance, William G

2004-11-01

288

Stimulation of Na+/H+ antiport is an early event in hypertrophy of renal proximal tubular cells.  

PubMed Central

Renal hypertrophy in vivo is achieved by an increase in protein content per cell and an increase in cell size with minimal hyperplasia. Hypertrophied renal tubular cells remain quiescent and demonstrate an increase in transcellular transport rates. This situation was simulated in vitro by exposing a confluent, quiescent primary culture of rabbit renal proximal tubular cells to either insulin, prostaglandin E1, or hypertonic NaCl for 24 or 48 hr. Protein per cell increased by 20-30% with little or no increase in [3H]thymidine incorporation into DNA. Mean cell volume was also increased in insulin- and hypertonic NaCl-treated but not in prostaglandin E1-treated cells. The lag period required to initiate DNA synthesis by a combination of insulin and hydrocortisone was the same in control and hypertrophied cells, indicating a quiescent state of the latter. Two hours of exposure to the growth stimuli increased amiloride-sensitive Na+ uptake, Na-dependent H+ efflux, and ouabain-sensitive Rb+ uptake, indicating that stimulation of Na+/H+ antiport (exchange) occurs as an early event in their action. Hypertrophied cells continued to demonstrate enhanced Na+/H+ antiport after the growth stimuli were removed for 3 hr, by which time their acute effects are reversed.

Fine, L G; Badie-Dezfooly, B; Lowe, A G; Hamzeh, A; Wells, J; Salehmoghaddam, S

1985-01-01

289

Characterization of the early events leading to totipotency in an Arabidopsis protoplast liquid culture by temporal transcript profiling.  

PubMed

The molecular mechanisms underlying plant cell totipotency are largely unknown. Here, we present a protocol for the efficient regeneration of plants from Arabidopsis thaliana protoplasts. The specific liquid medium used in our study leads to a high rate of reentry into the cell cycle of most cell types, providing a powerful system to study dedifferentiation/regeneration processes in independent somatic cells. To identify the early events in the establishment of totipotency, we monitored the genome-wide transcript profiles of plantlets and protoplast-derived cells (PdCs) during the first week of culture. Plant cells rapidly dedifferentiated. Then, we observed the reinitiation and reorientation of protein synthesis, accompanied by the reinitiation of cell division and de novo cell wall synthesis. Marked changes in the expression of chromatin-associated genes, especially of those in the histone variant family, were observed during protoplast culture. Surprisingly, the epigenetic status of PdCs and well-established cell cultures differed, with PdCs exhibiting rare reactivated transposons and epigenetic changes. The differentially expressed genes identified in this study are interesting candidates for investigating the molecular mechanisms underlying plant cell plasticity and totipotency. One of these genes, the plant-specific transcription factor ABERRANT LATERAL ROOT FORMATION4, is required for the initiation of protoplast division. PMID:23903317

Chupeau, Marie-Christine; Granier, Fabienne; Pichon, Olivier; Renou, Jean-Pierre; Gaudin, Valérie; Chupeau, Yves

2013-07-01

290

Downregulation of Varicella-Zoster Virus (VZV) Immediate-Early ORF62 Transcription by VZV ORF63 Correlates with Virus Replication In Vitro and with Latency  

Microsoft Academic Search

Received 19 August 2005\\/Accepted 11 January 2006 Varicella-zoster virus (VZV) open reading frame 63 (ORF63) protein is expressed during latency in human sensory ganglia. Deletion of ORF63 impairs virus replication in cell culture and establishment of latency in cotton rats. We found that cells infected with a VZV ORF63 deletion mutant yielded low titers of cell-free virus and produced very

Susan E. Hoover; Randall J. Cohrs; Zoila G. Rangel; Donald H. Gilden; Peter Munson; Jeffrey I. Cohen

2006-01-01

291

Downregulation of varicella-zoster virus (VZV) immediate-early ORF62 transcription by VZV ORF63 correlates with virus replication in vitro and with latency.  

PubMed

Varicella-zoster virus (VZV) open reading frame 63 (ORF63) protein is expressed during latency in human sensory ganglia. Deletion of ORF63 impairs virus replication in cell culture and establishment of latency in cotton rats. We found that cells infected with a VZV ORF63 deletion mutant yielded low titers of cell-free virus and produced very few enveloped virions detectable by electron microscopy compared with those infected with parental virus. Microarray analysis of cells infected with a recombinant adenovirus expressing ORF63 showed that transcription of few human genes was affected by ORF63; a heat shock 70-kDa protein gene was downregulated, and several histone genes were upregulated. In experiments using VZV transcription arrays, deletion of ORF63 from VZV resulted in a fourfold increase in expression of ORF62, the major viral transcriptional activator. A threefold increase in ORF62 protein was observed in cells infected with the ORF63 deletion mutant compared with those infected with parental virus. Cells infected with ORF63 mutants impaired for replication and latency (J. I. Cohen, T. Krogmann, S. Bontems, C. Sadzot-Delvaux, and L. Pesnicak, J. Virol. 79:5069-5077, 2005) showed an increase in ORF62 transcription compared with those infected with parental virus. In contrast, cells infected with an ORF63 mutant that is not impaired for replication or latency showed ORF62 RNA levels equivalent to those in cells infected with parental virus. The ability of ORF63 to downregulate ORF62 transcription may play an important role in virus replication and latency. PMID:16537613

Hoover, Susan E; Cohrs, Randall J; Rangel, Zoila G; Gilden, Donald H; Munson, Peter; Cohen, Jeffrey I

2006-04-01

292

Effects of Early High-Dose Levothyroxine Treatment on Auditory Brain Event-Related Potentials at School Entry in Children with Congenital Hypothyroidism  

Microsoft Academic Search

Aims: We tested whether brain event-related potentials (ERPs) are normal in children with congenital hypothyroidism (CH) after early high-dose levothyroxine treatment. Methods: Auditory ERPs were recorded in 33 normal controls and in 15 children with CH at 5 years 9\\/12. Based on bone maturation at diagnosis, the CH group was divided into severe (n = 8) and moderate (n =

S. Marti; M. Alvarez; J. Simoneau-Roy; S. Leroux; G. Van Vliet; P. Robaey

2006-01-01

293

The response of marine phytoplankton and sedimentary organic matter to the early Toarcian (Lower Jurassic) oceanic anoxic event in northern England  

Microsoft Academic Search

Early Toarcian organic-rich sediments, reflecting the Lower Jurassic oceanic anoxic event, were investigated in the Brown Moor Borehole, North Yorkshire (northern England). Integrated micropalaeontological (calcareous nannofossils and dinoflagellate cysts) and geochemical (rock-eval pyrolysis) analyses reveal a sequence of changes mainly driven by palaeoecological shifts. These changes mainly involve the composition, source and preservation rate of sedimentary organic matter as well

Raffaella Bucefalo Palliani; Emanuela Mattioli; James B. Riding

2002-01-01

294

Cognitive and behavioral development of at risk infants and toddlers exposed to stressful life events: The effects of trauma in early childhood  

Microsoft Academic Search

The present study examined the relations between traumatic life events and cognitive, behavioral, and relational competence in an at-risk sample of children between the ages of 11 and 41 months. As part of a larger, ongoing investigation, participants for the current study were 53 children enrolled in Early Head Start programs and their primary caregivers. The children participated in a

Zachary E. Warren

2005-01-01

295

Human cytomegalovirus function inhibits replication of herpes simplex virus  

SciTech Connect

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.

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

1988-01-01

296

Cell cycle dependency of murine cytomegalovirus replication in synchronized 3T3 cells.  

PubMed Central

Synchronized murine 3T3 cells have been used to investigate the possible dependency of murine cytomegalovirus replication upon the cell cycle. The normal latent period of 12 h characteristic of asynchronous 3T3 cells was protracted to more than 24 h after an early G1 infection in synchronous cells. In this case viral progeny were not detected until after the initiation of the host S-phase. Cells maintained in the G1 phase did not replicate virus. This failure could not be explained by a decrease in virus penetration but was apparently due to a requirement for an event associated with the host S-phase. Thymidine-induced inhibition of cell cycle traverse also blocked virus replication. Viral DNA synthesis did not initiate until after the initiation of host DNA. In contrast, herpes simplex virus type 1 replicated in 3T3 cells independently of the cell cycle.

Muller, M T; Hudson, J B

1977-01-01

297

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

PubMed Central

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

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

2014-01-01

298

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

PubMed

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

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

2013-08-23

299

A multiproxy geochemical record of the early Aptian Selli event (OAE1a) from the platform carbonates of southern Italy  

NASA Astrophysics Data System (ADS)

In the geological record, several events of rapid global warming have been recognized, triggered by huge injections of CO2 into the atmosphere. These events are associated with perturbations in overarching biogeochemical cycles and severe palaeoenvironmental disturbances. Especially short-term events (

Lechler, Maria; Jenkyns, Hugh C.; Owens, Jeremy D.; Pogge von Strandmann, Philip A. E.; Lyons, Timothy W.; Prosser, Giacomo; Parente, Mariano

2014-05-01

300

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

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.

Sample, Robert [Department of Microbiology, University of Mississippi Medical Center, Jackson, MS 39216 (United States); Bryan, Locke [Department of Microbiology, University of Mississippi Medical Center, Jackson, MS 39216 (United States); Long, Scott [Department of Microbiology, University of Mississippi Medical Center, Jackson, MS 39216 (United States); Majji, Sai [Department of Microbiology, University of Mississippi Medical Center, Jackson, MS 39216 (United States); Hoskins, Glenn [Department of Anatomy, University of Mississippi Medical Center, Jackson, MS 39216 (United States); Sinning, Allan [Department of Anatomy, University of Mississippi Medical Center, Jackson, MS 39216 (United States); Olivier, Jake [Department of Preventive Medicine, University of Mississippi Medical Center, Jackson, MS 39216 (United States); Chinchar, V. Gregory [Department of Microbiology, University of Mississippi Medical Center, Jackson, MS 39216 (United States)]. E-mail: vchinchar@microbio.umsmed.edu

2007-02-20

301

Overexpression of cellular inhibitor of apoptosis protein 2 is an early event in the progression of pancreatic cancer  

PubMed Central

Aim To determine the role of two antiapoptotic proteins of the inhibitor of apoptosis protein family, cellular inhibitor of apoptosis protein 1 (cIAP1) and cellular inhibitor of apoptosis protein 2 (cIAP2), in human pancreatic carcinogenesis. Methods mRNA levels were measured in pancreatic tissues and pancreatic cancer cell lines by quantitative reverse transcriptase PCR. Protein expression was assessed in pancreatic cancer cell lines by immunoblotting and in pancreatic tissues by immunohistochemistry, and correlated with pathological and survival data. Results cIAP1 expression was constantly high in non?neoplastic pancreatic tissues, in pancreatic intraepithelial neoplasia (PanIN) lesions, as well as in a subset of primary and metastatic pancreatic ductal adenocarcinomas (PDAC), and a preferential cytoplasmatic localisation was observed in the tumour tissues. cIAP1 expression was rare in a cohort of cystic tumours. cIAP2 mRNA levels were significantly higher (2.4 fold) in PDAC than in normal tissues. cIAP2 protein was overexpressed in PDAC, and was detectable in low? and high?grade PanIN lesions. Moreover, cIAP2 was often expressed in pancreatic cystic tumours. cIAP1 and cIAP2 mRNA and protein were detected in all the examined cell lines. Survival analysis revealed a shorter survival in patients with cIAP1/cIAP2?positive tumours. Conclusions cIAP1 might contribute to the regulation of the apoptotic process in the normal and in the neoplastic pancreas, depending on its subcellular localisation. Overexpression of cIAP2 is a common and early event in the progression of pancreatic cancer, and could therefore potentially influence the important pathophysiological aspects of PDAC, such as anoikis or chemoresistance.

Esposito, Irene; Kleeff, Jorg; Abiatari, Ivane; Shi, Xined; Giese, Nathalia; Bergmann, Frank; Roth, Wilfried; Friess, Helmut; Schirmacher, Peter

2007-01-01

302

Distribution of Early, Middle, and Late Noachian cratered surfaces in the Martian highlands: Implications for resurfacing events and processes  

NASA Astrophysics Data System (ADS)

Most of the geomorphic changes on Mars occurred during the Noachian Period, when the rates of impact crater degradation and valley network incision were highest. Fluvial erosion around the Noachian/Hesperian transition is better constrained than the longer-term landscape evolution throughout the Noachian Period, when the highland intercrater geomorphic surfaces developed. We interpret highland resurfacing events and processes using a new global geologic map of Mars (at 1:20,000,000 scale), a crater data set that is complete down to 1 km in diameter, and Mars Orbiter Laser Altimeter topography. The Early Noachian highland (eNh) unit is nearly saturated with craters of 32-128 km diameter, the Middle Noachian highland (mNh) unit has a resurfacing age of ~4 Ga, and the Late Noachian highland unit (lNh) includes younger composite surfaces of basin fill and partially buried cratered terrain. These units have statistically distinct ages, and their distribution varies with elevation. The eNh unit is concentrated in the high-standing Hellas basin annulus and in highland terrain that was thinly mantled by basin ejecta near 180° longitude. The mNh unit includes most of Arabia Terra, the Argyre vicinity, highland plateau areas between eNh outcrops, and the Thaumasia range. The lNh unit mostly occurs within highland basins. Crater depth/diameter ratios do not vary strongly between the eNh and mNh units, although crater losses to Noachian resurfacing appear greater in lower lying areas. Noachian resurfacing was spatially non-uniform, long-lived, and gravity-driven, more consistent with arid-zone fluvial and aeolian erosion and volcanism than with air fall mantling or mass wasting.

Irwin, Rossman P.; Tanaka, Kenneth L.; Robbins, Stuart J.

2013-02-01

303

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

PubMed

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

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

2013-11-01

304

Real-Time Cross-Correlation Image Analysis of Early Events in IgE Receptor Signaling  

PubMed Central

Signaling in mast cells and basophils is mediated through IgE and its high affinity cell surface receptor, Fc?RI. Crosslinking of the receptors by a cognate multivalent antigen leads to degranulation and release of mediators of the allergic immune response. Using multicolor fluorescence confocal microscopy, we probed the spatio-temporal dynamics of early events in the IgE receptor signal cascade. We monitored the recruitment of GFP-/CFP-labeled signaling proteins by acquiring sequential images with time resolution of 3 s during stimulation of RBL-2H3 mast cells with multivalent antigen. A fluorescent tag on the antigen allowed us to visualize the plasma membrane localization of crosslinked receptors, and fluorescent cholera toxin B served as a plasma membrane marker. We developed an automated image analysis scheme to quantify the recruitment of fluorescent intracellular proteins to the plasma membrane and to assess the time-dependent colocalization of these and other membrane-associated proteins with crosslinked receptors as measured by cross-correlation between the plasma membrane distributions of the two fluorophores. This automated method permits analysis of thousands of individual images from multiple experiments for each cross-correlation pair. We systematically applied this analysis to characterize stimulated interactions of IgE receptors with several signaling proteins, including the tyrosine kinases Lyn and Syk, and the adaptor protein LAT. Notably, for Syk-CFP we observed a rapid stimulated translocation to the plasma membrane but very little colocalization with aggregated receptors. Our results demonstrate the utility of this simple, automated method to monitor protein interactions quantitatively during cell signaling.

Das, Raibatak; Hammond, Stephanie; Holowka, David; Baird, Barbara

2008-01-01

305

Real-time cross-correlation image analysis of early events in IgE receptor signaling.  

PubMed

Signaling in mast cells and basophils is mediated through IgE and its high affinity cell surface receptor, FcepsilonRI. Crosslinking of the receptors by a cognate multivalent antigen leads to degranulation and release of mediators of the allergic immune response. Using multicolor fluorescence confocal microscopy, we probed the spatio-temporal dynamics of early events in the IgE receptor signal cascade. We monitored the recruitment of GFP-/CFP-labeled signaling proteins by acquiring sequential images with time resolution of 3 s during stimulation of RBL-2H3 mast cells with multivalent antigen. A fluorescent tag on the antigen allowed us to visualize the plasma membrane localization of crosslinked receptors, and fluorescent cholera toxin B served as a plasma membrane marker. We developed an automated image analysis scheme to quantify the recruitment of fluorescent intracellular proteins to the plasma membrane and to assess the time-dependent colocalization of these and other membrane-associated proteins with crosslinked receptors as measured by cross-correlation between the plasma membrane distributions of the two fluorophores. This automated method permits analysis of thousands of individual images from multiple experiments for each cross-correlation pair. We systematically applied this analysis to characterize stimulated interactions of IgE receptors with several signaling proteins, including the tyrosine kinases Lyn and Syk, and the adaptor protein LAT. Notably, for Syk-CFP we observed a rapid stimulated translocation to the plasma membrane but very little colocalization with aggregated receptors. Our results demonstrate the utility of this simple, automated method to monitor protein interactions quantitatively during cell signaling. PMID:18326662

Das, Raibatak; Hammond, Stephanie; Holowka, David; Baird, Barbara

2008-06-01

306

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

PubMed Central

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.

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

2010-01-01

307

Plant Virus RNAs. Coordinated Recruitment of Conserved Host Functions by (+) ssRNA Viruses during Early Infection Events1  

PubMed Central

Positive-sense single-stranded RNA viruses have developed strategies to exploit cellular resources at the expense of host mRNAs. The genomes of these viruses display a variety of structures at their 5? and 3? ends that differentiate them from cellular mRNAs. Despite this structural diversity, viral RNAs are still circularized by juxtaposition of their 5? and 3? ends, similar to the process used by cellular mRNAs. Also reminiscent of the mechanisms used by host mRNAs, translation of viral RNAs involves the recruitment of translation initiation factors. However, the roles played by these factors likely differ from those played by cellular mRNAs. In keeping with the general parsimony typical of RNA viruses, these host factors also participate in viral RNA replication. However, the dual use of host factors requires that viral RNA template utilization be regulated to avoid conflict between replication and translation. The molecular composition of the large ribonucleoprotein complexes that form the viral RNA replication and translation machineries likely evolves over the course of infection to allow for switching template use from translation to replication.

Thivierge, Karine; Nicaise, Valerie; Dufresne, Philippe J.; Cotton, Sophie; Laliberte, Jean-Francois; Le Gall, Olivier; Fortin, Marc G.

2005-01-01

308

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

NASA Astrophysics Data System (ADS)

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.

Osmaston, M. F.

2003-04-01

309

Disruption of PML-Associated Nuclear Bodies by IE1 Correlates with Efficient Early Stages of Viral Gene Expression and DNA Replication in Human Cytomegalovirus Infection  

Microsoft Academic Search

In human cytomegalovirus (HCMV) infection, both of the major immediate-early proteins IE1(IE68, UL123) and IE2(IE86, UL122) target to PML protein-associated nuclear bodies known as PODs or ND10 at very early times after infection. IE1 causes a redistribution of both PML and IE1 from the PODs into a nuclear diffuse form, whereas IE2 initially localizes adjacent to PODs but later associates

Jin-Hyun Ahn; Gary S. Hayward

2000-01-01

310

Outreach: Replicating Services for Young Handicapped Children.  

ERIC Educational Resources Information Center

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…

Gunn, Lynn, Ed.

311

Self-replicating colloidal clusters.  

PubMed

We construct schemes for self-replicating clusters of spherical particles, validated with computer simulations in a finite-temperature heat bath. Each particle has stickers uniformly distributed over its surface, and the rules for self-replication are encoded into the specificity and strength of interactions. Geometrical constraints imply that a compact cluster can copy itself only with help of a catalyst, a smaller cluster that increases the surface area to form a template. Replication efficiency requires optimizing interaction energies to destabilize all kinetic traps along the reaction pathway, as well as initiating a trigger event that specifies when the new cluster disassociates from its parent. Although there is a reasonably wide parameter range for self-replication, there is a subtle balance between the speed of the reaction, and the error rate. As a proof of principle, we construct interactions that self-replicate an octahedron, requiring a two-particle dimer for a catalyst. The resulting self-replication scheme is a hypercycle, and computer simulations confirm the exponential growth of both octahedron and catalyst replicas. PMID:24449887

Zeravcic, Zorana; Brenner, Michael P

2014-02-01

312

Membrane disruption and early events in the aggregation of the diabetes related peptide IAPP from a molecular prospective  

PubMed Central

Conspectus The aggregation of proteins is tightly controlled in living systems, and misfolded proteins are normally removed before aggregation of the misfolded protein can occur. But for reasons not clearly understood, in some individuals this degradation process breaks down, and misfolded proteins accumulate in insoluble protein aggregates (amyloid deposits) over time. Of the many proteins expressed in humans, a small but growing number have been found to form the long, highly ordered ?-sheet protein fibers that comprise amyloid deposits. Despite a lack of obvious sequence similarity, the amyloid forms of diverse proteins are strikingly similar, consisting of long, highly ordered insoluble fibers with a characteristic crossed ?-sheet pattern. Amyloidogenesis has been the focus of intense basic and clinical research, as a high proportion of amyloidogenic proteins has been linked to common degenerative diseases, including Alzheimer’s, type II diabetes, and Parkinson’s. The apparent link between amyloidogenic proteins and disease was initially attributed to the amyloid form of the protein; however, increasing evidence suggests the toxicity is due to intermediates generated during the assembly of amyloid fibers. These intermediates have been proposed to attack cells in a variety of ways, such as by generating inflammation, creating reactive oxygen species, and overloading the misfolded protein response pathway. One common, well-studied mechanism is the disruption of the plasma and organelle membranes. In this Account, we examine the early molecular-level events in the aggregation of the Islet amyloid polypeptide (IAPP, also called amylin) and its ensuing disruption of membranes. IAPP is a 37-residue peptide secreted in conjunction with insulin; it is highly amyloidogenic and often found in amyloid deposits in type II diabetics. IAPP aggregates are highly toxic to the ?-cells that produce insulin, and thus IAPP is believed to be one of the factors involved in the transition from early to later stages of type II diabetes. Using variants of IAPP that are combinations of toxic or non-toxic and amyloidogenic or nonamyloidogenic, we have shown that formation of amyloid fibers is a sufficient but not necessary condition for the disruption of ?-cells. Instead, the ability to induce membrane disruption in model membranes appears to be related to the peptide’s ability to stabilize curvature in the membrane, which in turn is related to the depth of penetration in the membrane. Although many similarities exist between IAPP and other amyloidogenic proteins, one important difference appears to be the role of small oligomers in the assembly process of amyloid fibers. In many amyloidogenic proteins, small oligomers form a distinct metastable intermediate that is frequently the most toxic species; however, in IAPP, small oligomers appear to be transient and are rapidly converted to amyloid fibers. Moreover, the aggregation and toxicity of IAPP is controlled by other cofactors present in the secretory granule from which it is released, such as zinc and insulin, in a control mechanism that is somehow unbalanced in type II diabetics. Investigations into this process are likely to give clues to the mysterious origins of type II diabetes on the molecular level.

Brender, Jeffrey R.; Salamekh, Samer; Ramamoorthy, Ayyalusamy

2011-01-01

313

Infection of Brachypodium distachyon by Formae Speciales of Puccinia graminis: Early Infection Events and Host-Pathogen Incompatibility  

PubMed Central

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

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

2013-01-01

314

The VP1 subunit of JC polyomavirus recapitulates early events in viral trafficking and is a novel tool to study polyomavirus entry  

PubMed Central

JC polyomavirus (JCV) is an important human pathogen that causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). In this study we further delineate the early events of JCV entry in human glial cells and demonstrate that a pentameric subunit of the viral capsid is able to recapitulate early events in viral trafficking. We show that JCV traffics to the endoplasmic reticulum (ER) by 6 h post infection, and that VP1 pentamers arrive at the ER with similar kinetics. Further, this JCV localization to the ER is critical for infection, as treatment of cells with agents that prevent ER trafficking, ER function, or ER quality control reduce JCV infectivity. These pentamers represent a new tool to study polyomavirus entry, and will be particularly useful in studying recently identified polyomaviruses that are difficult to propagate.

Nelson, Christian D.S.; Derdowski, Aaron; Maginnis, Melissa S.; O'Hara, Bethany A.; Atwood, Walter J.

2013-01-01

315

Aluminum26 in H4 chondrites: Implications for its production and its usefulness as a fine-scale chronometer for early solar system events  

Microsoft Academic Search

In order to investigate whether or not 26Al can be used as a fine-scale chronometer for early-solar-system events we measured, with an ion microprobe, Mg isotopes and Al\\/Mg ratios in separated plagioclase, olivine, and pyroxene crystals from the H4 chondrites Ste. Marguerite, Forest Vale, Beaver Creek and Quenggouk and compared the results with the canonical 26Al\\/27Al ratio for Ca,Al-rich inclusions

Ernst Zinner; Christa Göpel

2002-01-01

316

H2B homology region of major immediate-early protein 1 is essential for murine cytomegalovirus to disrupt nuclear domain 10, but is not important for viral replication in cell culture  

PubMed Central

Cytomegalovirus (CMV) major immediate–early protein 1 (IE1) has multiple functions and is important for efficient viral infection. As does its counterpart in human CMV, murine CMV (MCMV) IE1 also functions as a disruptor of mouse-cell nuclear domain 10 (ND10), where many different gene-regulation proteins congregate. It still remains unclear how MCMV IE1 disperses ND10 and whether this dispersion could have any effect on viral replication. MCMV IE1 is 595 aa long and has multiple functional domains that have not yet been fully analysed. In this study, we dissected the IE1 molecule by truncation and/or deletion and found that the H2B homology domain (amino acid sequence NDIFERI) is required for the dispersion of ND10 by IE1. Furthermore, we made additional deletions and point mutations and found that the minimal truncation in the H2B homology domain required for IE1 to lose the ability to disperse ND10 is just 3 aa (IFE). Surprisingly, the mutated IE1 still interacted with PML and co-localized with ND10 but failed to disperse ND10. This suggests that binding to ND10 key protein is essential to, but not sufficient for, the dispersal of ND10, and that some other unknown mechanism must be involved in this biological procedure. Finally, we generated MCMV with IFE-deleted IE1 (MCMVdlIFE) and its revertant (MCMVIFERQ). Although MCMVdlIFE lost the ability to disperse ND10, plaque assays and viral gene production assays showed that the deletion of IFE did not increase viral replication in cell culture. We conclude that the dispersion of ND10 appears not to be important for MCMV replication in a mouse-cell culture.

Cosme-Cruz, Ruth; Martinez, Francisco Puerta; Perez, Kareni J.

2011-01-01

317

The Early Jurassic tectono-magmatic events in southern Jiangxi and northern Guangdong provinces, SE China: Constraints from the SHRIMP zircon U-Pb dating  

NASA Astrophysics Data System (ADS)

The Jurassic to Cretaceous magmatism in the South China Block (SCB) has important geological significance for its tectonic evolution, particularly, the tectonic regime change. We report here new SHRIMP zircon U-Pb ages, geochemical and Sr-Nd isotopic results from the Early Jurassic magmatic rocks in eastern Nanling region of southern Jiangxi and northern Guangdong provinces, SE China. The SHRIMP zircon U-Pb analyses yield consistent Early Jurassic ages of 193 ± 2 Ma for granodiorite and 196 ± 1 Ma for gabbro-diabase from the Hanhu complex of southern Jiangxi Province. Field observation indicates that the gabbro-diabase coexists with syenite in granodiorite, and that the mafic components infiltrate into the syenite. Combined with the SHRIMP zircon U-Pb ages of 196 ± 2 Ma for granites and 195 ± 1 Ma for gabbros of the Xialan complex of northern Guangdong province, these contemporary ages represent an earliest tectono-magmatic events during the Yanshanian orogeny. These results reveal that there are tectonic extension and the post-collisional and intraplate magmatism events at or before 196 Ma, in contrast to the wide believed quiescent stage (205-180 Ma) of magmatic activity in SE China. The confirmation of these tectono-magmatic events in the eastern Nanling area thus sheds new light on the quiescent stage of magmatic activity in SE China during 205-180 Ma and provides new constraints to understand the Early Jurassic tectonic evolution of SE China.

Yu, X. Q.; Wu, G. G.; Zhao, Xixi; Gao, J. F.; Di, Y. J.; Zheng, Y.; Dai, Y. P.; Li, C. L.; Qiu, J. T.

2010-10-01

318

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

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.

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

2011-01-01

319

PA from an H5N1 highly pathogenic avian influenza virus activates viral transcription and replication and induces apoptosis and interferon expression at an early stage of infection  

PubMed Central

Background Although gene exchange is not likely to occur freely, reassortment between the H5N1 highly pathogenic avian influenza virus (HPAIV) and currently circulating human viruses is a serious concern. The PA polymerase subunit of H5N1 HPAIV was recently reported to activate the influenza replicon activity. Methods The replicon activities of PR8 and WSN strains (H1N1) of influenza containing PA from HPAIV A/Cambodia/P0322095/2005 (H5N1) and the activity of the chimeric RNA polymerase were analyzed. A reassortant WSN virus containing the H5N1 Cambodia PA (C-PA) was then reconstituted and its growth in cells and pathogenicity in mice examined. The interferon promoter, TUNEL, and caspase 3, 8, and 9 activities of C-PA-infected cells were compared with those of WSN-infected cells. Results The activity of the chimeric RNA polymerase was slightly higher than that of WSN, and C-PA replicated better than WSN in cells. However, the multi-step growth of C-PA and its pathogenicity in mice were lower than those of WSN. The interferon promoter, TUNEL, and caspase 3, 8, and 9 activities were strongly induced in early infection in C-PA-infected cells but not in WSN-infected cells. Conclusions Apoptosis and interferon were strongly induced early in C-PA infection, which protected the uninfected cells from expansion of viral infection. In this case, these classical host-virus interactions contributed to the attenuation of this strongly replicating virus.

2012-01-01

320

Induction of DNA Damage Signaling by Oxidative Stress in Relation to DNA Replication as Detected Using "Click Chemistry"  

PubMed Central

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 ?H2AX 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 ?H2AX 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 (?H2AX 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

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

2011-01-01

321

Inhibitors of virus replication: recent developments and prospects  

Microsoft Academic Search

The search for inhibitors of viral replication is dependent on understanding the events taking place at the molecular level during viral infection. All the essential steps during the viral life cycle are potential targets for antiviral drugs. Classical inhibitors of herpesvirus replication cause chain termination during viral DNA replication. Similarly, the HIV reverse transcriptase is the major target of anti-HIV

Julia Magden; Leevi Kääriäinen; Tero Ahola

2005-01-01

322

Brachial-Ankle Pulse Wave Velocity Predicts Decline in Renal Function and Cardiovascular Events in Early Stages of Chronic Kidney Disease  

PubMed Central

Objective: In this study, we investigated the predictive capacity of the brachial-ankle aortic pulse wave velocity (baPWV), a marker of arterial stiffness, for the decline in renal function and for cardiovascular events in the early stages of chronic kidney disease (CKD). Method: Two hundred forty-one patients who underwent a comprehensive check-up were included and were divided into two groups according to their estimated glomerular filtration rates (eGFR): patients with CKD categories G2, G3a and G3b (30 ? eGFR < 90 ml/min/1.73m2, eGFR < 90 group; n=117) and those with eGFR ? 90 ml/min/1.73 m2 (eGFR ? 90 group; n=124). The change in renal function, the eGFR change, was determined by the slope of eGFR against time. We analysed whether baPWV was associated with eGFR change or predicted cardiovascular events. Results: baPWV was independently associated with eGFR change in a multivariate analysis of the total patients (?=-0.011, p=0.011) and remained significantly associated with eGFR change in a subgroup analysis of the eGFR < 90 group (?=-0.015, p=0.035). baPWV was independently associated with cardiovascular events (odds ratio=1.002, p=0.048) in the eGFR < 90 group, but not in the eGFR ? 90 group. The receiver operative characteristic curve analysis showed that 1,568 cm/sec was the cut-off value of baPWV for predicting CV events in the eGFR < 90 group (area under curve=0.691, p=0.03) Conclusions: In patients with early stages of CKD, baPWV was independently associated with the decline in renal function and short-term cardiovascular events.

Yoon, Hye Eun; Shin, Dong Il; Kim, Sung Jun; Koh, Eun Sil; Hwang, Hyeon Seok; Chung, Sungjin; Shin, Seok Joon

2013-01-01

323

Gain at chromosomal region 5p15.33, containing TERT, is the most frequent genetic event in early stages of non-small cell lung cancer.  

PubMed

Chromosomal imbalances resulting in altered gene dosage play a role in the molecular pathogenesis of non-small cell lung cancer (NSCLC), but the target genes remain to be identified. To identify early-stage genetic events that drive progression of NSCLC, we conducted a high-resolution array comparative genomic hybridization (CGH) study, using an array of 4,046 bacterial artificial chromosome clones to screen for DNA copy number changes associated with individual genes in 36 tumors obtained from patients in early stages of NSCLC. Multiple early genetic events occurring on chromosome 5p were identified, with a minimal detection region at 5p15.33 approximately 12. The most frequent finding involved gain of 5p15.33, observed in 15 of 19 stage I (A+B) cancers (79%) and in 28 of the total 36 NSCLC cases (78%). This locus harbors the genes TERT, SLC6A19, and SLC6A18 and is a telomeric boundary at bacterial artificial chromosome (BAC) clone 91_J20. Other potential candidate genes evidencing high numbers of genomic copy number changes (> or =40% of patients) included the following genes, encountered in >50% of 19 stage I (A+B) cancers: CEP72 and TPPP (14 of 19; 74%); AHRR, EXOC3 (previously SEC6L1), SLC9A3, LOC442126, ZDHHC11, BRD9, and TRIP13 (13/19; 68%); and CLPTM1L (alias CRR9), SLC6A3 (previously DAT1), and LOC401169 (10/19; 53%). Fluorescence in situ hybridization validated the array CGH findings. The gain of 5p15.33 is thus one of the most consistent alterations in the early stages of lung cancer, and a series of genes in the critical 5p15.33 region may be used as novel biomarkers for the early detection and classification of lung cancer. PMID:18328944

Kang, Ji Un; Koo, Sun Hoe; Kwon, Kye Chul; Park, Jong Woo; Kim, Jin Man

2008-04-01

324

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

PubMed Central

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, Côte d'Ivoire. Methods Data from two consecutive prevention of HIV mother-to-child transmission programs were compared: the ANRS 1201/1202 Ditrame-Plus cohort (2001–2005) and the pooled data of the ANRS 049a Ditrame randomized trial and its following open-labeled cohort (1995–2000), used as a reference group. HIV-infected pregnant women ? 32–36 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 48–72 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: 0.3–1.1), 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: 2.2–11.2; 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.

Harambat, Jerome; Fassinou, Patricia; Becquet, Renaud; Toure, Pety; Rouet, Francois; Dabis, Francois; Msellati, Philippe; Blanche, Stephane; Timite-Konan, Marguerite; Salamon, Roger; Leroy, Valeriane

2008-01-01

325

High-Resolution Replication Profiles Define the Stochastic Nature of Genome Replication Initiation and Termination  

PubMed Central

Summary Eukaryotic genome replication is stochastic, and each cell uses a different cohort of replication origins. We demonstrate that interpreting high-resolution Saccharomyces cerevisiae genome replication data with a mathematical model allows quantification of the stochastic nature of genome replication, including the efficiency of each origin and the distribution of termination events. Single-cell measurements support the inferred values for stochastic origin activation time. A strain, in which three origins were inactivated, confirmed that the distribution of termination events is primarily dictated by the stochastic activation time of origins. Cell-to-cell variability in origin activity ensures that termination events are widely distributed across virtually the whole genome. We propose that the heterogeneity in origin usage contributes to genome stability by limiting potentially deleterious events from accumulating at particular loci.

Hawkins, Michelle; Retkute, Renata; Muller, Carolin A.; Saner, Nazan; Tanaka, Tomoyuki U.; de Moura, Alessandro P.S.; Nieduszynski, Conrad A.

2013-01-01

326

Amplification of JNK signaling is necessary to complete the murine gammaherpesvirus 68 lytic replication cycle.  

PubMed

Several studies have previously defined host-derived signaling events capable of driving lytic gammaherpesvirus replication or enhancing immediate-early viral gene expression. Yet signaling pathways that regulate later stages of the productive gammaherpesvirus replication cycle are still poorly defined. In this study, we utilized a mass spectrometric approach to identify c-Jun as an abundant cellular phosphoprotein present in late stages of lytic murine gammaherpesvirus 68 (MHV68) infection. Kinetically, c-Jun phosphorylation was enhanced as infection progressed, and this correlated with enhanced phosphorylation of the c-Jun amino-terminal kinases JNK1 and JNK2 and activation of AP-1 transcription. These events were dependent on progression beyond viral immediate-early gene expression, but not dependent on viral DNA replication. Both pharmacologic and dominant-negative blockade of JNK1/2 activity inhibited viral replication, and this correlated with inhibition of viral DNA synthesis and reduced viral gene expression. These data suggest a model in which MHV68 by necessity amplifies and usurps JNK/c-Jun signaling as infection progresses in order to facilitate late stages of the MHV68 lytic infection cycle. PMID:23015701

Stahl, James A; Paden, Clinton R; Chavan, Shweta S; MacLeod, Veronica; Edmondson, Ricky D; Speck, Samuel H; Forrest, J Craig

2012-12-01

327

It’s the little things: exploring the importance of commonplace events for early?career teachers’ motivation  

Microsoft Academic Search

This paper seeks to provide a rationale for further researching the everyday events that keep teachers motivated or that discourage them. We put forward the idea that routine Affect Triggering Incidents (ATIs) are an important area for researchers to investigate in terms of how they impact teacher motivation and resilience. Two groups of participants in separate consecutive studies kept weekly

Karl Kitching; Mark Morgan; Michael O’Leary

2009-01-01

328

Early Jurassic schizosphaerellid crisis in Cantabria, Spain: Implications for calcification rates and phytoplankton evolution across the Toarcian oceanic anoxic event  

Microsoft Academic Search

The Toarcian oceanic anoxic event (?183 Myr ago) represents a global perturbation marked by increasing organic carbon burial and a general decrease in calcium carbonate production likely triggered by elevated carbon dioxide levels in the atmosphere. Here we present quantitative analyses of calcareous nannofossil diversity and abundance from the Castillo de Pedroso section in Cantabria, northern Spain. We compare these

Fabrizio Tremolada; Bas Van de Schootbrugge; Elisabetta Erba

2005-01-01

329

Efficacy and safety of subcutaneous interferon-?-1a in patients with a first demyelinating event and early multiple sclerosis.  

PubMed

Introduction: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Evidence suggests that MS should be treated as early as possible in order to maximize the benefit of treatment. Areas covered: This review details current understanding about the treatment of relapsing-remitting MS (RRMS). The pharmacological and clinical data on the use of subcutaneous (s.c.) interferon ?-1a (IFN-?-1a) as a therapeutic option for RRMS are covered, with a focus on the importance of treating patients with MS as early as possible in the course of the disease, in order to delay permanent axonal damage that is responsible for the signs and symptoms of disease progression. Expert opinion: There is a wealth of data on the treatment of RRMS with s.c. IFN-?-1a indicating that patients treated during the early inflammatory stages of the disease have significantly improved short-term outcomes compared with patients who commence treatment late. It remains to be determined whether the short-term effects of early treatment will translate into long-lasting benefits, although it is hoped that ongoing research will help to answer this question. PMID:24965353

Freedman, Mark S

2014-08-01

330

Loss of chloroplast transcripts for proteins associated with photosystem II: an early event during heat-bleaching in Euglena gracilis  

Microsoft Academic Search

A shift in the ratio of chlorophyll (Chl) a and Chl b is an early indicator of heat bleaching in Euglena gracilis. This observation prompted us to consider whether or not changes in steady-state levels of chloroplast transcripts and in transcriptional activity could limit the synthesis of Chl a-binding proteins in bleaching plastids. We found that the mature transcripts for

Eric J. Thomas; William Ortiz

1995-01-01

331

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

ERIC Educational Resources Information Center

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…

Goodvin, Rebecca; Romdall, Lisa

2013-01-01

332

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

PubMed Central

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

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

2014-01-01

333

Linkage Replication for Chromosomal Region 13q32 in Schizophrenia: Evidence from a Brazilian Pilot Study on Early Onset Schizophrenia Families  

PubMed Central

We report analyses of a Brazilian study of early onset schizophrenia (BEOS) families. We genotyped 22 members of 4 families on a linkage SNP array and report here non-parametric linkage analyses using MERLIN® software. We found suggestive evidence for linkage on two chromosomal regions, 13q32 and 11p15.4. A LOD score of 2.71 was observed at 13q32 with a one LOD interval extending from 60.63–92.35 cM. From simulations, this LOD score gave a genome-wide empirical corrected p?=?0.33, after accounting for all markers tested. Similarly 11p15.4 showed the same maximum LOD of 2.71 and a narrower one LOD interval of 4–14 cM. Of these, 13q32 has been reported to be linked to schizophrenia by multiple different studies. Thus, our study provides additional supporting evidence for an aetiological role of variants at 13q32 in schizophrenia.

Gadelha, Ary; Ota, Vanessa Kiyomi; Cano, Jose Paya; Melaragno, Maria Isabel; Smith, Marilia A. C.; de Jesus Mari, Jair; Bressan, Rodrigo A.; Belangero, Sintia Iole; Breen, Gerome

2012-01-01

334

Reversible Inhibition of Murine Cytomegalovirus Replication by Gamma Interferon (IFN-?) in Primary Macrophages Involves a Primed Type I IFN-Signaling Subnetwork for Full Establishment of an Immediate-Early Antiviral State ? †  

PubMed Central

Activated macrophages play a central role in controlling inflammatory responses to infection and are tightly regulated to rapidly mount responses to infectious challenge. Type I interferon (alpha/beta interferon [IFN-?/?]) and type II interferon (IFN-?) play a crucial role in activating macrophages and subsequently restricting viral infections. Both types of IFNs signal through related but distinct signaling pathways, inducing a vast number of interferon-stimulated genes that are overlapping but distinguishable. The exact mechanism by which IFNs, particularly IFN-?, inhibit DNA viruses such as cytomegalovirus (CMV) is still not fully understood. Here, we investigate the antiviral state developed in macrophages upon reversible inhibition of murine CMV by IFN-?. On the basis of molecular profiling of the reversible inhibition, we identify a significant contribution of a restricted type I IFN subnetwork linked with IFN-? activation. Genetic knockout of the type I-signaling pathway, in the context of IFN-? stimulation, revealed an essential requirement for a primed type I-signaling process in developing a full refractory state in macrophages. A minimal transient induction of IFN-? upon macrophage activation with IFN-? is also detectable. In dose and kinetic viral replication inhibition experiments with IFN-?, the establishment of an antiviral effect is demonstrated to occur within the first hours of infection. We show that the inhibitory mechanisms at these very early times involve a blockade of the viral major immediate-early promoter activity. Altogether our results show that a primed type I IFN subnetwork contributes to an immediate-early antiviral state induced by type II IFN activation of macrophages, with a potential further amplification loop contributed by transient induction of IFN-?.

Kropp, Kai A.; Robertson, Kevin A.; Sing, Garwin; Rodriguez-Martin, Sara; Blanc, Mathieu; Lacaze, Paul; Hassim, Muhamad F. B. Noor; Khondoker, Mizanur R.; Busche, Andreas; Dickinson, Paul; Forster, Thorsten; Strobl, Birgit; Mueller, Mathias; Jonjic, Stipan; Angulo, Ana; Ghazal, Peter

2011-01-01

335

Regulation of chromosomal replication in Caulobacter crescentus.  

PubMed

The alpha-proteobacterium Caulobacter crescentus is characterized by its asymmetric cell division, which gives rise to a replicating stalked cell and a non-replicating swarmer cell. Thus, the initiation of chromosomal replication is tightly regulated, temporally and spatially, to ensure that it is coordinated with cell differentiation and cell cycle progression. Waves of DnaA and CtrA activities control when and where the initiation of DNA replication will take place in C. crescentus cells. The conserved DnaA protein initiates chromosomal replication by directly binding to sites within the chromosomal origin (Cori), ensuring that DNA replication starts once and only once per cell cycle. The CtrA response regulator represses the initiation of DNA replication in swarmer cells and in the swarmer compartment of pre-divisional cells, probably by competing with DnaA for binding to Cori. CtrA and DnaA are controlled by multiple redundant regulatory pathways that include DNA methylation-dependent transcriptional regulation, temporally regulated proteolysis and the targeting of regulators to specific locations within the cell. Besides being critical regulators of chromosomal replication, CtrA and DnaA are also master transcriptional regulators that control the expression of many genes, thus connecting DNA replication with other events of the C. crescentus cell cycle. PMID:22227374

Collier, Justine

2012-03-01

336

Events occurring during the previous lactation, the dry period, and peripartum as risk factors for early lactation mastitis in cows receiving 2 different intramammary dry cow therapies.  

PubMed

The objective of this study was to investigate the association between mastitis events occurring during the previous lactation, the dry period, and the peripartum period on the incidence of early lactation mastitis in cows receiving ceftiofur hydrochloride or penicillin dihydrostreptomycin as intramammary dry cow antibiotic therapy. Cows (n=402) from 2 large dairy farms in Central Florida were enrolled in the study at the time of dry-off processing and were randomly assigned to 1 of 2 dry cow therapies: ceftiofur hydrochloride or penicillin dihydrostreptomycin. Composite milk samples were collected at dry-off and after calving for bacteriological examination and somatic cell count. Peripartal health disorders were monitored during the first 30 d of lactation and included calving difficulty, metritis, ketosis, and left displaced abomasum. Milk production and individual somatic cell scores (SCS) were recorded monthly by the Dairy Herd Improvement Association. The main outcome variables were the risk of clinical mastitis during the first 30 and 60 d of lactation, and the risk of subclinical mastitis at the first 2 monthly Dairy Herd Improvement Association tests after calving (up to 70 d in milk). Additionally, the SCS and the presence of mastitis pathogens in milk at dry-off and at calving were analyzed. Explanatory variables consisted of events occurring during the previous lactation, at dry-off and during the dry period, at calving, and within the first 30 d after calving. Multiple events occurring during the previous lactation had a significant effect on the incidence of mastitis in the subsequent lactation. These events included low milk yield, intermediate lactation length, clinical mastitis, and lactation SCS average. Similarly, intramammary infections with environmental bacteria at dry-off increased the chances of clinical mastitis the first month after calving. Dry-off therapy had a significant effect on mastitis incidence; cows treated with ceftiofur hydrochloride had lower odds of having clinical and subclinical mastitis in the subsequent early lactation compared with cows treated with penicillin dihydrostreptomycin. PMID:22999278

Pinedo, P J; Fleming, C; Risco, C A

2012-12-01

337

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

PubMed

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

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

2012-10-01

338

Altered Protein Binding to the Octamer Motif Appears to be an Early Event in Programmed Neuronal Cell Death  

Microsoft Academic Search

Electrophoretic mobility-shift assays were used to characterize binding of nuclear proteins to consensus sequences for Sp1, E2F, octamer, and cAMP responsive enhancer element (CRE) during neuronal death in vitro after removal of nerve growth factor (NGF). Molecular events occurring prior to cell death in terminally differentiated PC12 cells could be divided into three phases: (i) within 2 hr of removing

Songli Wang; Randall N. Pittman

1993-01-01

339

Infants' Causal Representations of State Change Events  

PubMed Central

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.

Muentener, Paul; Carey, Susan

2010-01-01

340

Saquinavir Inhibits Early Events Associated with Establishment of HIV-1 Infection: Potential Role for Protease Inhibitors in Prevention  

PubMed Central

The maturation of newly formed human immunodeficiency virus type 1 (HIV-1) virions is a critical step for the establishment of productive infection. We investigated the potential of saquinavir (SQV), a protease inhibitor (PI) used in highly active antiretroviral therapy (HAART), as a candidate microbicide. SQV inhibited replication of clade B and clade C isolates in a dose-dependent manner in all cellular models tested: PM-1 CD4 T cells, peripheral blood mononuclear cells (PBMCs), monocyte-derived macrophages (MDMs), and immature monocyte-derived dendritic cells (iMDDCs). SQV also inhibited production of infectious virus in cervical, penile, and colorectal explants cocultured with T cells. Moreover, SQV demonstrated inhibitory potency against trans infection of T cells by in vitro-derived dendritic cells and by primary dendritic cells that emigrate from penile and cervical tissue explants. No cellular or tissue toxicity was detected in the presence of SQV, suggesting that this drug could be considered for development as a component of an effective microbicide, capable of blocking viral maturation and transmission of HIV-1 at mucosal surfaces.

Stefanidou, Martha; Herrera, Carolina; Armanasco, Naomi

2012-01-01

341

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

PubMed Central

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.

Monetti, Emanuela; Kadono, Takashi; Bouteau, Francois

2014-01-01

342

Who Needs Replication?  

ERIC Educational Resources Information Center

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

Porte, Graeme

2013-01-01

343

Proteomic analysis of early reprogramming events in murine somatic cells incubated with Xenopus laevis oocyte extracts demonstrates network associations with induced pluripotency markers.  

PubMed

The reprogramming of somatic cells into a pluripotent/embryonic-like state holds great potential for regenerative medicine, bypassing ethical issues associated with embryonic stem cells (ESCs). Numerous methods, including somatic cell nuclear transfer (SCNT), fusion to pluripotent cells, the use of cell extracts, and expression of transcription factors, have been used to reprogram cells into ES-like cells [termed induced pluripotent stem cells (iPSCs)]. This study investigated early events in the nuclei of permeabilized murine somatic cells incubated in cytoplasmic extract prepared from Xenopus laevis germinal vesicle-stage oocytes by identifying proteins that showed significant quantitative changes using proteomic techniques. A total of 69 protein spots from two-dimensional electrophoresis were identified as being significantly altered in expression after treatment, and 38 proteins were identified by tandem mass spectrometry. Network analysis was used to highlight pathway connections and interactions between these identified proteins, which were found to be involved in many functions--primarily nuclear structure and dynamics, transcription, and translation. The pluripotency markers Klf4, c-Myc, Nanog, and POU5F1 were highlighted by the interaction network analysis, as well as other compounds/proteins known to be repressed in pluripotent cells [e.g., protein kinase C (PRKC)] or enhanced during differentiation of ESCs (e.g., retinoic acid). The network analysis also indicated additional proteins and pathways potentially involved in early reprogramming events. PMID:23768116

Rathbone, Alex J; Liddell, Susan; Campbell, Keith H S

2013-08-01

344

Training-related changes in early visual processing of functionally illiterate adults: evidence from event-related brain potentials  

PubMed Central

Background Event-related brain potentials (ERPs) were used to investigate training-related changes in fast visual word recognition of functionally illiterate adults. Analyses focused on the left-lateralized occipito-temporal N170, which represents the earliest processing of visual word forms. Event-related brain potentials were recorded from 20 functional illiterates receiving intensive literacy training for adults, 10 functional illiterates not participating in the training and 14 regular readers while they read words, pseudowords or viewed symbol strings. Subjects were required to press a button whenever a stimulus was immediately repeated. Results Attending intensive literacy training was associated with improvements in reading and writing skills and with an increase of the word-related N170 amplitude. For untrained functional illiterates and regular readers no changes in literacy skills or N170 amplitude were observed. Conclusions Results of the present study suggest that the word-related N170 can still be modulated in adulthood as a result of the improvements in literacy skills.

2013-01-01

345

Ability to delay neuropathological events associated with astrocytic MAO-B increase in a Parkinsonian mouse model: Implications for early intervention on disease progression  

PubMed Central

We previously demonstrated that elevation of astrocytic monoamine oxidase B (MAO-B) levels in a doxycycline (dox)-inducible transgenic mouse model following 14 days of dox induction results in several neuropathologic features similar to those observed in the Parkinsonian midbrain (Mallajosyula et al., 2008). These include a specific, selective and progressive loss of dopaminergic neurons of the substantia nigra (SN), selective decreases in mitochondrial complex I (CI) activity and increased oxidative stress. Here, we report that the temporal sequence of events following MAO-B elevation initially involves increased oxidative stress followed by CI inhibition and finally neurodegeneration. Furthermore, dox removal (DR) at days 3 and 5 of MAO-B induction was sufficient to arrest further increases in oxidative stress as well as subsequent neurodegenerative events. In order to assess the contribution of MAO-B-induced oxidative stress to later events, we compared the impact of DR which reverses the MAO-B increase with treatment of animals with the lipophilic antioxidant compound EUK-189. EUK-189 was found to be as effective as DR in halting downstream CI inhibition and also significantly attenuated SN DA cell loss as a result of astrocytic MAO-B induction. This suggests that MAO-B-mediated ROS contributes to neuropathology associated with this model and that antioxidant treatment can arrest further progression of dopaminergic cell death. This has implications for early intervention therapies.

Siddiqui, Almas; Mallajosyula, Jyothi K.; Rane, Anand; Andersen, Julie K.

2010-01-01

346

Observations of an early Agulhas current retroflection event in 2001: A temporary cessation of inter-ocean exchange south of Africa?  

NASA Astrophysics Data System (ADS)

The exchange of heat and salt between the South Indian Ocean and South Atlantic Ocean, at the southern terminus of the Agulhas current, forms a crucial link in the global ocean circulation. It has been surmised that upstream retroflections in this current could produce temporary interruptions to the exchange, but that their impact would depend on the vertical extent of such retroflections and on their duration. The fortuitous presence at sea of a research vessel has now enabled us to investigate such an episode at subsurface levels in combination with remote sensing of the sea surface. We present here the first in situ evidence that an upstream or early retroflection can extend to a depth of well over 750 m and last for 5 months. This event was likely triggered upstream by the happenstance of two Natal Pulses, large cyclonic eddies inshore of the Agulhas current. These eddies short-circuited the Agulhas with its Return current, leading to the shedding of three large Agulhas rings in quick succession. The arrival of a third cyclonic eddy when the Retroflection was still quite retracted did not lead to another ring shedding event. The resulting early retroflection may have had the effect of stalling the shedding of Agulhas rings and their motion towards the Cape Basin. However, these early retroflections are too scarce to allow generic statements on their generation or consequences, and the relation with large-scale environmental factors. It is likely that the observed withdrawal of the retroflection into the Transkei Basin is a fortuitous result of a series of contingent interactions.

van Aken, H. M.; Lutjeharms, J. R. E.; Rouault, M.; Whittle, C.; de Ruijter, W. P. M.

2013-02-01

347

Identifying functional neighborhoods within the cell nucleus: proximity analysis of early S-phase replicating chromatin domains to sites of transcription, RNA polymerase II, HP1gamma, matrin 3 and SAF-A.  

PubMed

Higher order chromatin organization in concert with epigenetic regulation is a key process that determines gene expression at the global level. The organization of dynamic chromatin domains and their associated protein factors is intertwined with nuclear function to create higher levels of functional zones within the cell nucleus. As a step towards elucidating the organization and dynamics of these functional zones, we have investigated the spatial proximities among a constellation of functionally related sites that are found within euchromatic regions of the cell nucleus including: HP1gamma, nascent transcript sites (TS), active DNA replicating sites in early S-phase (PCNA) and RNA polymerase II sites. We report close associations among these different sites with proximity values specific for each combination. Analysis of matrin 3 and SAF-A sites demonstrates that these nuclear matrix proteins are highly proximal with the functionally related sites as well as to each other and display closely aligned and overlapping regions following application of the minimal spanning tree (MST) algorithm to visualize higher order network-like patterns. Our findings suggest that multiple factors within the nuclear microenvironment collectively form higher order combinatorial arrays of function. We propose a model for the organization of these functional neighborhoods which takes into account the proximity values of the individual sites and their spatial organization within the nuclear architecture. PMID:18618731

Malyavantham, Kishore S; Bhattacharya, Sambit; Barbeitos, Marcos; Mukherjee, Lopamudra; Xu, Jinhui; Fackelmayer, Frank O; Berezney, Ronald

2008-10-01

348

Development of an auroral absorption substorm - Studies of substorm related absorption events in the afternoon-early evening sector  

NASA Astrophysics Data System (ADS)

Northern-Hemisphere afternoon/evening-sector observations of auroral absorption substorms on November 3, 1975, September 28, 1977, and February 14, 1976, obtained with the Finnish riometer chain, a large number of additional riometer stations, and seven pulsation-magnetometer stations are reported in tables and graphs and discussed. The events considered occurred during magnetically disturbed periods (Kp greater than 3), with substorm onset in the magnetic midnight sector. The main features observed are a southward-moving preonset absorption bay, rapid westward propagation (separately at high and low L) of the onset, and slowly varying absorption (without pulsation activity) at L = 3-4 about 1 h after onset; these features are characterized in detail. The westward propagation correlates with PiB or IPDP magnetic-pulsation activity at L greater than about 6 or less than 4.8, respectively.

Rosenberg, T. J.; Wedeken, U.; Stauning, P.; Ranta, A.; Ranta, H.

1983-12-01

349

Activation of human herpesvirus replication by apoptosis.  

PubMed

A central feature of herpesvirus biology is the ability of herpesviruses to remain latent within host cells. Classically, exposure to inducing agents, like activating cytokines or phorbol esters that stimulate host cell signal transduction events, and epigenetic agents (e.g., butyrate) was thought to end latency. We recently showed that Kaposi's sarcoma-associated herpesvirus (KSHV, or human herpesvirus-8 [HHV-8]) has another, alternative emergency escape replication pathway that is triggered when KSHV's host cell undergoes apoptosis, characterized by the lack of a requirement for the replication and transcription activator (RTA) protein, accelerated late gene kinetics, and production of virus with decreased infectivity. Caspase-3 is necessary and sufficient to initiate the alternative replication program. HSV-1 was also recently shown to initiate replication in response to host cell apoptosis. These observations suggested that an alternative apoptosis-triggered replication program might be a general feature of herpesvirus biology and that apoptosis-initiated herpesvirus replication may have clinical implications, particularly for herpesviruses that almost universally infect humans. To explore whether an alternative apoptosis-initiated replication program is a common feature of herpesvirus biology, we studied cell lines latently infected with Epstein-Barr virus/HHV-4, HHV-6A, HHV-6B, HHV-7, and KSHV. We found that apoptosis triggers replication for each HHV studied, with caspase-3 being necessary and sufficient for HHV replication. An alternative apoptosis-initiated replication program appears to be a common feature of HHV biology. We also found that commonly used cytotoxic chemotherapeutic agents activate HHV replication, which suggests that treatments that promote apoptosis may lead to activation of latent herpesviruses, with potential clinical significance. PMID:23885073

Prasad, Alka; Remick, Jill; Zeichner, Steven L

2013-10-01

350

Unraveling the Early Events of Amyloid-? Protein (A?) Aggregation: Techniques for the Determination of A? Aggregate Size  

PubMed Central

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-? protein (A?) associated with Alzheimer’s disease. In particular, the review focuses on techniques that provide information about the size or quantity of oligomeric A? 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.

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

2012-01-01

351

The origin of replicators and reproducers  

PubMed Central

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.

Szathmary, Eors

2006-01-01

352

The evolution of replicators.  

PubMed

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

Szathmáry, E

2000-11-29

353

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

PubMed

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

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

2012-09-01

354

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

USGS Publications Warehouse

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.

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

2010-01-01

355

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

PubMed

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-pol?, PCNA, topoisomerase, Cdc45, pol?, and pol? 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

Wu, LiHong; Liu, Yang; Kong, DaoChun

2014-05-01

356

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

PubMed

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

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

2013-11-01

357

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

PubMed

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

Sun, Yu; He, Xiaolan; Glenny, David

2014-07-01

358

Mcl-1 downregulation by pro-inflammatory cytokines and palmitate is an early event contributing to ?-cell apoptosis  

PubMed Central

Pancreatic ?-cell apoptosis is a key feature of diabetes mellitus and the mitochondrial pathway of apoptosis is a major mediator of ?-cell death. We presently evaluated the role of the myeloid cell leukemia sequence 1 (Mcl-1), an antiapoptotic protein of the Bcl-2 family, in ?-cells following exposure to well-defined ?-cell death effectors, for example, pro-inflammatory cytokines, palmitate and chemical endoplasmic reticulum (ER) stressors. All cytotoxic stresses rapidly and preferentially decreased Mcl-1 protein expression as compared with the late effect observed on the other antiapoptotic proteins, Bcl-2 and Bcl-xL. This was due to ER stress-mediated inhibition of translation through eIF2? phosphorylation for palmitate and ER stressors and through the combined action of translation inhibition and JNK activation for cytokines. Knocking down Mcl-1 using small interference RNAs increased apoptosis and caspase-3 cleavage induced by cytokines, palmitate or thapsigargin, whereas Mcl-1 overexpression partly prevented Bax translocation to the mitochondria, cytochrome c release, caspase-3 cleavage and apoptosis induced by the ?-cell death effectors. Altogether, our data suggest that Mcl-1 downregulation is a crucial event leading to ?-cell apoptosis and provide new insights into the mechanisms linking ER stress and the mitochondrial intrinsic pathway of apoptosis. Mcl-1 is therefore an attractive target for the design of new strategies in the treatment of diabetes.

Allagnat, F; Cunha, D; Moore, F; Vanderwinden, J M; Eizirik, D L; Cardozo, A K

2011-01-01

359

Early emotional processing deficits in depersonalization: an exploration with event-related potentials in an undergraduate sample.  

PubMed

Emotional stimuli may draw attention to such an extent that they hamper the processing of subsequent signals, a phenomenon termed emotion-induced blindness (EIB). As depersonalization is associated with self-reported attenuated emotional responses, the present study explored whether individuals scoring high on the Cambridge Depersonalization Scale (CDS; n=15) exhibit a diminished EIB effect relative to low CDS scoring individuals (n=15), and whether attentional processes reflected in event-related potentials (ERPs) are implicated in this effect. We obtained an EIB effect such that emotional distractors that preceded targets with a lag of 200ms reduced correct detection of targets. Although the magnitude of this effect was similar for high and low CDS participants, high CDS participants exhibited a significantly lower ERP amplitude at the frontal lead in the 200-300ms window than did low CDS individuals to targets that followed emotional versus neutral distractors. This latter effect was significantly related to the Alienation factor of the CDS. This pattern suggests that difficulties in the discrimination between emotional and neutral stimuli relate to the feeling of unreality in depersonalization. PMID:23149021

Quaedflieg, Conny W E M; Giesbrecht, Timo; Meijer, Ewout; Merckelbach, Harald; de Jong, Peter J; Thorsteinsson, Haraldur; Smeets, Tom; Simeon, Daphne

2013-06-30

360

Disruption of pregnancy in mouse by aristolic acid: I. Plausible explanation in relation to early pregnancy events.  

PubMed

Aristolic acid (AA), obtained from Aristolochia indica Linn, disrupted nidation in mice when administered on Day 1 of pregnancy. The implantation inhibiting effect of the compound was assessed with respect to certain parameters which are characteristics of early pregnancy, such as tubal transport of ova into the uterus, hyperpermeability of the endometrial capillaries, increase in uterine weight and total protein content, endometrial bed preparation and changes in uterine phosphatase enzymes during Days 4-6 of pregnancy. The compound did not affect tubal transport of eggs, but the uterine blue reaction, caused by extravasation of the dye, pontamine blue, at future implantation sites was inhibited significantly in treated mice. Histological picture of the uterus revealed AA-induced impairment of development (i.e. decidualization) and reconciled with decreases found in uterine weight and its total protein contents in treated animals. In control untreated mice, specific uterine alkaline phosphatase (ALP) activity increased significantly from Days 4 through 6 of pregnancy, but this was prevented in treated mice. On the other hand, specific uterine acid phosphatase (AP) activity was high on Day 5, while in treated mice uterine AP activity remained low during Days 4 and 5 and increased significantly thereafter. It was inferred that AA interferes with steroidal conditioning of the uterus and renders it hostile to ovum implantation. PMID:3829677

Ganguly, T; Pakrashi, A; Pal, A K

1986-12-01

361

A dihydro-pyrido-indole potently inhibits HSV-1 infection by interfering the viral immediate early transcriptional events.  

PubMed

In our continued quest for identifying novel molecules from ethnomedicinal source we have isolated an alkaloid 7-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole, also known as Harmaline (HM), from an ethnomedicinal herb Ophiorrhiza nicobarica. The compound exhibited a potent anti-HSV-1 activity against both wild type and clinical isolates of HSV-1. Further we demonstrated that HM did not interfere in viral entry but the recruitment of lysine-specific demethylase-1 (LSD1) and the binding of immediate-early (IE) complex on ICP0 promoter. This leads to the suppression of viral IE gene synthesis and thereby the reduced expression of ICP4 and ICP27. Moreover, HM at its virucidal concentration is nontoxic and reduced virus yields in cutaneously infected Balb/C mice. Thus, the interference in the binding of IE complex, a decisive factor for HSV lytic cycle or latency by HM reveals an interesting target for developing non-nucleotide antiherpetic agent with different mode of action than Acyclovir. PMID:24576908

Bag, Paromita; Ojha, Durbadal; Mukherjee, Hemanta; Halder, Umesh C; Mondal, Supriya; Biswas, Aruna; Sharon, Ashoke; Van Kaer, Luc; Chakrabarty, Sekhar; Das, Gobardhan; Mitra, Debashis; Chattopadhyay, Debprasad

2014-05-01

362

Mechanism of a flow-gated angiogenesis switch: Early signaling events at cell-matrix and cell-cell junctions  

PubMed Central

A bias towards angiogenesis from the venous circulation has long been known, but its cause remains unclear. Here we explore the possibility that high interstitial pressure in tumors and the resultant net filtration pressure gradient that would induce flow from the interstitium into the venous circulation or lymphatics could also be an important mechanical regulator of angiogenesis. The objective of this study was to test the hypothesis that basal-to-apical (B-A) transendothelial flow promotes angiogenesis and to investigate potential mechanisms. Macro- and microvascular endothelial monolayers were cultured on type I collagen gels in a microfluidic cell culture device and subjected to apical-to-basal (A-B) and B-A transendothelial flows. Samples were perfusion fixed and analyzed for morphological responses, localization and degree of phosphorylation of certain signaling proteins. Application of B-A, but not A-B flow, to cultured endothelial monolayers was found to promote capillary morphogenesis and resulted in distinct localization patterns of VE-Cadherin and increased FAK phosphorylation. These results suggest that B-A flow triggers the transition of vascular endothelial cells from a quiescent to invasive phenotype and that the flow-mediated response involves signaling at cell-cell and cell-matrix interfaces. These results support the hypothesis that transendothelial pressure gradients resulting in B-A flow promotes sprouting angiogenesis and are consistent with early observations that tumor angiogenesis occurs from the venous side of the circulation.

Vickerman, Vernella; Kamm, Roger D.

2014-01-01

363

Early signaling events that underlie fate decisions of naive CD4+ T cells towards distinct T-helper cell subsets  

PubMed Central

Summary CD4+ T-helper (Th) cells are a major cell population that plays an important role in governing acquired immune responses to a variety of foreign antigens as well as inducing some types of autoimmune diseases. There are at least four distinct Th cell subsets (Th1, Th2, Th17, and inducible T-regulatory cells), each of which has specialized functions to control immune responses. Each of these cell types emerge from naive CD4+ T cells after encounter with foreign antigens presented by dendritic cells (DCs). Each Th cell subset expresses a unique set of transcription factors and produce hallmark cytokines. Both T-cell receptor (TCR)-mediated stimulation and the cytokine environment created by activated CD4+ T cells themselves, by `partner' DCs and/or other cell types during the course of differentiation, play an important role in the fate decisions towards distinct Th subsets. Here, we review how TCR-mediated signals in collaboration with the cytokine environment influence the fate decisions of naive CD4+ T cells towards distinct Th subsets at the early stages of activation. We also discuss the roles of TCR-proximal signaling intermediates and of the Notch pathway in regulating the differentiation to distinct Th phenotypes.

Yamane, Hidehiro; Paul, William E.

2012-01-01

364

Increased endothelial expression of Toll-like receptor 2 at sites of disturbed blood flow exacerbates early atherogenic events  

PubMed Central

Toll-like receptors (TLRs) are pattern recognition receptors of innate immunity. TLRs initiate inflammatory pathways that may exacerbate chronic inflammatory diseases like atherosclerosis. En face laser scanning confocal microscopy (LSCM) of isolated aortic segments revealed the distribution of intimal TLR2 expression and the atheroprotective outcomes resulting from a TLR2 deficiency. TLR2 expression was restricted to endothelial cells in regions of disturbed blood flow, such as the lesser curvature region, in atherosclerosis-prone, low-density lipoprotein receptor–deficient (LDLr?/?) mice. Diet-induced hyperlipidemia in LDLr?/? mice increased this regional endothelial TLR2 expression. Bone marrow (BM) reconstitution of LDLr?/? and LDLr?/?TLR2?/? mice created chimeric mice with green fluorescent protein (GFP) expression in BM-derived cells (BMGFP+). Lesser curvature BMGFP+ leukocyte accumulation, lipid accumulation, foam cell generation and endothelial cell injury were all increased by hyperlipidemia, whereas hyperlipidemic double mutant BMGFP+LDLr?/?TLR2?/? mice had reduced BMGFP+ leukocyte accumulation, lipid accumulation, foam cells, and endothelial cell injury. This is the first report of in vivo site-specific expression of endothelial cell TLR2. Expression of this receptor on endothelial cells contributed to early atherosclerotic processes in lesion-prone areas of the mouse aorta.

Mullick, Adam E.; Soldau, Katrin; Kiosses, William B.; Bell, Thomas A.; Tobias, Peter S.; Curtiss, Linda K.

2008-01-01

365

Early diagnosis of Wolf-Hirschhorn syndrome triggered by a life-threatening event: congenital diaphragmatic hernia.  

PubMed

Wolf-Hirschhorn syndrome (WHS, OMIM 194190) is a chromosomal disorder characterized by retarded mental and physical growth, microcephaly, Greek helmet appearance of the facies, seizures/epilepsy. Closure defects of lip or palate, and cardiac septum defects occur in 30-50% of cases. Its cause is a deletion in the short arm of chromosome 4. We present a male patient, born after 37 weeks gestation, as the fourth pregnancy of non-consanguineous healthy parents, with unilateral cleft lip and palate, hypertelorism, a right-sided ear tag, and mild epispadias. At age 10 weeks he developed acute respiratory distress and acute bowel obstruction requiring emergency laparotomy. This revealed a left-sided posterolateral diaphragmatic defect, type Bochdalek, with incarceration of the small intestines necessitating major bowel resection. Clinical genetic investigation suggested a chromosome anomaly, but regular karyotyping was normal. However, FISH analysis showed a microdeletion in the short arm of chromosome 4 (4p-), consistent with WHS. A combination of this syndrome with congenital diaphragmatic hernia (CDH) has been rarely described. CDH can present either as an isolated defect at birth, or with multiple congenital abnormalities, or as part of a defined syndrome or chromosomal disorder. Therefore CDH, although not common in WHS, can lead to its diagnosis relatively early in life. We strongly recommend a clinical genetic evaluation of each CDH patient with facial anomalies taking into consideration 4p- deletion syndrome. PMID:15108210

van Dooren, M F; Brooks, A S; Hoogeboom, A J M; van den Hoonaard, T L; de Klein, J E M M; Wouters, C H; Tibboel, D

2004-06-01

366

The icy highlands scenario for early Mars: modeling of transient melting events and comparison with the geological evidence  

NASA Astrophysics Data System (ADS)

Explaining the geological evidence for fluvial erosion on Mars’ most ancient terrain remains a key challenge to planetary science despite decades of research. Previously, we performed 3D simulations of the global climate and water cycle in the Noachian under a thicker (0.1-2 bar) primitive atmosphere and faint young Sun (75% of present flux). These simulations revealed a possible mechanism for replenishing valley network sources: because of altitude-dependent adiabatic surface cooling, net transport of ice to the equatorial and southern Noachian highlands occurs via precipitation (snowfall) over long timescales. Here we investigate potential mechanisms for episodic melting of the highland ice deposits once they have formed. We present simulations of the melting and runoff rates induced by volcanic SO2/H2S emissions and the resulting formation of sulphate aerosols. Through modeling and basic theory, we evaluate recent suggestions that early Mars could have been warmed above freezing by water ice clouds or forced into a long-lived runaway greenhouse state by impacts. Finally, we discuss how large-scale variations in the VN distribution may inform us about the varying state of the atmosphere during the Noachian era.

Wordsworth, Robin; Kerber, L.; Forget, F.; Head, J. W.; Madeleine, J.; Millour, E.; Scanlon, K.

2013-10-01

367

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

NASA Astrophysics Data System (ADS)

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.

Gusman, Aditya Riadi; Tanioka, Yuichiro

2013-05-01

368

An examination of backgrounds to early-run minimum-bias events in ATLAS at the LHC  

NASA Astrophysics Data System (ADS)

The initial stages of the Large Hadron Collider (LHC) run will be a source of critical information---about the ATLAS detector and about the physics of pp collisions at s = 14 TeV, including parton distribution evolution and the cross-section of sigmapp. The accelerator itself will be the source of some detector interest, as we have a first look at what have so far been speculations on the quality of the vacuum in the experimental insertion, and the cleanliness of the beam from the accelerator. The shakedown period, with its low beam squeeze, low luminosity, and undemanding trigger menus, will be very useful in addressing some of these questions, as it lacks the pileup and radiation levels that will arrive with higher luminosity---making it an important opportunity to investigate minimum-bias events in relative isolation. For the short lifetime of the Minimum Bias Trigger Scintillators (MBTS), which are expected to fail within a few months of running, they will aid in discriminating the minimum bias signal of inelastic non-single-diffractive pp collisions. Using single- or double-coincidence signatures, the MBTS system and other trigger and analysis strategies attempt to avoid triggering on otherwise empty bunch crossings and eliminate the effects of beam-gas collisions and beam-halo effects which would lead these spurious triggers and reduce the general minimum-bias trigger efficiency. An examination of the effects of beam halo and beam-gas interactions on the minimum-bias trigger response is made. The signatures of the beam halo and beam gas are examined from the standard ATLAS tracking reconstruction.

Stradling, Alden Reid

369

Chemistry of Early Self-Replicating Systems.  

National Technical Information Service (NTIS)

The NASA Specialized Center of Research and Training (NSCORT) in Exobiology is a consortium of scientists at the University of California at San Diego (UCSD), The Salk Institute for Biological Studies (Salk) and The Scripps Research Institute (TSRI). All ...

J. L. Bada

1996-01-01

370

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

PubMed Central

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.

Mansilla, Sabrina F.; Soria, Gaston; Vallerga, Maria Belen; Habif, Martin; Martinez-Lopez, Wilner; Prives, Carol; Gottifredi, Vanesa

2013-01-01

371

Neurotensin receptor 1 gene activation by the Tcf/beta-catenin pathway is an early event in human colonic adenomas.  

PubMed

Alterations in the Wnt/APC (adenomatous polyposis coli) signalling pathway, resulting in beta-catenin/T cell factor (Tcf)-dependent transcriptional gene activation, are frequently detected in familial and sporadic colon cancers. The neuropeptide neurotensin (NT) is widely distributed in the gastrointestinal tract. Its proliferative and survival effects are mediated by a G-protein coupled receptor, the NT1 receptor. NT1 receptor is not expressed in normal colon epithelial cells, but is over expressed in a number of cancer cells and tissues suggesting a link to the outgrowth of human colon cancer. Our results demonstrate that the upregulation of NT1 receptor occurring in colon cancer is the result of Wnt/APC signalling pathway activation. We first established the functionality of the Tcf response element within the NT1 receptor promoter. Consequently, we observed the activation of NT1 receptor gene by agents causing beta-catenin cytosolic accumulation, as well as a strong decline of endogenous receptor when wt-APC was restored. At the cellular level, the re-establishment of wt-APC phenotype resulted in the impaired functionality of NT1 receptor, like the breakdown in NT-induced intracellular calcium mobilization and the loss of NT pro-invasive effect. We corroborated the Wnt/APC signalling pathway on the NT1 receptor promoter activation with human colon carcinogenesis, and showed that NT1 receptor gene activation was perfectly correlated with nuclear or cytoplasmic beta-catenin localization while NT1 receptor was absent when beta-catenin was localized at the cell-cell junction in early adenomas of patients with familial adenomatous polyposis, hereditary non-polyposis colorectal cancer and loss of heterozygosity tumours. In this report we establish a novel link in vitro between the Tcf/beta-catenin pathway and NT1 receptor promoter activation. PMID:16299383

Souazé, Frédérique; Viardot-Foucault, Véronique; Roullet, Nicolas; Toy-Miou-Leong, Mireille; Gompel, Anne; Bruyneel, Erik; Comperat, Eva; Faux, Maree C; Mareel, Marc; Rostène, William; Fléjou, Jean-François; Gespach, Christian; Forgez, Patricia

2006-04-01

372

Exploring Teacher and Student Perspectives in an Early Childhood Classroom through an Ethnographic Lens.  

ERIC Educational Resources Information Center

This study explored teacher and student perspectives of a specific event in an early childhood classroom. The study replicates previous research on the construct of positionings to study social interaction in a prekindergarten integrated classroom. Subjects were one teacher and one 5-year-old student. A 20-minute segment of videotape was observed…

McMurray, Paula; And Others

373

Replication fork inhibition in seqA mutants of Escherichia coli triggers replication fork breakage.  

PubMed

SeqA protein negatively regulates replication initiation in Escherichia coli and is also proposed to organize maturation and segregation of the newly replicated DNA. The seqA mutants suffer from chromosomal fragmentation; since this fragmentation is attributed to defective segregation or nucleoid compaction, two-ended breaks are expected. Instead, we show that, in SeqA's absence, chromosomes mostly suffer one-ended DNA breaks, indicating disintegration of replication forks. We further show that replication forks are unexpectedly slow in seqA mutants. Quantitative kinetics of origin and terminus replication from aligned chromosomes not only confirm origin overinitiation in seqA mutants, but also reveal terminus under-replication, indicating inhibition of replication forks. Pre-/post-labelling studies of the chromosomal fragmentation in seqA mutants suggest events involving single forks, rather than pairs of forks from consecutive rounds rear-ending into each other. We suggest that, in the absence of SeqA, the sister-chromatid cohesion 'safety spacer' is destabilized and completely disappears if the replication fork is inhibited, leading to the segregation fork running into the inhibited replication fork and snapping the latter at single-stranded DNA regions. PMID:24806348

Rotman, Ella; Khan, Sharik R; Kouzminova, Elena; Kuzminov, Andrei

2014-07-01