These are representative sample records from related to your search topic.
For comprehensive and current results, perform a real-time search at

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

PubMed Central

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.; Schon, 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.; Martin-Garcia, Julio; Freire, Ernesto; Ptak, Roger G.; Sodroski, Joseph



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

PubMed Central

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

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



Early traumatic events in psychopaths.  


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



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. PMID:23793816

Pedersen, Brent S.; De, Subhajyoti



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


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



Early Replication of Short Telomeres in Budding Yeast  

E-print Network

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

Halazonetis, Thanos


Early intermediates in bacteriophage T4 DNA replication and recombination.  

PubMed Central

We investigated, by density gradients and subsequent electron microscopy, vegetative T4 DNA after single or multiple infection of Escherichia coli with wild-type T4. Our results can be summarized as follows. (i) After single infection (i.e., when early intermolecular recombination could not occur), most, if not all, T4 DNA molecules initiated the first round of replication with a single loop. (ii) After multiple infection, recombinational intermediates containing label from both parents first appeared as early as 1 min after the onset of replication, long before all parental DNA molecules had finished their first round and before secondary replication was detectable. (iii) At the same time, in multiple infections only, complex, highly branched concatemeric T4 DNA first appeared. (iv) Molecules in which two loops or several branches were arranged in tandem were only found after multiple infections. (v) Secondary loops within primary loops were seen after both single and multiple infections, but they were rare and many appeared off center. Thus, recombination in wild-type T4-infected cells occurred very early, and the generation of multiple tandem loops or branches in vegetative T4 DNA depended on recombination. These results are consistent with the previous finding (A. Luder and G. Mosig, Proc. Natl. Acad. Sci. U.S.A. 79:1101-1105, 1982) that most secondary growing points of T4 are not initiated from origin sequences but from recombinational intermediates. By these and previous results, the various DNA molecules that we observed are most readily explained as intermediates in DNA replication and recombination according to a model proposed earlier to explain various other aspects of T4 DNA metabolism (Mosig et al., p. 277-295, in D. Ray, ed., The Initiation of DNA Replication, Academic Press, Inc., New York, 1981). Images PMID:6834472

Dannenberg, R; Mosig, G



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. PMID:22590552

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



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. PMID:24073225

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



Replication of Colicin E1 Plasmid DNA in Cell Extracts: II. Selective Synthesis of Early Replicative Intermediates*  

PubMed Central

The major products of colicin E1 plasmid DNA synthesis in cell extracts are completely replicated molecules and a class of molecules containing newly synthesized small DNA fragments. The addition of 10% glycerol and/or 2 mM spermidine to extracts blocks synthesis of completely replicated molecules while enhancing synthesis of molecules containing newly synthesized DNA fragments. The latter molecules, which contain on the average two DNA fragments of approximately 6 S, are early replicative intermediates for synthesis of completely replicated molecules. Synthesis of the intermediates is sensitive to rifampicin and depends on RNA synthesis. RNA components are linked to the 6S DNA molecules. PMID:4598305

Sakakibara, Yoshimasa; Tomizawa, Jun-Ichi



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

SciTech Connect

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

Li Guangyu; Dziuba, Natallia; Friedrich, Brian [Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555-0435 (United States); Murray, James L. [Zirus, Inc., 1384 Buford Business Boulevard, Suite 700, Buford, GA 30518 (United States); Ferguson, Monique R., E-mail: mrfergus@utmb.ed [Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555-0435 (United States)



At short telomeres tel1 directs early replication and phosphorylates rif1.  


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

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



At Short Telomeres Tel1 Directs Early Replication and Phosphorylates Rif1  

PubMed Central

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

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



Dihydropyridines Inhibit Translation and Early Replication of Hepatitis C Virus  

E-print Network

, efonidipine emerged as the most effective HCV replication and translation inhibitor with the least toxicity. Using a real-time evolution strategy, we developed and characterized a mutant virus which was resistant to DHPs and several other drugs which modify...

Klemashevich, Cory



Dynamics of DNA Replication during Premeiosis and Early Meiosis in Wheat  

PubMed Central

Meiosis is a specialised cell division that involves chromosome replication, two rounds of chromosome segregation and results in the formation of the gametes. Meiotic DNA replication generally precedes chromosome pairing, recombination and synapsis in sexually developing eukaryotes. In this work, replication has been studied during premeiosis and early meiosis in wheat using flow cytometry, which has allowed the quantification of the amount of DNA in wheat anther in each phase of the cell cycle during premeiosis and each stage of early meiosis. Flow cytometry has been revealed as a suitable and user-friendly tool to detect and quantify DNA replication during early meiosis in wheat. Chromosome replication was detected in wheat during premeiosis and early meiosis until the stage of pachytene, when chromosomes are associated in pairs to further recombine and correctly segregate in the gametes. In addition, the effect of the Ph1 locus, which controls chromosome pairing and affects replication in wheat, was also studied by flow cytometry. Here we showed that the Ph1 locus plays an important role on the length of meiotic DNA replication in wheat, particularly affecting the rate of replication during early meiosis in wheat. PMID:25275307

Rey, Maria-Dolores; Prieto, Pilar



Essentiality of the Early Transcript in the Replication Origin of the Lactococcal Prolate Phage c2†  

PubMed Central

The genome of the prolate-headed lytic lactococcal bacteriophage c2 is organized into two divergently oriented blocks consisting of the early genes and the late genes. These blocks are separated by the noncoding origin of DNA replication. We examined the functional role of transcription of the origin in a plasmid model system. Deletion of the early promoter PE1 abolished origin function. Introduction of mutations into PE1 which did not eliminate promoter activity or replacement of PE1 with an unrelated but functional promoter did not abolish replication. The A-T-rich region upstream of PE1, which is conserved in prolate phages, was not required for plasmid replication. Replacement of the PE1 transcript template sequence with an unrelated sequence with a similar G+C content abolished replication, showing that the sequence encoding the transcript is essential for origin function. Truncated transcript and internal deletion constructs did not support replication except when the deletion was at the very 3? end of the DNA sequence coding for the transcript. The PE1 transcript could be detected for all replication-proficient constructs. Recloning in a plasmid vector allowed detection of PE1 transcripts from some fragments that did not support replication, indicating that stability of the transcript alone was not sufficient for replication. The data suggest that production of a transcript of a specific length and with a specific sequence or structure is essential for the function of the phage c2 origin in this model system. PMID:15547273

Schiemann, Anja H.; Rakonjac, Jasna; Callanan, Michael; Gordon, James; Polzin, Kayla; Lubbers, Mark W.; O'Toole, Paul W.



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

PubMed Central

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

Lemaitre, Jean-Marc; Geraud, Gerard; Mechali, Marcel



The early days of plastid retrograde signaling with respect to replication and transcription  

PubMed Central

The plastid signal was originally defined as a pathway that informs the nucleus of the chloroplast status and results in the modulation of expression of nuclear-encoded plastid protein genes. However, the transfer of chloroplast genes into the nuclear genome is a prerequisite in this scheme, although it should not have been established during the very early phase of chloroplast evolution. We recently demonstrated in a primitive red alga that the plastid-derived Mg-protoporphyrin IX activates nuclear DNA replication (NDR) through the stabilization of a G1 cyclin, which coordinates the timing of organelle and NDR. This mechanism apparently does not involve any transcriptional regulation in the nucleus, and could have been established prior to gene transfer events. However, a retrograde signal mediating light-responsive gene expression may have been established alongside gene transfer, because essential light sensing and regulatory systems were originally incorporated into plant cells by the photosynthetic endosymbiont. In this short article, we discuss the origins, early days and evolution of the plastid retrograde signal(s). PMID:23316208

Tanaka, Kan; Hanaoka, Mitsumasa



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. PMID:20194695

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



DNA breaks early in replication process associated with B cell cancers

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.


Expert Panel Workshop on Early-Life Events and Cancer

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.


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. PMID:23087128

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



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. PMID:17005913

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



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.



Early Reproductive Events and Breast Cancer

The 11/25/2002 document below precedes an NCI workshop held in February 2003. This scientific workshop was held to present and review the available scientific data on reproductive events in a woman's life that may impact her subsequent risk of developing breast cancer. NCI has drawn on the outcomes of the February workshop to develop new, updated materials on this topic. See NCI's current fact sheet on Abortion, Miscarriage, and Breast Cancer Risk. Document posted: 11/25/2002


Autophagy during early stages contributes to bovine viral diarrhea virus replication in MDBK cells.  


Autophagy (or autophagocytosis) is an essential and precise control process by which cells degrade unnecessary or dysfunctional cellular components or organelles in the cytoplasm in response to nutrient depletion, exogenous pathogens, or other stimuli. This process results in the removal of damaged or surplus organelles and macromolecular complexes via a lysosome-dependent mechanism. Bovine viral diarrhea virus (BVDV) is a ssRNA virus of the Flaviviridae family (genus Pestivirus). BVDV infection results in major economic losses due to poor reproductive performance and poor calf performance in cattle herds. In our previous studies, we have shown that BVDV NADL infection significantly increases autophagy in MDBK cells. To further define the interactions between autophagy and BVDV infection, we investigated the effects of autophagy on the replication of BVDV NADL. The findings showed that autophagy was inhibited by treatment with 3-methyladenine (3-MA) or wortmannin and that the knockdown of LC3 and Beclin1 using lentivirus-mediated RNA interference (RNAi) suppressed BVDV NADL replication. In contrast, the findings showed the replication of BVDV NADL was significantly increased by treatment with the autophagy inducer rapamycin within 18?h post-infection (pi). However, the mRNA levels of BVDV NADL 5'UTRs showed a downward trend after 18?h pi, and this effect was reversed by chloroquine treatment. Therefore, we inferred that infection with BVDV NADL increases autophagy, which in turn favors BVDV NADL replication at early stages. PMID:24347372

Fu, Qiang; Shi, Huijun; Zhang, Hui; Ren, Yan; Guo, Fei; Qiao, Jun; Jia, Bin; Wang, Pengyan; Chen, Chuangfu



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;



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

PubMed Central

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

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



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


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

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



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


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

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



Early Reproductive Events and Breast Cancer: Workshop Statement

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.


Early Reproductive Events and Breast Cancer: Workshop Participants

Posted: 02/21/2003 Posted: 02/21/2003 Early Reproductive Events and Breast Cancer: Workshop Participants Martin Abeloff, M.D.Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins W. Reyn ArcherHill and Knowlton Alan A. Arslan, M.D.New York University


Towards an Early Warning System for Heat Events  

Microsoft Academic Search

Severe and sustained episodes of hot weather during the summer season are associated with marked short?term increases in morbidity and mortality in the United States and Europe. The death toll in an unprepared region can be substantial, as was evidenced in the 2003 heat event in Western Europe. There is growing interest in developing early warning systems to advise the

K. L. Ebi



Summary Report: Early Reproductive Events and Breast Cancer Workshop

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.


Early events in the neoplastic transformation of respiratory epithelium.  


The complex process of epithelial carcinogenesis is composed of discrete biologic events including the early activation events of "initiation" and "promotion." For lung cancer, these events are only now being elucidated. Despite the identification of possible target genes and their mutations, the "initiation" events for lung cancer remain poorly understood. The identification of these "initiation" events is a crucial step toward the development of practical molecular markers for early detection of this disease. The reversible process of tumor promotion remains somewhat enigmatic but is a promising target for chemoprevention. A wide range of substances, including asbestos and various substances in cigarette smoke, behave as tumor promoters for lung cancer. They appear to promote tumor formation by inducing cellular proliferation mediated in part by growth factors. The intracellular signals these factors provide are ultimately translated into cellular growth via steps involving nuclear transcription factors. Early response genes such as the jun and fos gene family members encode such nuclear transcription factors which are expressed in lung cancer cells and primary bronchial epithelial cells. The expression of these transcription factors is highly responsive to stimulation by growth factors including serum, transforming growth factor, and gastrin-releasing peptide. A more thorough understanding of this process will allow the development of molecular and/or pharmacologic antagonists that can interfere with the biologic process of tumor promotion and therefore function as chemoprevention agents. PMID:1389694

Birrer, M J; Alani, R; Cuttitta, F; Preis, L H; Sabich, A L; Sanders, D A; Siegfried, J M; Szabo, E; Brown, P H



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. PMID:24837437

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



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


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

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



A novel class of early replicating fragile sites that contribute to genome instability in B cell lymphomas  

PubMed Central

Summary DNA double strand breaks (DSBs) in B lymphocytes arise stochastically during replication or as a result of targeted DNA damage by activation induced cytidine deaminase (AID). Here we identify recurrent, early replicating and AID independent DNA lesions, termed early replication fragile sites (ERFS), by genome-wide localization of DNA repair proteins in B cells subjected to replication stress. ERFS colocalize with highly expressed gene clusters and are enriched for repetitive elements and CpG dinucleotides. Although distinct from late-replicating common fragile sites (CFS), the stability of ERFSs and CFSs is similarly dependent on the replication-stress response kinase ATR. ERFSs break spontaneously during replication, but their fragility is increased by hydroxyurea, ATR inhibition or deregulated c-Myc expression. Moreover, greater than 50% of recurrent amplifications/deletions in human diffuse large B cell lymphoma map to ERFSs. In summary, we have identified a source of spontaneous DNA lesions that drives instability at preferred genomic sites. PMID:23352430

Barlow, Jacqueline; Faryabi, Robert B.; Callen, Elsa; Wong, Nancy; Malhowski, Amy; Chen, Hua Tang; Gutierez-Cruz, Gustavo; Sun, Hong-Wei; McKinnon, Peter; Wright, George; Casellas, Rafael; Robbiani, Davide F.; Staudt, Louis; Fernandez-Capetillo, Oscar; Nussenzweig, Andre



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


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

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



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


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

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



Discovery of gramine derivatives that inhibit the early stage of EV71 replication in vitro.  


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



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

SciTech Connect

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

Anderson, Jenny L. [Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611 (United States); Hope, Thomas J. [Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611 (United States)], E-mail:



Premature condensation induces breaks at the interface of early and late replicating chromosome bands bearing common fragile sites  

PubMed Central

Various studies suggest a tight relationship between chromosome rearrangements driving tumor progression and breaks at loci called common fragile sites. Most of these sites are induced after perturbation of the replication dynamics, notably by aphidicolin treatment. We have mapped the majority of these sites to the interface of R and G bands, which calls into question the previous assignment of aphidicolin-sensitive sites to R bands. This observation suggests that most of them correspond to loci that ensure the transition between early and late replicating domains. We show that calyculin A, which triggers chromosome condensation at any phase of the cell cycle but does not markedly impair replication, induces damage in the chromosomes of human lymphocytes treated in G2 but not in G1 phase. We demonstrate that these lesions colocalize with those induced by aphidicolin treatment. Hence, common fragile site stability is compromised, whether aphidicolin delays replication or calyculin A advances condensation. We also show that, in cells that go through an unperturbed S phase, completion of their replication and/or replication-associated chromatin reorganization occur all along the G2 phase, which may explain their inability to condense properly after calyculin A treatment during this phase of the cell cycle. PMID:16330769

El Achkar, Eliane; Gerbault-Seureau, Michelle; Muleris, Martine; Dutrillaux, Bernard; Debatisse, Michelle



Induction of Transcription Factor Early Growth Response Protein 1 during HSV-1 Infection Promotes Viral Replication in Corneal Cells  

PubMed Central

Aims To understand the mechanisms of Early Growth Response Protein 1 (Egr-1) induction upon HSV-1 lytic infection and its roles in regulating viral gene expression and replication. Study Design Rabbit corneal cell line SIRC and other cell lines were infected by HSV-1 to investigate the Egr-1 induction and its occupancy on the viral genome in different conditions. UV-inactivated HSV-1 and a recombinant virus over-expressing Egr-1 were generated to evaluate the regulatory effects on viral gene expression and replication during the infection. Methodology Egr-1 induction triggered by viral infection was determined by Western Blot analyses and immune-fluorescent microscopy. Real-time RT-PCR and a novel Cignal™ Reporter Assay were used for quantitative measurement of Egr-1 expression. Chromatin Immuno-precipitation (ChIP) was performed to address the Egr-1 occupancy to the viral regulatory sequences and the influence on viral replication was assessed by plaque assays. Results Our results indicated that Egr-1 expression requires viral gene expression since the UV-inactivated HSV-1 failed to produce Egr-1 protein. Blockade of viral replication did not block the Egr-1 protein synthesis, supporting the hypothesis that HSV-1 replication was not essential for Egr-1 production. Chromatin immune-precipitation (ChIP) and RT-PCR assays demonstrated that induced Egr-1 was able to interact with key regulatory elements near HSV-1 immediate-early (IE) genes and promote viral gene expression. Recombinant virus overexpressing Egr-1 revealed that Egr-1 enhanced the viral replication and the release of infectious virus. Conclusion Together these results concluded that HSV-1 triggers the expression of an important host transcription factor Egr-1 via a unique mechanism and benefit the viral gene expression and replication.

Hsia, S. C.; Graham, L. P.; Bedadala, G. R.; Balish, M. B.; Chen, F.; Figliozzi, R. W.



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

E-print Network

Early Jurassic mass extinction: A global long-term event Crispin T. S. Little Department of Geology extinctions occurred in the early Toarcian, following a regional anoxic event. The Early Jurassic mass between the Early Jurassic Pliensbachian and Toarcian stages. This is a much smaller peak in total

Benton, Michael


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



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

PubMed Central

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

Wu, Brendan W.



Changed lineage composition is an early event in breast carcinogenesis.  


The epithelium compartment of the human breast is made up of a branching ductal-lobular system, which is lined by a single layer of luminal epithelial cells surrounded by contractile myoepithelial cells. The co-ordinated development of these two cell types, and maintenance of their relative proportions, is fundamentally important for normal breast morphogenesis. Changes in cell type composition is one of the hallmark features of breast cancer progression, and the vast majority of breast tumors are comprised of luminal cells only, with a complete absence of myoepithelial cells. Despite this striking alteration in relative proportions of luminal and myoepithelial cells in invasive breast cancers compared with normal breast tissue, the steps in this dramatic change in cellular composition remain poorly characterised, nor is it known whether loss of myoepithelial cells is an early event in carcinogenesis. In a panel of breast tissues, we quantitated the proportion of luminal cells relative to the surrounding myoepithelial cell layer in a panel of normal and pre-invasive breast tissue samples, including lesions with proliferative disease without atypia (PDWA), columnar cell lesions (CCL), atypical ductal hyperplasia (ADH), and DCIS, and correlated these findings with proliferation in the same lesions. The study findings showed that changes in lineage composition correlate with increased proliferation, and are one of the earliest events in breast carcinogenesis. Therefore not only are myoepithelial cells important in distinguishing between invasive and non-invasive tumors, their relative proportion compared with luminal cell numbers may provide a new potential indicator of which premalignant lesions are at higher risk of progression to invasive disease. PMID:23584793

Hilton, Heidi N; Kantimm, Silke; Graham, J Dinny; Clarke, Christine L



Fatty acid amide hydrolase deficiency limits early pregnancy events  

PubMed Central

Synchronized preimplantation embryo development and passage through the oviduct into the uterus are prerequisites for implantation, dysregulation of which often leads to pregnancy failure in women. Cannabinoid/endocannabinoid signaling via cannabinoid receptor CB1 is known to influence early pregnancy. Here we provide evidence that a critical balance between anandamide synthesis by N-acylphosphatidylethanolamine–selective phospholipase D (NAPE-PLD) and its degradation by fatty acid amide hydrolase (FAAH) in mouse embryos and oviducts creates locally an appropriate “anandamide tone” for normal development of embryos and their oviductal transport. FAAH inactivation yielding higher anandamide or experimentally induced higher cannabinoid [(-)-?9-tetrahydrocannabinol] levels constrain preimplantation embryo development with aberrant expression of Cdx2, Nanog, and Oct3/4, genes known to direct lineage specification. Defective oviductal embryo transport arising from aberrant endocannabinoid signaling also led to deferred on-time implantation and poor pregnancy outcome. Intercrossing between wild-type and Faah–/– mice rescued developmental defects, not oviductal transport, implying that embryonic and maternal FAAH plays differential roles in these processes. The results suggest that FAAH is a key metabolic gatekeeper, regulating on-site anandamide tone to direct preimplantation events that determine the fate of pregnancy. This study uncovers what we believe to be a novel regulation of preimplantation processes, which could be clinically relevant for fertility regulation in women. PMID:16886060

Wang, Haibin; Xie, Huirong; Guo, Yong; Zhang, Hao; Takahashi, Toshifumi; Kingsley, Philip J.; Marnett, Lawrence J.; Das, Sanjoy K.; Cravatt, Benjamin F.; Dey, Sudhansu K.



Replication Study of the First Step to Success Early Intervention Program  

ERIC Educational Resources Information Center

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

Lien-Thorne, Stephanie; Kamps, Debra



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

NASA Technical Reports Server (NTRS)

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

Weber, Arthur L.



Spread-spectrum VLF observations of early/fast and LEP events  

NASA Astrophysics Data System (ADS)

Subionospherically-propagating very low frequency (VLF) signals are sensitive to changes in the electrical properties of the D-region ionosphere. Lightning may produce such changes in the form of early/fast events and lightning-induced electron precipitation (LEP) events. While LEP events may be used to probe the energy distribution of electrons in the Earth's radiation belts, early/fast events are indicative of direct coupling of lightning energy to the overlying ionosphere and are closely associated with the occurrence of transient luminous events (TLEs). In this paper, we present observations of early/fast events and LEP events detected using narrowband (200-Hz) VLF transmitters. A spread-spectrum VLF analysis technique is employed to utilize the full 200-Hz bandwidth of the narrowband VLF signal and to analyze the effect of these events on VLF propagation as a function of frequency within the 200-Hz band. Observations underscore the utility of the spread-spectrum analysis technique.

Wang, T.; Moore, R. C.



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

PubMed Central

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

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



Early Detection of Important Animal Health Events J. L. Andrews  

E-print Network

tested; � Syndrome; and � Diagnosis. However, no incidence of major animal health events was reported, one entry noted that over ten-thousand cattle, 100% of the farm, had suffered heart failure. When

Stockie, John


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


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. PMID:23825525

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



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

ERIC Educational Resources Information Center

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

Bickel, Robert; McDonough, Meghan; Williams, Tony



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.



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


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



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


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

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



Synchrony between Early Jurassic extinction, oceanic anoxic event, and the Karoo-Ferrar flood basalt volcanism  

Microsoft Academic Search

A well-known second-order mass extinction took place during the Pliensbachian and Toarcian Stages of the Early Jurassic. First recognized as a minor Pliensbachian peak in the global extinction rate, it has alternatively been interpreted as a regional response to the early Toarcian oceanic anoxic event. Detailed studies established it as a global long-term event spanning five successive ammonoid zones. Here

József Pálfy; Paul L. Smith



RESEARCH ARTICLE Cellular SNF2H Chromatin-Remodeling Factor Promotes Herpes Simplex Virus 1 Immediate-Early Gene Expression and Replication  

E-print Network

ABSTRACT Like other DNA viruses that replicate in the nucleus, herpes simplex virus 1 (HSV-1) regulates the association of histones with its genome to promote viral replication and gene expression. We previously demonstrated that SNF2H, a member of the ISWI family of chromatin-remodeling factors, is concentrated in HSV-1 replication compartments in the nuclei of infected cells, suggesting that this cellular enzyme plays a role in viral replication. We show here that small interfering RNA (siRNA)mediated knockdown of SNF2H in HEp-2 cells resulted in an approximately 20-fold decrease in HSV-1 replication, arguing that SNF2H promotes efficient HSV-1 replication. Decreases in HSV-1 replication were observed with multiple SNF2H-specific siRNAs, and the extent of the replication decrease correlated with the amount of SNF2H knockdown, indicating that the phenotype resulted from decreased SNF2H levels rather than off-target effects of the siRNAs. We also observed a decrease in the accumulation of immediate-early (IE) gene products in HSV-1-infected cells in which SNF2H was knocked down. Histone H3 occupancy on viral promoters was increased in HSV-1-infected cells that were transfected with SNF2H-specific siRNAs, suggesting that SNF2H promotes removal of histones from viral promoters during infection. Furthermore, chromatin immunoprecipitation (ChIP) studies showed that SNF2H associated with the HSV-1 genome during infection, which suggests that SNF2H may directly remodel viral chromatin. We hypothesize that SNF2H is recruited to viral promoters during HSV-1 infection, where it can remodel the chromatin state of the viral genome, facilitate the transcription of immediate-early genes, and enhance viral replication.

unknown authors


A lysozyme-like protein in Brucella abortus is involved in the early stages of intracellular replication.  


Secretion of proteins in Gram-negative bacteria is a high-energy-consuming process that requires translocation across two membranes and a periplasmic space composed of a mesh-like layer, the peptidoglycan. To achieve this, bacteria have evolved complex secretion systems that cross these barriers, and in many cases there are specific peptidoglycanases that degrade the peptidoglycan to allow the proper assembly of the secretion machinery. We describe here the identification and characterization of a muramidase in Brucella abortus that participates in the intracellular multiplication in professional and nonprofessional phagocytes. We demonstrated that this protein has peptidoglycanase activity, that a strain with a clean deletion of the gene displayed a defect in the early stages of the intracellular multiplication curve, and that this is dependent on the lytic activity. While neither the attachment nor the invasion of the strain was affected, we demonstrated that it had a defect in excluding the lysosomal marker LAMP-1 but not in acquiring the reticulum endoplasmic marker calnexin, indicating that the gene participates in the early stages of the intracellular trafficking but not in the establishment of the replicative niche. Analysis of the assembly status and functionality of the VirB secretion apparatus indicated that the mutant has affected the proper function of this central virulence factor. PMID:23319555

Del Giudice, Mariela G; Ugalde, Juan E; Czibener, Cecilia



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.



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

SciTech Connect

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

Federico, Maurizio, E-mail:



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


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



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

PubMed Central

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



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

PubMed Central

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

Bonhomme, Ludovic; Valot, Benoit; Tardieu, Francois; Zivy, Michel



Early events in immune evasion by the lentivirus maedi-visna occurring within infected lymphoid tissue.  

PubMed Central

Infections caused by lentiviruses, including human immunodeficiency virus, are characterized by slowly progressive disease in the presence of a virus-specific immune response. The earliest events in the virus-host interaction are likely to be important in determining disease establishment and progression, and the kinetics of these early events following lentiviral infection are described here. Lymphatic cannulation in the sheep has been used to monitor both the virus and the immune response in efferent lymph after infection of the node with maedi-visna virus (MVV). Viral replication and dissemination could be detected and consisted of a wave of MVV-infected cells leaving the node around 9 to 18 days postinfection. No cell-free virus was recovered despite the fact that soluble MVV p25 was detected in lymph plasma. The maximum frequency of MVV-infected cells was only 11 in 10(6) but over the first 20 days of infection amounted to greater than 10(4) virus-infected cells leaving the node. There was a profound increase in the output of activated lymphoblast from the lymph nodes of infected sheep, characterized by an increased percentage of CD8+ lymphoblasts. All of the CD8+ lymphoblasts at the peak of the response expressed both major histocompatibility complex class II DR and DQ molecules but not interleukin-2 receptor (CD25). The in vitro proliferative response of efferent lymph cells existing the node after challenge with MVV to both recombinant human interleukin-2 and the mitogen concanavalin A was decreased between days 8 and 16 postinfection, and a specific proliferative response to MVV was not detected until after day 15. Despite the high level of CD8+ lymphoblasts in efferent lymph, direct MVV-specific cytotoxic activity was demonstrated in only one of the five MVV-challenged sheep. MVV-specific antibody responses, including neutralization and MVV p25 immune complexes in efferent lymph, were detectable during the major period of virus dissemination. The relationship of these findings to the evasion of the host's acute immune response by MVV is discussed. Images PMID:8394444

Bird, P; Blacklaws, B; Reyburn, H T; Allen, D; Hopkins, J; Sargan, D; McConnell, I



Perivascular innate immune events modulate early murine vein graft adaptations  

PubMed Central

Objective Innate immunity drives numerous cardiovascular pathologies. Vein bypass grafting procedures are frequently accompanied by low-grade wound contamination. We hypothesized that a peri-graft innate immune challenge, via an outside-in route, augments inflammatory responses, which subsequently drive a component of negative vein graft wall adaptations; moreover, adipose tissue mediates this immune response. Methods The inferior vena cava from a donor mouse was implanted into the common carotid artery of a recipient mouse utilizing a validated cuff technique (9-week-old male C57BL/6J mice). Slow-release low-dose (5 ?g) lipopolysaccharide (LPS) (n = 9) or vehicle (n = 9) was applied peri-graft; morphologic analysis was completed (day 28). In parallel, vein-grafted mice received peri-graft LPS (n = 12), distant subcutaneous LPS (n = 6), or vehicle (n = 12), then day-1 and -3 harvest of grafts and adipose tissue for cytokines and toll-like receptor (TLR) signaling mRNA expression (qRT-PCR). Results All recipient mice survived, and all vein grafts were patent. Acute low-dose local LPS challenge enhanced vein graft lumen loss (P = .04) and tended to augment intimal hyperplasia (P = .06). The surgical trauma of vein grafting universally upregulated key pro- and anti-inflammatory mediators within the day-1 graft wall, but varied on TLR signaling gene expression. Local and distant LPS accentuated these patterns until at least postoperative day 3. LPS challenge enhanced the inflammatory response in adipose tissue (locally > distantly); local LPS upregulated adipose TLR-4 dramatically. Conclusions Perivascular and distant inflammatory challenges potentiate the magnitude and duration of inflammatory responses in the early vein graft wall, negatively modulating wall adaptations, and thus, potentially contribute to vein graft failure. Furthermore, surgery activates innate immunity in adipose tissue, which is augmented (regionally > systemically) by LPS. Modulation of these local and distant inflammatory signaling networks stands as a potential strategy to enhance the durability of vascular interventions such as vein grafts. (J Vasc Surg 2013;57:486-92.) Clinical Relevance Vein graft failure is traditionally considered as a process driven by luminal hemodynamic forces and endothelial injury. We report that the “outside-in” mechanism of local perivascular and distant inflammatory challenges potentiate the magnitude and duration of inflammatory responses in the early vein graft wall, negatively modulating wall adaptations, and thus potentially contribute to vein graft failure. Modulation of these inflammatory signaling networks (eg, extension of antibiotic administration beyond standard wound prophylaxis regimens) stands as a potential strategy to enhance the durability of vascular interventions such as vein grafts. PMID:23127978

Nguyen, Binh T.; Yu, Peng; Tao, Ming; Hao, Shuai; Jiang, Tianyu; Ozaki, C. Keith



A New Observation Technique Applied to Early/Fast VLF Scattering Events  

NASA Astrophysics Data System (ADS)

Early/fast very low frequency (VLF, 3-30 kHz) events are understood to result from ionospheric conductivity changes associated with lightning. Early/fast amplitude and phase perturbations have been observed coincidentally with various optical observations of transient luminous events (TLEs), including elves, sprites, and sprite halos, each of which can have temporal characteristics consistent with those of early/fast VLF events. It is yet unresolved, however, whether a specific type of TLE is directly related to the ionospheric conductivity changes responsible for the typical early/fast event. In this paper, we present spread spectrum VLF scattering observations of early/fast events. The spread spectrum analysis technique determines the amplitude and phase of a subionospherically propagating VLF signal as a function of time during the early/fast event and as a function of frequency across the 200 Hz bandwidth of the VLF transmission. VLF scattering observations, each identified with causative lightning logged by the National Lightning Detection Network (NLDN), are compared with the predictions of the Long-Wave Propagation Capability (LWPC) code, a three-dimensional earth-ionosphere waveguide propagation and scattering model. Theoretical predictions for VLF scattering from ionization changes associated with elves are compared with those associated with sprite halos, and each are compared with experimental observations. Results indicate that the observed frequency dependence of VLF scattering during early/fast events results from the combination of scattering source properties and Earth-ionosphere waveguide propagation effects. Observations are more consistent with the modeled amplitude perturbations associated with sprite halos than those with elves.

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



Live cell imaging of early autophagy events: omegasomes and beyond.  


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

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



The effects of early sensory deprivation on adult rat behavior under competition stress: An attempt at replication of a study by Alexander Wolf  

Microsoft Academic Search

An attempt was made to replicate an earlier experiment by Alexander Wolf which had indicated that animals temporarily deprived of the use of a particular sensory function in early infancy performed less well as adults in a competitive situation where use of that function was required. Although many modifications of technique were required, the present experiment confirmed the main empirical

Eugene F. Gauron; Wesley C. Becker



Development of fluorescent reporter tagged RIB gene cassettes for replicative transformation, early expression, and enhanced riboflavin production in Eremothecium ashbyi.  


Eremothecium ashbyi is a riboflavin overproducing filamentous fungus in which the metabolic pathways have not been genetically characterized. Two genes of the riboflavin biosynthetic (RIB) pathway, RIB1 and RIB3, which encode GTP-cyclohydrolase II (GCH II) and 3,4-dihydroxy-2-butanone 4-phosphate (DHBP) synthase respectively, were selected for the present study. The two RIB genes under their native promoters were obtained from Ashbya gossypii genomic library. Yeast enhanced green fluorescent protein (yEGFP) and mCherry genes were tagged to the C-terminal ends of RIB1 and RIB3 genes to analyse the functionality of the RIB transgenes in E. ashbyi. Shuttle vectors with the reporter tagged RIB genes contained the Escherichia coli kan(R) gene and Saccharomyces cerevisiae ARS element. On transformation with these plasmids, the ARS element was found to be functional in E. ashbyi. The E. ashbyi transcription factors could recognize the Ashbya RIB gene promoters and express the reporter tagged RIB genes as cytoplasmic proteins, in early cell development. Replicative transformants carrying RIB1-mCherry plasmids showed 2.95 times more GCH II activity and 2.44 times more riboflavin production when compared to untransformed. This is the first report of genetic transformation of E. ashbyi and is of significance as the first step towards genetic engineering of this genus. PMID:23063183

Sengupta, Sudeshna; Kaufmann, Andreas; Chandra, T S



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.



Knowledge | Replication Knowledg owledge | Replication Knowledge | R  

E-print Network

Knowledge | Replication Knowledg owledge | Replication Knowledge | R wledge | ReplicationKnowledge | Re dge | ReplicationKnowledge | Repl e | ReplicationKnowledge | Replica | ReplicationKnowledge | Replicatio Replication Knowledge | Replication ication Knowledge | Replication ationKnowledge | Replication

Shull, Kenneth R.


Stepwise atmospheric carbon-isotope excursion during the Toarcian Oceanic Anoxic Event (Early Jurassic, Polish Basin)  

Microsoft Academic Search

During the Mesozoic (250–64Ma) intervals of about 0.5Myr were subject to severe environmental changes, including high sea-surface temperature and very low oxygen content of marine water. These Oceanic Anoxic Events, or OAEs, occurred simultaneously with profound disturbance to the carbon cycle. The carbon-isotope anomaly in the Early Jurassic that marks the Toarcian Oceanic Anoxic Event (T-OAE) at ~182Ma is characterized

Stephen P. Hesselbo; Grzegorz Pienkowski



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))



Early and Intermediate-Stage Variants of Simian Immunodeficiency Virus Replicate Efficiently in Cells Lacking CCR5  

Microsoft Academic Search

Primate lentiviruses are thought to use the chemokine receptor CCR5 as the major coreceptor for entry into cells. Here we show that some variants of simian immunodeficiency virus (SIV) replicate efficiently in periph- eral blood mononuclear cells (PBMCs) lacking a functional CCR5. There were differences in the replication patterns of sequential variants that evolved during SIVMne infection; the late-stage pathogenic

Serene Forte; Mary-Elizabeth Harmon; Mario J. Pineda; Julie Overbaugh



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

E-print Network

are found at Kostenki on the west bank of the Don River in Russia. During the 1950s, A.N. Rogachev excavatedEvidence for kill-butchery events of early Upper Paleolithic age at Kostenki, Russia John F, Universitetskaya nab., 1, 199034 St. Petersburg, Russia c Institute of the History of Material Culture, Russian

Holliday, Vance T.


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


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

Microsoft Academic Search

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

R. M. Allen; H. Kanamori



Genetic and Epigenetic Changes in Mammary Epithelial Cells May Mimic Early Events in Carcinogenesis  

Microsoft Academic Search

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 p16INK4a promoter sequences, create a previously unappreciated preclonal phase of tumorigenesis in which a subpopulation of mammary epithelial cells are positioned for progression to malignancy

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



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

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


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

PubMed Central

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

Hyrien, O; Mechali, M



Persistence of carbon release events through the peak of early Eocene global warmth  

NASA Astrophysics Data System (ADS)

The Early Eocene Climatic Optimum (53-50 million years ago) was preceded by approximately six million years of progressive global warming. This warming was punctuated by a series of rapid hyperthermal warming events triggered by the release of greenhouse gases. Over these six million years, the carbon isotope record suggests that the events became more frequent but smaller in magnitude. This pattern has been suggested to reflect a thermodynamic threshold for carbon release that was more easily crossed as global temperature rose, combined with a decrease in the size of carbon reservoirs during extremely warm conditions. Here we present a continuous, 4.25-million-year-long record of the stable isotope composition of carbonate sediments from the equatorial Atlantic, spanning the peak of early Eocene global warmth. A composite of this and pre-existing records shows that the carbon isotope excursions that identify the hyperthermals exhibit continuity in magnitude and frequency throughout the approximately 10-million-year period covering the onset, peak and termination of the Early Eocene Climate Optimum. We suggest that the carbon cycle processes behind these events, excluding the largest event, the Palaeocene-Eocene Thermal Maximum (about 56 million years ago), were not exceptional. Instead, we argue that the hyperthermals may reflect orbital forcing of the carbon cycle analogous to the mechanisms proposed to operate in the cooler Oligocene and Miocene.

Kirtland Turner, Sandra; Sexton, Philip F.; Charles, Christopher D.; Norris, Richard D.



[The analysis of early stressful life events and parental relationships among patients after suicide attempts].  


A lot of data in literature shows the importance of early stressful life events for the later existence and possible difficulties including suicide behaviours in adult life. The aim of the study was to identify the intensity of traumatic events in childhood and adolescence and distinguish the most significant categories of those events. Remarkable is the fact that the patients who experienced in the childhood situations of emotional abuse focused on the negative attitude of the environment (79%) and physical violence (78%) represented the largest proportion of subjects. Specific difficulties during childhood and adolescence among patients after suicide attempts were proven. Patients after suicide attempts in a large extent early experienced situations connected with emotional distance, negative feedback from the environment, manifestations of rejection and humiliation and misunderstanding. Males more than females declared experiencing situations classified as physical violence, low economic status of the family, interpersonal loss and general trauma. Comparatively often both groups pointed at perilous parents' acts. Females more often pointed at events concerning sexual domain. Very strong emotions assisted stressful life events, particularly significant among females and characterized by anxiety and helplessness. Patients after suicide attempts most often described their fathers as over controlling, demanding and intrusive with the deficiency of care and protectiveness. This pattern was equally distinct in the group of females and males. PMID:24466693

Musikowska, Barbara; Ma?gorzata, Kubiak; Sein Anand, Jacek



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.




SciTech Connect

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. [Jeremiah Horrocks Institute, University of Central Lancashire, PR1 2HE Preston (United Kingdom)



DNA Replication Timing, Genome Stability and Cancer  

PubMed Central

Normal cellular division requires that the genome be faithfully replicated to ensure that unaltered genomic information is passed from one generation to the next. DNA replication initiates from thousands of origins scattered throughout the genome every cell cycle; however, not all origins initiate replication at the same time. A vast amount of work over the years indicates that different origins along each eukaryotic chromosome are activated in early, middle or late S phase. This temporal control of DNA replication is referred to as the replication-timing program. The replication-timing program represents a very stable epigenetic feature of chromosomes. Recent evidence has indicated that the replication-timing program can influence the spatial distribution of mutagenic events such that certain regions of the genome experience increased spontaneous mutagenesis compared to surrounding regions. This influence has helped shape the genomes of humans and other multicellular organisms and can affect the distribution of mutations in somatic cells. It is also becoming clear that the replication-timing program is deregulated in many disease states, including cancer. Aberrant DNA replication timing is associated with changes in gene expression, changes in epigenetic modifications and an increased frequency of structural rearrangements. Furthermore, certain replication timing changes can directly lead to overt genomic instability and may explain unique mutational signatures that are present in cells that have undergone the recently described processes of “chromothripsis” and “kataegis”. In this review, we will discuss how the normal replication timing program, as well as how alterations to this program, can contribute to the evolution of the genomic landscape in normal and cancerous cells. PMID:23327985

Donley, Nathan



Tyrosine phosphorylation is an early and specific event involved in primary keratinocyte differentiation.  

PubMed Central

Very little is known about early molecular events triggering epithelial cell differentiation. We have examined the possible role of tyrosine phosphorylation in this process, as observed in cultures of primary mouse keratinocytes after exposure to calcium or 12-O-tetradecanoylphorbol-13-acetate (TPA). Immunoblotting with phosphotyrosine-specific antibodies as well as direct phosphoamino acid analysis revealed that induction of tyrosine phosphorylation occurs as a very early and specific event in keratinocyte differentiation. Very little or no induction of tyrosine phosphorylation was observed in a keratinocyte cell line resistant to the differentiating effects of calcium. Treatment of cells with tyrosine kinase inhibitors prevented induction of tyrosine phosphorylation by calcium and TPA and interfered with the differentiative effects of these agents. These results suggest that specific activation of tyrosine kinase(s) may play an important regulatory role in keratinocyte differentiation. Images PMID:1689456

Filvaroff, E; Stern, D F; Dotto, G P



Decreased delta event-related synchronization in patients with early vascular dementia.  


Electroencephalogram (EEG) activity, recorded while performing an "odd ball" detection task, was compared between patients with early vascular dementia (VD), healthy young controls and healthy elderly controls performing the same task. The data were analyzed using the event-related synchronization/desynchronization (ERS/ERD) method. VD patients, compared with controls, showed decreased ERS effects in the delta frequency band (0.5-3.5Hz) of EEG after the target stimulus appeared in frontal, central and parietal regions. Similarly, elderly controls also showed a decreased ERS compared with young controls only in central and parietal regions. As part of this analysis, we introduce a novel quantitative index, the Event-related Energy Change Progression (EECP), which provides a reliable measure that distinguishes these groups and thereby provides a promising marker for early diagnosis of VD. PMID:21309443

Xu, Jin; Zhao, Songzhen; Zhang, Haoshi; Zheng, Chongxun



Characterization of competent cells and early events of Agrobacterium -mediated genetic transformation in Arabidopsis thaliana  

Microsoft Academic Search

The insertion of foreign DNA in plants occurs through a complex interaction between Agrobacteria and host plant cells. The marker gene ß-glucuronidase of Escherichia coli and cytological methods were used to characterize competent cells for Agrobacterium-mediated transformation, to study early cellular events of transformation, and to identify the potential host-cell barriers that limit transformation in Arabidopsis thaliana L. Heynh. In

Rajbir S. Sangwan; Yvan Bourgeois; Spencer Brown; Gérard Vasseur; Brigitte Sangwan-Norreel



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

ERIC Educational Resources Information Center

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

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



Early Phase Coverage of X-ray Flares Associated with Tidal Disruption Events  

NASA Astrophysics Data System (ADS)

X-ray spectral lines are expected at the beginning of the X-ray flares associated with tidal disruption events (TDE), providing great opportunity to probe the spin of dormant supermassive black holes (SMBHs) as well as detect Bardeen-Petterson (BP) effect. Little is known about the early phase of TDEs observationally. Coverage of the early phase will shed light on accretion physics under extreme conditions inaccessible in other systems. We propose an intensive coverage of the early phase of bright TDE X-ray flares with joint XMM and Swift observations. The observations would lead to the first detection of BP disks expected around spinning SMBHs and the first application of reverberation mapping of the innermost accretion flow around a previously quiescent SMBH.

Yu, Wenfei



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. PMID:10233967

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



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

SciTech Connect

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

Doniger, J.; DiPaolo, J.A.



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



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

PubMed Central

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

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



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

PubMed Central

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

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



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

USGS Publications Warehouse

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

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



Exposure to potentially traumatic events in early childhood: differential links to emergent psychopathology  

PubMed Central

Objective To examine associations between exposure to potentially traumatic events (PTEs) and clinical patterns of symptoms and disorders in preschool children. Method Two hundred and thirteen referred and non-referred children, ages 24 to 48 months (MN = 34.9, SD = 6.7 months) were studied. Lifetime exposure to PTEs (family violence and non-interpersonal events) and recent stressful life events were assessed with the Preschool Age Psychiatric Assessment (PAPA) and Child Life Events Scale. Child psychiatric symptoms and disorders were assessed with parent-reports in the PAPA, a comprehensive, developmentally sensitive interview. Sociodemographic risk, parental anxiety and depressive symptoms (Center for Epidemiologic Studies Depression, Beck Anxiety Inventory), and child developmental level (Mullen Scales of Early Learning) also were assessed. Results Violence exposure was broadly associated with psychiatric status in the areas of depression, separation anxiety, posttraumatic stress, and conduct problems, whereas potentially traumatic non-interpersonal exposure was associated with phobic anxiety. The majority of the associations between violence exposure and preschoolers’ symptoms were significant even when other key factors, including economic disadvantage and parental mood and anxiety symptoms, were controlled statistically. However, parental depressive/anxious symptoms may have partially or fully mediated the relationships between violence exposure and depressive and conduct symptoms. Conclusions Evidence of robust associations between violence exposure and early childhood internalizing and externalizing disorders and symptoms highlights the need for longitudinal prospective research concerning neurodevelopmental mechanisms and pathways. Findings underscore the relevance of assessing trauma exposure, particularly interpersonal violence, to identify young children at risk. PMID:20840502

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



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


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

Mercorelli, Beatrice; Luganini, Anna; Muratore, Giulia; Massari, Serena; Terlizzi, Maria Elena; Tabarrini, Oriana; Gribaudo, Giorgio; Palù, Giorgio; Loregian, Arianna



Early arrival of Southern Source Water in the deep North Atlantic prior to Heinrich event 2  

NASA Astrophysics Data System (ADS)

The Atlantic Meridional Overturning Circulation (AMOC) plays an important role in the Northern Hemisphere climate system. Significant interest went into the question of how excessive freshwater input through melting of continental ice can affect its overturning vigor and, hence, heat supply, to higher northern latitudes. Such forcing can be tested by investigating its behavior during extreme iceberg discharge events into the open North Atlantic during the last glacial period, the so-called Heinrich events (HE). Here we present neodymium (Nd) isotope compositions of past seawater, a sensitive chemical water mass tag, extracted from sediments of Ocean Drilling Program Site 1063 in the western North Atlantic (Bermuda Rise), covering the period surrounding HE 2, the Last Glacial Maximum, and the early deglaciation. These data are compared with a record of the kinematic circulation tracer (231Pa/230Th)xs extracted from the same sediment core. Both tracers indicate significant circulation changes preceding intense ice rafting during HE 2 by almost 2 kyr. Moreover, the Nd isotope record suggests the presence of deeply ventilating North Atlantic Deep Water early during Marine Isotope Stage 2 until it was replaced by Southern Source Water at ˜27 ka. The early switch to high (Pa/Th)xs and radiogenic ?Nd in relation to intensified ice rafting during HE 2 suggests that ice rafting into the open North Atlantic during major HE 2 was preceded by an early change of the AMOC. This opens the possibility that variations in AMOC contributed to or even triggered the ice sheet instability rather than merely responding to it.

Gutjahr, Marcus; Lippold, JöRg



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



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



Physical and sexual abuse in childhood as predictors of early onset cardiovascular events in women  

PubMed Central

Background Although child abuse is widespread and has been associated with cardiovascular disease (CVD) risk factors, its association with CVD events is not established. Methods and Results We examined associations of child abuse with CVD events among 66,798 women in the Nurses’ Health Study 2. Proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for myocardial infarction (n=262), stroke (n=251), and total CVD (n=513). Severe physical abuse was reported by 9% and forced sex by 11% of participants. Adjusting for age, race, childhood body type, parental education and family CVD history, the HR for CVD events was 0.91 (95% CI: 0.70–1.17) for mild physical abuse, 1.02 (0.82–1.26) for moderate physical abuse, and 1.46 (1.11–1.92) for severe physical abuse compared to none. Compared to women without childhood sexual abuse, the HR was 1.10 (0.88–1.35) for unwanted sexual touching, and 1.56 (1.23–1.99) for forced sex. After adjustment for adult lifestyle and medical risk factors, the HR for severe physical abuse was 1.13 (0.85–1.51) and that for forced sex was 1.25 (0.98–1.60); these intermediates accounted for much of the association of severe child abuse with CVD. Associations were similar for retrospectively and prospectively reported events. Women with abuse were less likely to release medical records. The associations were stronger for unconfirmed self-reported events than endpoints which were corroborated with additional information or medical record review. Conclusions Severe child abuse is a prevalent risk for early adult CVD that is partially mediated by preventable risk factors. PMID:22787111

Rich-Edwards, J.W.; Mason, S.; Rexrode, K.; Spiegelman, D.; Hibert, E.; Kawachi, I.; Jun, H.J.; Wright, R.J.



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


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

Bendixen, Mons



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

NASA Astrophysics Data System (ADS)

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

Mattioli, Emanuela; Plancq, Julien; Raucsik, Béla



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



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

PubMed Central

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

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



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

Microsoft Academic Search

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

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


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



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

NASA Astrophysics Data System (ADS)

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

Joachim, C.; Mutterlose, J.



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.



Role of Human Immunodeficiency Virus Type 1 Matrix Phosphorylation in an Early Postentry Step of Virus Replication  

Microsoft Academic Search

The matrix domain (MA) is important for targeting of human immunodeficiency virus type 1 Gag assembly to the plasma membrane, envelope incorporation into virions, preintegration complex import into the nucleus, and nuclear export of viral RNA. Myristylation and phosphorylation are key regulatory events for MA function. Previous studies have indicated that MA phosphorylation at serine (Ser) residues is important for

Rajnish Kaushik; Lee Ratner



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. PMID:24300239

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



Age-related differences in event-related potentials for early visual processing of emotional faces.  


With advancing age, processing resources are shifted away from negative emotional stimuli and toward positive ones. Here, we explored this 'positivity effect' using event-related potentials (ERPs). Participants identified the presence or absence of a visual probe that appeared over photographs of emotional faces. The ERPs elicited by the onsets of angry, sad, happy and neutral faces were recorded. We examined the frontocentral emotional positivity (FcEP), which is defined as a positive deflection in the waveforms elicited by emotional expressions relative to neutral faces early on in the time course of the ERP. The FcEP is thought to reflect enhanced early processing of emotional expressions. The results show that within the first 130 ms young adults show an FcEP to negative emotional expressions, whereas older adults show an FcEP to positive emotional expressions. These findings provide additional evidence that the age-related positivity effect in emotion processing can be traced to automatic processes that are evident very early in the processing of emotional facial expressions. PMID:23677489

Hilimire, Matthew R; Mienaltowski, Andrew; Blanchard-Fields, Fredda; Corballis, Paul M



Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging  

PubMed Central

Protein damage contributes prominently to cellular aging. To address whether this occurs at a specific period during aging or accumulates gradually, we monitored the biochemical, cellular, and physiological properties of folding sensors expressed in different tissues of C. elegans. We observed the age-dependent misfolding and loss of function of diverse proteins harboring temperature-sensitive missense mutations in all somatic tissues at the permissive condition. This widespread failure in proteostasis occurs rapidly at an early stage of adulthood, and coincides with a severely reduced activation of the cytoprotective heat shock response and the unfolded protein response. Enhancing stress responsive factors HSF-1 or DAF-16 suppresses misfolding of these metastable folding sensors and restores the ability of the cell to maintain a functional proteome. This suggests that a compromise in the regulation of proteostatic stress responses occurs early in adulthood and tips the balance between the load of damaged proteins and the proteostasis machinery. We propose that the collapse of proteostasis represents an early molecular event of aging that amplifies protein damage in age-associated diseases of protein conformation. PMID:19706382

Ben-Zvi, Anat; Miller, Elizabeth A.; Morimoto, Richard I.



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. PMID:23759402

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



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

PubMed Central

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

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



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


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

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



Early cell adhesion events differ between osteoporotic and non-osteoporotic osteoblasts.  


In osteoporosis, the regenerative capacity of bone is compromised, which may involve altered osteoblast (OB) activity. This could be attributed to an inappropriate synthesis and assembly of an extracellular matrix (ECM), altered cell adhesion to the ECM, or be due to inappropriate downstream activation of adhesion-mediated signaling cascades through proteins such as focal adhesion kinase (FAK). The purpose of our study was to compare early adhesion-mediated events using previously described and characterized clinically derived OBs obtained from human patients undergoing major joint arthroplasty for osteoporosis or osteoarthritis. The presence or absence of osteoporosis was established with a radiographic index. Using light microscopy and crystal violet staining, we show that OB cells derived from sites of osteoporosis do not attach and spread as well as non-osteoporotic (OP) OB cells. OP cells initially have a more rounded morphology, and show significantly less (P < 0.001) attachment to serum-coated tissue culture plastic over a 24 h time period. Immunofluorescent labeling after 24 h of attachment showed that OP OB focal adhesions (FAs) and stress fibers were less defined, and that the OP cells were smaller and had a more motile phenotype. When normalized protein lysates were Western blotted for phosphotyrosine (PY) a band corresponding to pp125FAK was identified. FAK tyrosine phosphorylation was evident at 6 h in both the OP and non-OP OBs, but decreased or was absent through 24 h in OP OBs. These results suggest early adhesion-mediated events, such as cell adhesion, attachment, and FAK signaling via PY may be altered in OP OBs. PMID:11781027

Perinpanayagam, H; Zaharias, R; Stanford, C; Brand, R; Keller, J; Schneider, G



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.



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


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



Characterisation of the early events in atypical tomato root colonisation by a biocontrol agent, Pythium oligandrum.  


The specific oomycete-plant relationship established between a biological agent, Pythium oligandrum, and tomato (Lycopersicon esculentum Mill.) plants was examined over the first 48 h after inoculation of tomato roots with the antagonist. One of the most significant effects was the quick colonisation of cortical and vascular root areas by P. oligandrum (until 9 h post-inoculation); it was similar to invasions by the major pathogens of Pythium genus, and much faster than those by Pythium-minor pathogens. Despite the multiplication of hyphae in the root areas, fungal colonisation was associated with neither host wall disruption nor host cell alterations. The colonising hyphae looked healthy till the ninth hour after inoculation, then, they progressively became highly vacuolated. Cytological observations showed that, over the first 14 h of experiment, oomycete invasion was accompanied with rare host-induced defence reactions. Biochemical analysis evidenced an accumulation of phenolic compounds starting 3 h after inoculation. The 14th hour corresponded to the beginning of rishitin (phytoalexin) synthesis. Accumulation of biochemical host defence compounds was concomitant with early signs of hyphae alterations. During the next 34 h several host reactions were regularly amplified as evidenced by the plugging of invaded host cells with heterogeneous osmiophilic or high electron-dense (ED) materials. Fungal cell decay was accompanied with the formation of oogonia in the cortex, vascular parenchyma and xylem vessels. All these early events suggest a peculiar relationship established between P. oligandrum and the plant. PMID:15763660

Le Floch, Gaétan; Benhamou, Nicole; Mamaca, Emina; Salerno, Maria-Isabel; Tirilly, Yves; Rey, Patrice



Brain event-related potentials: diagnosing early-stage Alzheimer's disease.  


A pattern of components from brain event-related potentials (ERPs) (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. PMID:16430992

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



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. PMID:16430992

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



Relationship between early and late stages of information processing: an event-related potential study  

PubMed Central

The brain is capable of elaborating and executing different stages of information processing. However, exactly how these stages are processed in the brain remains largely unknown. This study aimed to analyze the possible correlation between early and late stages of information processing by assessing the latency to, and amplitude of, early and late event-related potential (ERP) components, including P200, N200, premotor potential (PMP) and P300, in healthy participants in the context of a visual oddball paradigm. We found a moderate positive correlation among the latency of P200 (electrode O2), N200 (electrode O2), PMP (electrode C3), P300 (electrode PZ) and the reaction time (RT). In addition, moderate negative correlation between the amplitude of P200 and the latencies of N200 (electrode O2), PMP (electrode C3), P300 (electrode PZ) was found. Therefore, we propose that if the secondary processing of visual input (P200 latency) occurs faster, the following will also happen sooner: discrimination and classification process of this input (N200 latency), motor response processing (PMP latency), reorganization of attention and working memory update (P300 latency), and RT. N200, PMP, and P300 latencies are also anticipated when higher activation level of occipital areas involved in the secondary processing of visual input rise (P200 amplitude). PMID:23355929

Portella, Claudio; Machado, Sergio; Arias-Carrion, Oscar; Sack, Alexander T.; Silva, Julio Guilherme; Orsini, Marco; Leite, Marco Antonio Araujo; Silva, Adriana Cardoso; Nardi, Antonio E.; Cagy, Mauricio; Piedade, Roberto; Ribeiro, Pedro



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)



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


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

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



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

PubMed Central

In late-onset Alzheimer's disease (AD), multiple brain regions are not affected simultaneously. Comparing the gene expression of the affected regions to identify the differences in the biological processes perturbed can lead to greater insight into AD pathogenesis and early characteristics. We identified differentially expressed (DE) genes from single cell microarray data of four AD affected brain regions: entorhinal cortex (EC), hippocampus (HIP), posterior cingulate cortex (PCC), and middle temporal gyrus (MTG). We organized the DE genes in the four brain regions into region-specific gene coexpression networks. Differential neighborhood analyses in the coexpression networks were performed to identify genes with low topological overlap (TO) of their direct neighbors. The low TO genes were used to characterize the biological differences between two regions. Our analyses show that increased oxidative stress, along with alterations in lipid metabolism in neurons, may be some of the very early events occurring in AD pathology. Cellular defense mechanisms try to intervene but fail, finally resulting in AD pathology as the disease progresses. Furthermore, disease annotation of the low TO genes in two independent protein interaction networks has resulted in association between cancer, diabetes, renal diseases, and cardiovascular diseases. PMID:25147748

Perry, George; Ray, Monika



Effects of the early social environment on behavioral responses of dairy calves to novel events.  


Providing young animals the opportunity to engage in more complex social interactions is hypothesized to improve their capacity to cope with changing environments. To test the effects of the early social environment on the behavioral responses of dairy calves to novelty we compared (1) individual with pair housing and (2) group housing with companions of similar age with group housing with a more experienced conspecific. Fifty-four dairy calves were separated from the cow soon after birth and housed individually (n=6 calves) or in pairs (n=6 pairs), or in pens composed of groups of 3 young calves (n=6 groups) or groups of 2 young calves and an older calf (n=6 groups). At 65 to 69 d of age, calf responses were tested in an environmental novelty test and a social novelty test. Individually housed calves were more active [i.e., spent less time standing (means ± SEM): 201.4 vs. 280.3±30.5 s/test; and more time running: 83.2 vs. 57.3±19.1 s/test] and more reactive (i.e., defecated more frequently; 1.3 vs. 0.6±0.2 events/test) when tested in the novel arena, compared with pair-housed calves. During the social novelty test, individually housed calves spent less time running (51.8 vs. 96.4±11.6 s/test), showed a longer latency to socially interact (111.1 vs. 20.4±21.7 s/test), and spent more time involved in social interactions (130.7 vs. 79.7±19.0 s/test) with the unfamiliar calf than did pair-housed calves. Individually housed calves were also more reactive to the presence of an unfamiliar calf as indicated by increased rates of defecation (2.3 vs. 0.7±0.5 events/test) and kicking (2.2 vs. 0.7±0.4 events/test) compared with pair-housed calves. Calves housed in groups with an older companion were more reactive to the novel environment than were calves housed in groups of similar age: they defecated (1.0 vs. 0.6±0.2 events/test) and vocalized (23.6 vs. 15.3±3.8 events/test) more during the test. These calves also spent less time exploring (266.3 vs. 355.0±27.4 events/test) and had a lower frequency of kicking (0.1 vs. 2.0±0.5 events/test) when tested with an unfamiliar calf. We conclude that calves housed individually are more reactive to environmental and social novelty when compared with calves housed in pairs and that calves housed with an older companion are less reactive to a novel calf when compared with calves housed in groups of similar age. PMID:22916920

De Paula Vieira, A; de Passillé, A M; Weary, D M



The genomic instability associated with integrated simian virus 40 DNA is dependent on the origin of replication and early control region.  


DNA rearrangements in the form of deletions and duplications are found within and near integrated simian virus 40 (SV40) DNA in nonpermissive cell lines. We have found that rearrangements also occur frequently with integrated pSV2neo plasmid DNA. pSV2neo contains the entire SV40 control region, including the origin of replication, both promoters, and the enhancer sequences. Linearized plasmid DNA was electroporated into X1, an SV40-transformed mouse cell line that expresses SV40 large T antigen (T Ag) and shows very frequent rearrangements at the SV40 locus, and into LMtk-, a spontaneously transformed mouse cell line that contains no SV40 DNA. Stability was analyzed by subcloning G-418-resistant clones and examining specific DNA fragments for alterations in size. Five independent X1 clones containing pSV2neo DNA were unstable at both the neo locus and the T Ag locus. By contrast, four X1 clones containing mutants of pSV2neo with small deletions in the SV40 core origin and three X1 clones containing a different neo plasmid lacking SV40 sequences were stable at the neo locus, although they were still unstable at the T Ag locus. Surprisingly, five independent LMtk- clones containing pSV2neo DNA were unstable at the neo locus. LMtk- clones containing origin deletion mutants were more stable but were not as stable as the X1 clones containing the same plasmid DNA. We conclude that the SV40 origin of replication and early control region are sufficient viral components for the genomic instability at sites of SV40 integration and that SV40 T Ag is not required. PMID:8289382

Hunter, D J; Gurney, E G



The genomic instability associated with integrated simian virus 40 DNA is dependent on the origin of replication and early control region.  

PubMed Central

DNA rearrangements in the form of deletions and duplications are found within and near integrated simian virus 40 (SV40) DNA in nonpermissive cell lines. We have found that rearrangements also occur frequently with integrated pSV2neo plasmid DNA. pSV2neo contains the entire SV40 control region, including the origin of replication, both promoters, and the enhancer sequences. Linearized plasmid DNA was electroporated into X1, an SV40-transformed mouse cell line that expresses SV40 large T antigen (T Ag) and shows very frequent rearrangements at the SV40 locus, and into LMtk-, a spontaneously transformed mouse cell line that contains no SV40 DNA. Stability was analyzed by subcloning G-418-resistant clones and examining specific DNA fragments for alterations in size. Five independent X1 clones containing pSV2neo DNA were unstable at both the neo locus and the T Ag locus. By contrast, four X1 clones containing mutants of pSV2neo with small deletions in the SV40 core origin and three X1 clones containing a different neo plasmid lacking SV40 sequences were stable at the neo locus, although they were still unstable at the T Ag locus. Surprisingly, five independent LMtk- clones containing pSV2neo DNA were unstable at the neo locus. LMtk- clones containing origin deletion mutants were more stable but were not as stable as the X1 clones containing the same plasmid DNA. We conclude that the SV40 origin of replication and early control region are sufficient viral components for the genomic instability at sites of SV40 integration and that SV40 T Ag is not required. Images PMID:8289382

Hunter, D J; Gurney, E G



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

PubMed Central

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



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

PubMed Central

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

Bijou, Sidney W.



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


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

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



A Candida albicans early stage biofilm detachment event in rich medium  

PubMed Central

Background Dispersal from Candida albicans biofilms that colonize catheters is implicated as a primary factor in the link between contaminated catheters and life threatening blood stream infections (BSI). Appropriate in vitro C. albicans biofilm models are needed to probe factors that induce detachment events. Results Using a flow through system to culture C. albicans biofilms we characterized a detachment process which culminates in dissociation of an entire early stage biofilm from a silicone elastomer surface. We analyzed the transcriptome response at time points that bracketed an abrupt transition in which a strong adhesive association with the surface is weakened in the initial stages of the process, and also compared batch and biofilm cultures at relevant time points. K means analysis of the time course array data revealed categories of genes with similar patterns of expression that were associated with adhesion, biofilm formation and glycoprotein biosynthesis. Compared to batch cultures the biofilm showed a pattern of expression of metabolic genes that was similar to the C. albicans response to hypoxia. However, the loss of strong adhesion was not obviously influenced by either the availability of oxygen in the medium or at the silicone elastomer surface. The detachment phenotype of mutant strains in which selected genes were either deleted or overexpressed was characterized. The microarray data indicated that changes associated with the detachment process were complex and, consistent with this assessment, we were unable to demonstrate that transcriptional regulation of any single gene was essential for loss of the strong adhesive association. Conclusion The massive dispersal of the early stage biofilm from a biomaterial surface that we observed is not orchestrated at the level of transcriptional regulation in an obvious manner, or is only regulated at this level by a small subpopulation of cells that mediate adhesion to the surface. PMID:19187560



miR-196 is an essential early-stage regulator of tail regeneration, upstream of key spinal cord patterning events.  


Salamanders have the remarkable ability to regenerate many body parts following catastrophic injuries, including a fully functional spinal cord following a tail amputation. The molecular basis for how this process is so exquisitely well-regulated, assuring a faithful replication of missing structures every time, remains poorly understood. Therefore a study of microRNA expression and function during regeneration in the axolotl, Ambystoma mexicanum, was undertaken. Using microarray-based profiling, it was found that 78 highly conserved microRNAs display significant changes in expression levels during the early stages of tail regeneration, as compared to mature tissue. The role of miR-196, which was highly upregulated in the early tail blastema and spinal cord, was then further analyzed. Inhibition of miR-196 expression in this context resulted in a defect in regeneration, yielding abnormally shortened tails with spinal cord defects in formation of the terminal vesicle. A more detailed characterization of this phenotype revealed downstream components of the miR-196 pathway to include key effectors/regulators of tissue patterning within the spinal cord, including BMP4 and Pax7. As such, our dataset establishes miR-196 as an essential regulator of tail regeneration, acting upstream of key BMP4 and Pax7-based patterning events within the spinal cord. PMID:19682983

Sehm, Tina; Sachse, Christoph; Frenzel, Corina; Echeverri, Karen



Early Events Associated with Infection of Epstein-Barr Virus Infection of Primary B-Cells  

PubMed Central

Epstein Barr virus (EBV) is closely associated with the development of a vast number of human cancers. To develop a system for monitoring early cellular and viral events associated with EBV infection a self-recombining BAC containing 172-kb of the Epstein Barr virus genome BAC-EBV designated as MD1 BAC (Chen et al., 2005, J.Virology) was used to introduce an expression cassette of green fluorescent protein (GFP) by homologous recombination, and the resultant BAC clone, BAC-GFP-EBV was transfected into the HEK 293T epithelial cell line. The resulting recombinant GFP EBV was induced to produce progeny virus by chemical inducer from the stable HEK 293T BAC GFP EBV cell line and the virus was used to immortalize human primary B-cell as monitored by green fluorescence and outgrowth of the primary B cells. The infection, B-cell activation and cell proliferation due to GFP EBV was monitored by the expression of the B-cell surface antigens CD5, CD10, CD19, CD23, CD39, CD40 , CD44 and the intercellular proliferation marker Ki-67 using Flow cytometry. The results show a dramatic increase in Ki-67 which continues to increase by 6–7 days post-infection. Likewise, CD40 signals showed a gradual increase, whereas CD23 signals were increased by 6–12 hours, maximally by 3 days and then decreased. Monitoring the viral gene expression pattern showed an early burst of lytic gene expression. This up-regulation of lytic gene expression prior to latent genes during early infection strongly suggests that EBV infects primary B-cell with an initial burst of lytic gene expression and the resulting progeny virus is competent for infecting new primary B-cells. This process may be critical for establishment of latency prior to cellular transformation. The newly infected primary B-cells can be further analyzed for investigating B cell activation due to EBV infection. PMID:19784370

Halder, Sabyasachi; Murakami, Masanao; Verma, Subhash C.; Kumar, Pankaj; Yi, Fuming; Robertson, Erle S.



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

NASA Astrophysics Data System (ADS)

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

Posenato, Renato



Redox Signaling Is an Early Event in the Pathogenesis of Renovascular Hypertension  

PubMed Central

Activation of the renin-angiotensin-aldosterone system plays a critical role in the development of chronic renal damage in patients with renovascular hypertension. Although angiotensin II (Ang II) promotes oxidative stress, inflammation, and fibrosis, it is not known how these pathways intersect to produce chronic renal damage. We tested the hypothesis that renal parenchymal cells are subjected to oxidant stress early in the development of RVH and produce signals that promote influx of inflammatory cells, which may then propagate chronic renal injury. We established a reproducible murine model of RVH by placing a tetrafluoroethhylene cuff on the right renal artery. Three days after cuff placement, renal tissue demonstrates no histologic abnormalities despite up regulation of both pro- and anti-oxidant genes. Mild renal atrophy was observed after seven days and was associated with induction of Tnf? and influx of CD3+ T cells and F4/80+ macrophages. By 28 days, kidneys developed severe renal atrophy with interstitial inflammation and fibrosis, despite normalization of plasma renin activity. Based on these considerations, we propose that renal parenchymal cells initiate a progressive cascade of events leading to oxidative stress, interstitial inflammation, renal fibrosis, and atrophy. PMID:24025423

Hartono, Stella P.; Knudsen, Bruce E.; Zubair, Adeel S.; Nath, Karl A.; Textor, Stephen J.; Lerman, Lilach O.; Grande, Joseph P.



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


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

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



Modulation of early and late event-related potentials by emotion  

PubMed Central

Although emotionally salient stimuli influence higher order information processing, the relative vulnerability of specific stages of cognitive processing to modulation by emotional input remains elusive. To test the temporal dynamics of emotional interference during executive function, we recorded event-related potentials (ERPs) while participants performed an effortful anticipation task with aversive emotional and neutral distracters. Participants were presented with a modified delayed Stroop task that dissociated the anticipation of an easier or more difficult task (instructional cues to attend to word vs. color) from the response to the Stroop stimulus, while aversive and neutral pictures were displayed during the delay period. Our results indicated a relative decrease in the amplitude of the contingent negative variation (CNV) during aversive trials that was greater during the early anticipatory phase than during the later response preparation phase, and greater during (the more difficult) color than word trials. During the initial stage of cue processing, there was also significant interaction between emotion and anticipatory difficulty on N1 amplitude, where emotional stimuli led to significantly enhanced negativity during color cues relative to word cues. These results suggest that earlier processes of orientation and effortful anticipation may reflect executive engagement that is influenced by emotional interference while later phases of response preparation may be modulated by emotional interference regardless of anticipatory difficulty. PMID:23162444

Hart, Sarah J.; Lucena, Nathaniel; Cleary, Katherine M.; Belger, Aysenil; Donkers, Franc C. L.



Early events in neurotrophin signalling via Trk and p75 receptors.  


Biological responses to neurotrophins appear to be mediated by multiple signalling pathways. These emanate from, and are regulated by, the contributions of both Trk and p75 receptors. Early events in Trk signalling are becoming more clearly defined and point to cooperate interaction of both Ras-dependent and Ras-independent pathways. Work over the past year has clarified the steps by which Trk receptor occupation leads to Ras activation and has highlighted the required roles of Ras and extracellular signal regulated kinases in certain neurotrophin responses, including neurite outgrowth. Pharmacologic and mutagenesis studies have additionally supported the importance of the phosphatidylinositol-3' kinase and SNT protein pathways in neurotrophin signalling. Although many findings point to clear involvement for p75 in neurotrophin signalling, the molecular mechanisms by which these occur are just beginning to be identified. Recent studies indicate that p75 dramatically influences Trk activity and ligand interactions, and may mediate signals through the ceramide second-messenger pathway. PMID:8580709

Greene, L A; Kaplan, D R



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



Radiation and chemotherapy bystander effects induce early genomic instability events: Telomere shortening and bridge formation coupled with mitochondrial dysfunction  

Microsoft Academic Search

The bridge breakage fusion cycle is a chromosomal instability mechanism responsible for genomic changes. Radiation bystander effects induce genomic instability; however, the mechanism driving this instability is unknown. We examined if radiation and chemotherapy bystander effects induce early genomic instability events such as telomere shortening and bridge formation using a human colon cancer explant model. We assessed telomere lengths, bridge

Sheeona Gorman; Miriam Tosetto; Fiona Lyng; Orla Howe; Kieran Sheahan; Diarmuid O’Donoghue; John Hyland; Hugh Mulcahy; Jacintha O'Sullivan



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



Early events in the formation of a tissue structure from dispersed bovine adrenocortical cells following transplantation into scid mice  

Microsoft Academic Search

The early events that follow the transplantation of dispersed bovine adrenocortical cells into scid mice were investigated. We introduced adrenocortical cells into a small cylinder inserted beneath the kidney capsule, where they form a tissue structure that becomes vascularized and secretes steroids that replace those from the animal's own adrenal glands, which are removed during the transplantation surgery. We studied

James R. Tunstead; Michael Thomas; Peter J. Hornsby



Dissociation of centrosome replication events from cycles of DNA synthesis and mitotic division in hydroxyurea-arrested Chinese hamster ovary cells  

Microsoft Academic Search

Relatively little is known about the mecha- nisms used by somatic cells to regulate the replication of the centrosome complex. Centrosome doubling was studied in CHO cells by electron microscopy and im- munofluorescence microscopy using human autoim- mune anticentrosome antiserum, and by Northern blotting using the cDNA encoding portion of the cen- trosome autoantigen pericentriolar material (PCM)-I. Centrosome doubling could

Ron Balczon; Liming Bao; Warren E. Zimmer; Kevin Brown; Raymond P. Zinkowski; B. R. Brinkley II



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


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



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

PubMed Central

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

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



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. PMID:24944583



The Nrf2 Activator, tBHQ, Differentially Affects Early Events Following Stimulation of Jurkat Cells  

PubMed Central

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

Rockwell, Cheryl E.



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

PubMed Central

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

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



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. PMID:21383955

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



Low ABCB1 Gene Expression Is an Early Event in Colorectal Carcinogenesis  

PubMed Central

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.; Saeb?, Mona; Hamfjord, Julian



The Contribution of Early Traumatic Events to Schizophrenia in Some Patients: A Traumagenic Neurodevelopmental Model  

Microsoft Academic Search

THE current diathesis-stress model of schizophrenia proposes that a genetic deficit creates a predisposing vulnerability in the form of oversenstivity to stress. This model positions all psychosocial events on the stress side of the diathesis-stress equation. As an example of hypotheses that emerge when consideration is given to repositioning adverse life events as potential contributors to the diathesis, this article

John Read; Bruce D. Perry; Andrew Moskowitz; Jan Connolly



Preserving the past: an early interview improves delayed event memory in children with intellectual disabilities  

E-print Network

for understanding the contribution of such information processing abilities to eyewitness Event memory in children with intellectual disabilities 5   testimony. Such research might also inform evidence-based guidelines to support the practice of forensic...  staged  the  event,  and  Emma  Stephens  and  Judith  Lunn  for  contributions  to  interviewing  and  data  processing.    Correspondence  concerning  this  article  should  be  addressed  to  Deirdre...

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



RUNX3 inactivation by frequent promoter hypermethylation and protein mislocalization constitute an early event in breast cancer progression  

Microsoft Academic Search

Background We had previously established that inactivation of RUNX3 occurs by frequent promoter hypermethylation and protein mislocalization\\u000a in invasive ductal carcinomas (IDC) of breast. Here, we hypothesize that inactivation of RUNX3 occurring in ductal carcinoma\\u000a in situ (DCIS) represent early event in breast carcinogenesis. \\u000a Methods The study cohort of 40 patients included 17 pure DCIS cases and 23 cases of DCIS

Manish Mani Subramaniam; Jason Yongsheng Chan; Richie Soong; Kosei Ito; Yoshiaki Ito; Khay Guan Yeoh; Manuel Salto-Tellez; Thomas Choudary Putti



Consumption of hydrogen-rich water protects against ferric nitrilotriacetate-induced nephrotoxicity and early tumor promotional events in rats.  


The aim of this work was to test whether consumption with hydrogen-rich water (HW) alleviated renal injury and inhibited early tumor promotional events in Ferric nitrilotriacetate (Fe-NTA)-treated rats. Rats were injected with Fe-NTA solution (7.5mg Fe/kg body weight) intraperitoneally to induce renal injury and simultaneously treated with HW (1.3 ± 0.2mg/l). We found that consumption with HW ameliorated Fe-NTA-induced renal injuries including suppressing elevation of serum creatinine and blood urea nitrogen and inhibited early tumor promotional events including decreasing ornithine decarboxylase activity and incorporation of [3H]thymidine into renal DNA. Consumption with HW suppressed Fe-NTA-induced oxidative stress through decreasing formation of lipid peroxidation and peroxynitrite and activities of NADPH oxidase and xanthine oxidase, increasing activity of catalase, and restoring mitochondrial function in kidneys. Consumption with HW suppressed Fe-NTA-induced inflammation marked by reduced NF-?B, IL-6, and MCP-1 expression and macrophage accumulating in kidneys. In addition, consumption with HW suppressed VEGF expression, STAT3 phosphorylation and PCNA expression in kidneys of Fe-NTA-treated rats. Consumption with HW decreased the incidence of renal cell carcinoma and suppressed tumor growth in Fe-NTA-treated in rats. In conclusion, drinking with HW attenuated Fe-NTA-induced renal injury and inhibited early tumor promotional events in rats. PMID:24140467

Li, Fang-Yin; Zhu, Shao-Xing; Wang, Zong-Ping; Wang, Hua; Zhao, Yang; Chen, Gui-Ping



Caffeine-Induced Uncoupling of Mitosis from the Completion of DNA Replication in Mammalian Cells  

Microsoft Academic Search

Caffeine was shown to induce mitotic events in mammalian cells before DNA replication (S phase) was completed. Synchronized BHK cells that were arrested in early S phase underwent premature chromosome condensation, nuclear envelope breakdown, morphological ``rounding up,'' and mitosis-specific phosphoprotein synthesis when they were exposed to caffeine. These mitotic responses occurred only after the cells had entered S phase and

Robert Schlegel; Arthur B. Pardee



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

E-print Network

immune deficiency syndrome (AIDS). To initiate an ... The reaction scheme shown encompasses only the common events that occur upon TCR .... An example of a typical state variable differential equation is provided in (3) for free fully.

Greg Buzzard


[Eventful life stories. Members of student fraternities persecuted in Silesia in the early 19th century].  


This study supplemented by three charts and a list of biographies, is, for the first time, encompassing their life-data, their resumés and even their professional careers as well as political commitments shown by more than 200 Silesian students. They, at the University of Breslau, but also at other German universities, had joined the student fraternities in the 20-ies and early 30-ies of the 19th century and, in consequence, were persecuted by state authorities, notably in Prussia and, in the majority of cases, had been sentenced to prison terms of varying degrees. The first demagogic persecution, which happened in the first half of the twenties, culminating in 1822 in the Breslau Arminen Trail and ending up with the staging of the Youth-Association-Trail in 1826, had implicated about 100 Silesians, with a smaller portion of them - apart from teh three Youth-Association Silesians who were sentenced to five years imprisonment in a fortress - getting away with a relatively short "political fortress imprisonment". Later a considerable part of them made a career in the prussian judicial authority, in the institutions of higher learning, as parish priests, physicians and scientists, whereas any political engagement remained a rare exception. Out of the 137 Silesian members of the student fraternities affected by the second wave of persecution, the overwhelming majority of them being Protestants and originating partly from the middle classes, mostly artisans, and from intellectual background, with about a hundred of them being given essentially higher sentences ranging from six years up to capital punishment and, in the event of reprieves, they had to serve their sentences between six months and four-to-six years in a fortress. The majority of them made a medium-level professional career, never exceeding the medium ranks, as judicial officers, lawyers in state or communal services, parish priests, teachers or physicians. However, from this group of persecuted persons, a far greater number became active in politics, especially during the 1848/49 revolution in their capacities as Deputies in the German National parliament, or in the Prussian Constitutional Assembly. But they became even active as leading figures on the level of local and regional societies. While conservative executive personalities emerged only rarely from the group of persecuted Silesian student fraternities - the highest office attainable was head of a county administration - a greater number of proponents and elites emerged from these circles in favour of liberalism and, even far more, in favour of the German Democracy. In isolated instances, the socialist movement obtained its protagonists from Silesian fraternities. A biographical study has confirmed the finding that in the first half of the 19th century student fraternities were a political institution which since 1848 had been at the service of the political parties in Germany with a view to recruiting from them their supporters and their party executives. PMID:15648115

Schmidt, Walter



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

USGS Publications Warehouse

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

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



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



Can early training of show jumpers bias outcome of selection events?  

Microsoft Academic Search

Evaluation of free jumping at sub-maximal heights is common practice within selection procedures for young breeding stallions. Early training might cause an unjustified bias. To investigate this, data from a 5-year longitudinal study on 30 horses were used. Half of these horses (experimental group) had received early training between 6months and 4years, the other half (control group) had not. Between

Susana Santamaría; Maarten F. Bobbert; Wim Back; Albert Barneveld; P. René van Weeren



Human Mitochondrial DNA Replication  

PubMed Central

Elucidation of the process of DNA replication in mitochondria is in its infancy. For many years, maintenance of the mitochondrial genome was regarded as greatly simplified compared to the nucleus. Mammalian mitochondria were reported to lack all DNA repair systems, to eschew DNA recombination, and to possess but a single DNA polymerase, polymerase ?. Pol? was said to replicate mitochondrial DNA exclusively via one mechanism, involving only two priming events and a handful of proteins. In this “strand-displacement model,” leading strand DNA synthesis begins at a specific site and advances approximately two-thirds of the way around the molecule before DNA synthesis is initiated on the “lagging” strand. Although the displaced strand was long-held to be coated with protein, RNA has more recently been proposed in its place. Furthermore, mitochondrial DNA molecules with all the features of products of conventional bidirectional replication have been documented, suggesting that the process and regulation of replication in mitochondria is complex, as befits a genome that is a core factor in human health and longevity. PMID:23143808

Holt, Ian J.; Reyes, Aurelio



Exposure to traumatic events and the behavioral health of children enrolled in an early childhood system of care.  


Children may be exposed to numerous types of traumatic events that can negatively affect their development. The scope to which studies have examined an array of events among young children has been limited, thereby restricting our understanding of exposure and its relationship to behavioral functioning. The current cross-sectional study describes traumatic event exposure in detail and its relationship to behavioral health among an at-risk sample of young children (N = 184), under 6 years of age, upon enrollment into an early childhood, family-based, mental health system of care. Caregivers completed home-based semistructured interviews that covered children's exposure to 24 different types of traumatic events and behavioral and emotional functioning. Findings indicated that nearly 72% of young children experienced 1 or more types of traumatic events. Multiple regression model results showed that exposure was significantly associated with greater behavioral and emotional challenges with children's age, gender, race/ethnicity, household income, and caregiver's education in the model. These findings highlight the prevalence of traumatic exposures among an at-risk sample of young children in a system of care and suggest that this exposure is associated with behavioral and emotional challenges at a young age. PMID:23225035

Snyder, Frank J; Roberts, Yvonne Humenay; Crusto, Cindy A; Connell, Christian M; Griffin, Amy; Finley, Meghan K; Radway, Susan; Marshall, Tim; Kaufman, Joy S



Exposure to Traumatic Events and the Behavioral Health of Children Enrolled in an Early Childhood System of Care  

PubMed Central

Children may be exposed to numerous types of traumatic events that can negatively affect their development. The scope to which studies have examined an array of events among young children has been limited, thereby restricting our understanding of exposure and its relationship to behavioral functioning. The current cross-sectional study describes traumatic event exposure in detail and its relationship to behavioral health among an at-risk sample of young children (N = 184), under 6 years of age, upon enrollment into an early childhood, family-based, mental health system of care. Caregivers completed home-based semistructured interviews that covered children’s exposure to 24 different types of traumatic events and behavioral and emotional functioning. Findings indicated that nearly 72% of young children experienced 1 or more types of traumatic events. Multiple regression model results showed that exposure was significantly associated with greater behavioral and emotional challenges with children’s age, gender, race/ethnicity, household income, and caregiver’s education in the model. These findings highlight the prevalence of traumatic exposures among an at-risk sample of young children in a system of care and suggest that this exposure is associated with behavioral and emotional challenges at a young age. PMID:23225035

Snyder, Frank J.; Roberts, Yvonne Humenay; Crusto, Cindy A.; Connell, Christian M.; Griffin, Amy; Finley, Meghan K.; Radway, Susan; Marshall, Tim; Kaufman, Joy S.



Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development.  


Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months. PDAC has been linked with obesity and glucose intolerance, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years before diagnosis, when occult disease is probably present. We show that plasma BCAAs are also elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression but not in mice with Kras-driven tumors in other tissues, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease. Together, these findings suggest that increased whole-body protein breakdown is an early event in development of PDAC. PMID:25261994

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



Carbonate platform drowning events along the northern Tethyan margin during the early Cretaceous  

NASA Astrophysics Data System (ADS)

During the early Cretaceous, the carbonate platform attached to the northern Tethyan margin experienced a series of platform drowning episodes, which can be widely traced. The five episodes recognized cover the early Valanginian to early Hauterivian (D1), middle Hauterivian (D2), late Hauterivian to early Barremian (D3), early to early late Aptian (D4), and late Aptian to early Albian (D5). The particular sensitivity towards drowning in this platform system was probably related to its marginal paleoposition (ca. 30 degree N) with regards to reef growth, to its attachment to the European continent (a periodic source of reef-unfriendly weathering products), as well as to prevailing paleoceanographic conditions (sea-level change, upwelling intensity, presence or absence of connections to the boreal realm). Drowning episodes are usually preceded by changes in carbonate production from a chlorozoan to a foramol mode, with important increases in accumulation rates. The drowning episodes themselves are documented by erosional surfaces and/or by the formation of strongly condensed beds rich in coarse sand, glauconite, phosphate, and biosilica. The presence of ammonites is a key to their dating. If resolvable, the onset of drowning appears to be diachronous, and its evolution is by stepwise onlap onto the platform (D1, D4). Termination of drowning appears in all cases synchronous. Drowning episodes D1, D4, and D5 are correlated to positive excursions in the delta C-13 record, albeit with a slight diachronity in their onsets (drowning episodes lead the delta C-13 record), whereas episode D2 correlates to a negative excursion and episode D3 to a long and steady increase in delta C-13 values. This suggests that no uniform mechanism can be assumed for all five episodes but that each episode needs to be examined in its own context. An important element in all episodes is the change in weathering style and intensity in the continental hinterland, which profoundly affected detrital and nutrient fluxes.

Föllmi, K. B.; van de Schootbrugge, B.; Godet, A.; Bodin, S.; Linder, P.; Adatte, Th.



Modeling and analysis of early events in T-lymphocyte antigen-activated intracellular-signaling pathways  

NASA Astrophysics Data System (ADS)

The T-cell antigen-activated signaling pathway is a highly regulated intracellular biochemical system that is crucial for initiating an appropriate adaptive immune response. To improve the understanding of the complex regulatory mechanisms controlling the early events in T-cell signaling, a detailed mathematical model was developed that utilizes ordinary differential equations to describe chemical reactions of the signaling pathway. The model parameter values were constrained by experimental data on the activation of a specific signaling intermediate and indicated an initial rapid cascade of phosphorylation events followed by a comparatively slow signal downregulation. Nonlinear analysis of the model suggested that thresholding and bistability occur as a result of the embedded positive and negative feedback loops within the model. These nonlinear system properties may enhance the T-cell receptor specificity and provide sub-threshold noise filtering with switch-like behavior to ensure proper cell response. Additional analysis using a reduced second-order model led to further understanding of the observed system behavior. Moreover, the interactions between the positive and negative feedback loops enabled the model to exhibit, among a variety of other feasible dynamics, a sustained oscillation that corresponds to a stable limit cycle in the two-dimensional phase plane. Quantitative analysis in this paper has helped identify potential regulatory mechanisms in the early T-cell signaling events. This integrated approach provides a framework to quantify and discover the ensemble of interconnected T-cell antigen-activated signaling pathways from limited experimental data.

Zheng, Yanan; Balakrishnan, Venkataramanan; Buzzard, Greg; Geahlen, Robert; Harrison, Marietta; Rundell, Ann



Early Healing Events around Titanium Implant Devices with Different Surface Microtopography: A Pilot Study in an In Vivo Rabbit Model  

PubMed Central

In the present pilot study, the authors morphologically investigated sandblasted, acid-etched surfaces (SLA) at very early experimental times. The tested devices were titanium plate-like implants with flattened wide lateral sides and jagged narrow sides. Because of these implant shape and placement site, the device gained a firm mechanical stability but the largest portion of the implant surface lacked direct contact with host bone and faced a wide peri-implant space rich in marrow tissue, intentionally created in order to study the interfacial interaction between metal surface and biological microenvironment. The insertion of titanium devices into the proximal tibia elicited a sequence of healing events. Newly formed bone proceeded through an early distance osteogenesis, common to both surfaces, and a delayed contact osteogenesis which seemed to follow different patterns at the two surfaces. In fact, SLA devices showed a more osteoconductive behavior retaining a less dense blood clot, which might be earlier and more easily replaced, and leading to a surface-conditioning layer which promotes osteogenic cell differentiation and appositional new bone deposition at the titanium surface. This model system is expected to provide a starting point for further investigations which clarify the early cellular and biomolecular events occurring at the metal surface. PMID:22545015

Orsini, Ester; Salgarello, Stefano; Martini, Desiree; Bacchelli, Beatrice; Quaranta, Marilisa; Pisoni, Luciano; Bellei, Emma; Joechler, Monika; Ottani, Vittoria



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.



Early markers of major adverse events in children after cardiac operations  

Microsoft Academic Search

Objectives: The purpose of this study was to determine the physiologic variables that predict major adverse events in children in the intensive care unit after cardiac operations. Methods: A cohort observational study was conducted. At the time of admission to the intensive care unit and 4, 8, 12, and 24 hours later the following variables were recorded: mean arterial pressure,

Trevor Duke; Warwick Butt; Mike South; Tom R. Karl



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



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

ERIC Educational Resources Information Center

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

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



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



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.



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

ERIC Educational Resources Information Center

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

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



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

ERIC Educational Resources Information Center

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

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



Spiders do not evoke greater early posterior negativity in the event-related potential as snakes.  


It has been long believed that both snakes and spiders are archetypal fear stimuli for humans. Furthermore, snakes have been assumed as stronger threat cues for nonhuman primates. However, it is still unclear whether spiders hold a special status in human perception. The current study explored to what extent spider pictures draw early visual attention [as assessed with early posterior negativity (EPN)] when compared with insects similar to spiders. To measure the EPN, participants watched a random rapid serial presentation of pictures, which consisted of two conditions: spider condition (spider, wasp, bumblebee, beetle) and snake condition (snake, bird). EPN amplitudes revealed no significant difference between spider, wasp, bumblebee, and beetle pictures, whereas EPN amplitudes were significantly larger for snake pictures relative to bird pictures. In addition, EPN amplitudes were significantly larger for snake pictures relative to spider pictures. These results suggest that the early visual attentional capture of animate objects is stronger for snakes, whereas spiders do not appear to hold special early attentional value. PMID:25026534

He, Hongshen; Kubo, Kenta; Kawai, Nobuyuki



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



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.



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


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

Bauer, Patricia J; Larkina, Marina



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

Microsoft Academic Search

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

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



Role of intestinal inflammation as an early event in obesity and insulin resistance  

PubMed Central

Purpose of review To highlight recent evidence supporting a concept that intestinal inflammation is a mediator or contributor to development of obesity and insulin resistance. Recent findings Current views suggest that obesity-associated systemic and adipose tissue inflammation promote insulin resistance, which underlies many obesity-linked health risks. Diet-induced changes in gut microbiota also contribute to obesity. Recent findings support a concept that high fat diet and bacteria interact to promote early inflammatory changes in the small intestine that contribute to development of or susceptibility to obesity and insulin resistance. This review summarizes the evidence supporting a role of intestinal inflammation in diet-induced obesity and insulin resistance and discusses mechanisms. Summary The role of diet-induced intestinal inflammation as an early biomarker and mediator of obesity, and insulin resistance warrants further study. PMID:21587067

Ding, Shengli; Lund, Pauline K.



Early folding events protect aggregation-prone regions of a ?-rich protein  

PubMed Central

Summary Protein folding and aggregation inevitably compete with one another. This competition is even keener for proteins with frustrated landscapes, such as those rich in ?-structure. Interestingly, despite their rugged energy landscapes and high ?-sheet content, intracellular lipid-binding proteins (iLBPs) appear to successfully avoid aggregation, as they are not implicated in aggregation diseases. In this study, we used a canonical iLBP, cellular retinoic acid-binding protein 1 (CRABP1), to better understand how folding is favored over aggregation. Analysis of folding kinetics of point mutants reveals that the folding pathway of CRABP1 involves early barrel closure. This folding mechanism protects sequences in CRABP1 that comprise cores of aggregates as identified by NMR. The amino acid conservation pattern in other iLBPs suggests that early barrel closure may be a general strategy for successful folding and minimization of aggregation. We suggest that folding mechanisms more broadly may incorporate steps that disfavor aggregation. PMID:23454187

Budyak, Ivan L.; Krishnan, Beena; Marcelino-Cruz, Anna M.; Ferrolino, Mylene C.; Zhuravleva, Anastasia; Gierasch, Lila M.



Early life events and their consequences for later disease: A life history and evolutionary perspective  

Microsoft Academic Search

Biomedical science has little considered the relevance of life history theory and evolutionary and ecological developmental biology to clinical medicine. However, the observa- tions that early life influences can alter later disease risk—the ''developmental origins of health and disease'' (DOHaD) paradigm—have led to a recognition that these perspectives can inform our understanding of human biology. We propose that the DOHaD

Peter D. Gluckman; Mark A. Hanson; Alan S. Beedle



Early events in rabies virus infection of the central nervous system in skunks ( Mephitis mephitis )  

Microsoft Academic Search

Twenty-four striped skunks were inoculated intramuscularly (long digital extensor muscle of right pelvic limb) with street\\u000a rabies virus. Groups of two clinically normal skunks were killed at various times after inoculation; skunks that developed\\u000a rabies were killed in early stages of the clinical signs. Four clinically normal skunks (numbered 1–4) had slight infection\\u000a in lumbar spinal ganglia, spinal cord and

K. M. Charlton; G. A. Casey; A. I. Wandeler; S. Nadin-Davis



The Caulobacter crescentus ctrA P1 promoter is essential for the coordination of cell cycle events that prevent the overinitiation of DNA replication  

PubMed Central

The master regulator CtrA oscillates during the Caulobacter cell cycle due to temporally regulated proteolysis and transcription. It is proteolysed during the G1–S transition and reaccumulates in predivisional cells as a result of transcription from two sequentially activated promoters, P1 and P2. CtrA reinforces its own synthesis by directly mediating the activation of P2 concurrently with repression of P1. To explore the role of P1 in cell cycle control, we engineered a mutation into the native ctrA locus that prevents transcription from P1 but not P2. As expected, the ctrA P1 mutant exhibits striking growth, morphological and DNA replication defects. Unexpectedly, we found CtrA and its antagonist SciP, but not DnaA, GcrA or CcrM accumulation to be dramatically reduced in the ctrA P1 mutant. SciP levels closely paralleled CtrA accumulation, suggesting that CtrA acts as a rheostat to modulate SciP abundance. Furthermore, the reappearance of CtrA and CcrM in predivisional cells was delayed in the P1 mutant by 0.125 cell cycle unit in synchronized cultures. High levels of ccrM transcription despite low levels of CtrA and increased transcription of ctrA P2 in the ctrA P1 mutant are two examples of robustness in the cell cycle. Thus, Caulobacter can adjust regulatory pathways to partially compensate for reduced and delayed CtrA accumulation in the ctrA P1 mutant. PMID:22790399

Schredl, Alexander T.; Perez Mora, Yannet G.; Herrera, Anabel; Cuajungco, Math P.



Combined oxygen- and carbon-isotope records through the Early Jurassic: multiple global events and two modes of carbon-cycle\\/temperature coupling  

Microsoft Academic Search

The Jurassic comprises some 55 million years of Earth history. However, within the Jurassic, only one major environmental change (hyperthermal) event is really well known - the Early Toarcian Oceanic Anoxic Event (OAE) at ~183 Ma - and until very recently the extent to which the accompanying environmental changes were global has been strongly debated. Nevertheless, partly as a result

S. P. Hesselbo; C. Korte



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.



Early-life events may trigger biochemical pathways for Alzheimer's disease: the "LEARn" model.  


Alzheimer's disease (AD), the most common form of dementia among the elderly, manifests mostly late in adult life. However, it is presently unclear when the disease process starts and how long the pathobiochemical processes take to develop. Our goal is to address the timing and nature of triggers that lead to AD. To explain the etiology of AD, we have recently proposed a "Latent Early-life Associated Regulation" (LEARn) model, which postulates a latent expression of specific genes triggered at the developmental stage. This model integrates both the neuropathological features (e.g., amyloid-loaded plaques and tau-laden tangles) and environmental factors (e.g., diet, metal exposure, and hormones) associated with the disease. Environmental agents perturb gene regulation in a long-term fashion, beginning at early developmental stages, but these perturbations do not have pathological results until significantly later in life. The LEARn model operates through the regulatory region (promoter) of the gene and by affecting the methylation status within the promoter of specific genes. PMID:18668339

Lahiri, Debomoy K; Zawia, Nasser H; Greig, Nigel H; Sambamurti, Kumar; Maloney, Bryan



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

NASA Astrophysics Data System (ADS)

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

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



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

SciTech Connect

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

Hong, Julian C.; Kruser, Tim J. [Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin (United States); Gondi, Vinai [Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin (United States); Central Dupage Hospital Cancer Center, Warrenville, Illinois (United States); Mohindra, Pranshu; Cannon, Donald M.; Harari, Paul M. [Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin (United States); Bentzen, Søren M., E-mail: [Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin (United States)



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

PubMed Central

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.



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

NASA Astrophysics Data System (ADS)

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

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



Hypermethylation of the nel-like 1 gene is a common and early event and is associated with poor prognosis in early-stage esophageal adenocarcinoma.  


The nel-like1 (NELL1) gene maps to chromosome 11p15, which frequently undergoes loss of heterozygosity in esophageal adenocarcinoma (EAC). NELL1 promoter hypermethylation was examined by real-time methylation-specific polymerase chain reaction in 259 human esophageal tissues. Hypermethylation of this promoter showed highly discriminative receiver-operator characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinoma (ESCC) and EAC from normal esophagus (NE) (P<0.001). NELL1 normalized methylation values were significantly higher in Barrett's metaplasia (BE), dysplastic Barrett's (D) and EAC than in NE (P<0.0000001). NELL1 hypermethylation frequency was zero in NE but increased early during neoplastic progression, to 41.7% in BE from patients with Barrett's alone, 52.5% in D and 47.8% in EAC. There was a significant correlation between NELL1 hypermethylation and BE segment length. Three (11.5%) of 26 ESCCs exhibited NELL1 hypermethylation. Survival correlated inversely with NELL1 hypermethylation in patients with stages I-II (P=0.0264) but not in stages III-IV (P=0.68) EAC. Treatment of KYSE220 ESCC and BIC EAC cells with 5-aza-2'-deoxycytidine reduced NELL1 methylation and increased NELL1 mRNA expression. NELL1 mRNA levels in EACs with an unmethylated NELL1 promoter were significantly higher than those in EACs with a methylated promoter (P=0.02). Promoter hypermethylation of NELL1 is a common, tissue-specific event in human EAC, occurs early during Barrett's-associated esophageal neoplastic progression, and is a potential biomarker of poor prognosis in early-stage EAC. PMID:17452981

Jin, Z; Mori, Y; Yang, J; Sato, F; Ito, T; Cheng, Y; Paun, B; Hamilton, J P; Kan, T; Olaru, A; David, S; Agarwal, R; Abraham, J M; Beer, D; Montgomery, E; Meltzer, S J



Expression of human E46K-mutated ?-synuclein in BAC-transgenic rats replicates early-stage Parkinson's disease features and enhances vulnerability to mitochondrial impairment  

PubMed Central

Parkinson’s disease (PD), the second most common neurodegenerative disorder, is etiologically heterogeneous, with most cases thought to arise from a combination of environmental factors and genetic predisposition; about 10% of cases are caused by single gene mutations. While neurotoxin models replicate many of the key behavioral and neurological features, they often have limited relevance to human exposures. Genetic models replicate known disease-causing mutations, but are mostly unsuccessful in reproducing major features of PD. In this study, we created a BAC (bacterial artificial chromosome) transgenic rat model of PD expressing the E46K mutation of ?-synuclein, which is pathogenic in humans. The mutant protein was expressed at levels ~2–3-fold above endogenous ?-synuclein levels. At 12 months of age, there was no overt damage to the nigrostriatal dopamine system; however, (i) alterations in striatal neurotransmitter metabolism, (ii) accumulation and aggregation of ?-synuclein in nigral dopamine neurons, and (iii) evidence of oxidative stress suggest this model replicates several preclinical features of PD. Further, when these animals were exposed to rotenone, a mitochondrial toxin linked to PD, they showed heightened sensitivity, indicating that ?-synuclein expression modulates the vulnerability to mitochondrial impairment. We conclude that these animals are well-suited to examination of gene-environment interactions that are relevant to PD. PMID:23153578

Cannon, Jason R.; Geghman, Kindiya D.; Tapias, Victor; Sew, Thomas; Dail, Michelle K.; Li, Chenjian; Greenamyre, J. Timothy



Temporal profile of replication of human chromosomes.  


Chromosomes in human cancer cells are expected to initiate replication from predictably localized origins, firing reproducibly at discrete times in S phase. Replication products obtained from HeLa cells at different stages of S phase were hybridized to cDNA and genome tiling oligonucleotide microarrays to determine the temporal profile of replication of human chromosomes on a genome-wide scale. About 1,000 genes and chromosomal segments were identified as sites containing efficient origins that fire reproducibly. Early replication was correlated with high gene density. An acute transition of gene density from early to late replicating areas suggests that discrete chromatin states dictate early versus late replication. Surprisingly, at least 60% of the interrogated chromosomal segments replicate equally in all quarters of S phase, suggesting that large stretches of chromosomes are replicated by inefficient, variably located and asynchronous origins and forks, producing a pan-S phase pattern of replication. Thus, at least for aneuploid cancer cells, a typical discrete time of replication in S phase is not seen for large segments of the chromosomes. PMID:15845769

Jeon, Yesu; Bekiranov, Stefan; Karnani, Neerja; Kapranov, Philipp; Ghosh, Srinka; MacAlpine, David; Lee, Charles; Hwang, Deog Su; Gingeras, Thomas R; Dutta, Anindya



Temporal profile of replication of human chromosomes  

PubMed Central

Chromosomes in human cancer cells are expected to initiate replication from predictably localized origins, firing reproducibly at discrete times in S phase. Replication products obtained from HeLa cells at different stages of S phase were hybridized to cDNA and genome tiling oligonucleotide microarrays to determine the temporal profile of replication of human chromosomes on a genome-wide scale. About 1,000 genes and chromosomal segments were identified as sites containing efficient origins that fire reproducibly. Early replication was correlated with high gene density. An acute transition of gene density from early to late replicating areas suggests that discrete chromatin states dictate early versus late replication. Surprisingly, at least 60% of the interrogated chromosomal segments replicate equally in all quarters of S phase, suggesting that large stretches of chromosomes are replicated by inefficient, variably located and asynchronous origins and forks, producing a pan-S phase pattern of replication. Thus, at least for aneuploid cancer cells, a typical discrete time of replication in S phase is not seen for large segments of the chromosomes. PMID:15845769

Jeon, Yesu; Bekiranov, Stefan; Karnani, Neerja; Kapranov, Philipp; Ghosh, Srinka; MacAlpine, David; Lee, Charles; Hwang, Deog Su; Gingeras, Thomas R.; Dutta, Anindya



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


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



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. PMID:24344186

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



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 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.



Project VIISA Outreach. Outreach Services To Assist States To Replicate a Training Model for Early Interventionists in a Low Incidence Disability Condition: Blindness and Visual Impairment. Final Report.  

ERIC Educational Resources Information Center

This report discusses the activities and outcomes an inservice training model. This model was designed to help states provide ongoing training to early intervention, early childhood, and vision personnel. The focus is on personnel that specialize inserving visually impaired children from time of birth to age five. The purpose of the project is to…

Utah State Univ., Logan. Dept. of Communicative Disorders.


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


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. PMID:11542112

Erwin, D H; Valentine, J W; Sepkoski, J J



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)



Activation of Jun kinase is an early event in hepatic regeneration.  

PubMed Central

Compensatory hepatic regeneration after partial hepatectomy (PH) is dependent upon the extent of resection. This study analyzes the regulation of the AP-1 transcription factor c-Jun during hepatic regeneration. There is a progressive increase in c-jun mRNA levels after sham operation, one-third PH, and two-thirds PH. A concomitant increase in AP-1 binding activity is also observed. The c-Jun protein is a major constituent of the AP-1 complex in quiescent and early regenerating liver. The activity of c-Jun nuclear kinase (JNK), which phosphorylates the activation domain of the c-Jun protein, is markedly stimulated after one-third PH. JNK1 or an immunologically related kinase is a constituent of this stimulated JNK activity after PH. When primary cultures of adult rat hepatocytes are incubated with epidermal growth factor or transforming growth factor-alpha, AP-1 transcriptional activity is increased and the activation domain of the c-Jun protein is further potentiated. Phosphopeptide mapping of the endogenous c-Jun protein in proliferating cultured hepatocytes demonstrates phosphorylation of the c-Jun activation domain. Combining the results of these in vivo and culture studies, we conclude that the minimal stimulation of one-third PH activates JNK, which phosphorylates the c-Jun activation domain in hepatocytes, resulting in enhanced transcription of AP-1-dependent genes. Images PMID:7860764

Westwick, J K; Weitzel, C; Leffert, H L; Brenner, D A



Gastrin and gastrin receptor activation: an early event in the adenoma-carcinoma sequence  

PubMed Central

BACKGROUND AND AIMS—Gastrin and the cholecystokinin type B/gastrin receptor (CCKBR) have been shown to be expressed in colorectal adenocarcinoma. Both exogenous and autocrine gastrin have been demonstrated to stimulate growth of colorectal cancer but it is not known if gastrin affects the growth of colonic polyps. The purpose of this study was to determine if gastrin and CCKBR are expressed in human colonic polyps and to determine at which stage of progression this occurs.?METHODS—A range of human colonic polyps was assessed for gastrin and CCKBR gene and protein expression.?RESULTS—Normal colonic mucosa did not express gastrin or CCKBR. Gastrin and CCKBR reverse transcription-polymerase chain reaction products were detected and verified by specific hybridisation with an oligo probe on Southern blots. Gastrin and CCKBR were expressed in 78% and 81% of polyps, respectively. Both genes were coexpressed in 97% of cases. Immunohistochemistry identified progastrin in 91%, glycine extended gastrin 17 in 80%, and amidated gastrin 17 in only 47% of polyps. CCKBR was present in 96% of polyps. Expression of gastrin and CCKBR was seen in all histological types and sizes of polyps.?CONCLUSIONS—This study is the first to show widespread expression of both gastrin and its receptor in colorectal polyps. Their activation occurs early in the adenoma-carcinoma sequence. Gastrin may promote progression through the adenoma-carcinoma sequence.???Keywords: gastrin; colon; adenomas; polyps; autocrine PMID:11076881

Smith, A; Watson, S



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:



Size-resolved aerosol chemical analysis of extreme haze pollution events during early 2013 in urban Beijing, China.  


Using size-resolved filter sampling and chemical characterization, high concentrations of water-soluble ions, carbonaceous species and heavy metals were found in both fine (PM2.1) and coarse (PM2.1-9) particles in Beijing during haze events in early 2013. Even on clear days, average mass concentration of submicron particles (PM1.1) was several times higher than that previously measured in most of abroad urban areas. A high concentration of particulate matter on haze days weakens the incident solar radiation, which reduces the generation rate of secondary organic carbon in PM1.1. We show that the peak mass concentration of particles shifted from 0.43-0.65?m on clear days to 0.65-1.1?m on lightly polluted days and to 1.1-2.1?m on heavily polluted days. The peak shifts were also found for the following species: organic carbon, elemental carbon, NH4(+), SO4(2-), NO3(-), K, Cu, Zn, Cd and Pb. Our findings demonstrate that secondary inorganic aerosols (36%) and organic matter (26%) dominated the fine particle mass on heavily polluted days, while their contribution reduced to 29% and 18%, respectively, on clear days. Besides fine particles, anthropogenic chemical species also substantially accumulated in the coarse mode, which suggests that particles with aerodynamic diameter larger than 2.1?m cannot be neglected during severe haze events. PMID:25106045

Tian, Shili; Pan, Yuepeng; Liu, Zirui; Wen, Tianxue; Wang, Yuesi



The Roles of Chromatin Remodelling Factors in Replication  

Microsoft Academic Search

Dynamic changes of chromatin structure control DNA-dependent events, including DNA replication.\\u000a Along with DNA, chromatin organization must be replicated to maintain genetic and epigenetic information\\u000a through cell generations. Chromatin remodelling is important for several steps in replication: determination\\u000a and activation of origins of replication, replication machinery progression, chromatin assembly and\\u000a DNA repair. Histone chaperones such as the FACT complex assist

Ana Neves-Costa; Patrick Varga-Weisz


Temperature and carbon isotope histories for early Eocene hyperthermals: events linked by a similar causal mechanism? (Invited)  

NASA Astrophysics Data System (ADS)

Early Paleogene ‘hyperthermals’, including the well studied Paleocene-Eocene thermal maximum (PETM; ~56 Ma), Eocene Thermal Maximum 2 (ETM2; ~54 Ma), and H2 (~ 100 kyr after the ETM2) were transient global warming phases, associated with massive injection of 13C-depleted carbon into the ocean-atmosphere system. We identified the PETM in marginal marine sediment sequences from the Southwest Pacific Ocean (~65 °S) and the US margin of the Gulf Coastal Plain (~30 °N). We reconstruct a ~7 °C PETM warming for these sites, using the biomarker-based paleothermometer TEX86, which indicates maximum PETM temperatures of 35°C in the Gulf Coast and over 30°C in the Southern Ocean. Dinoflagellate cyst assemblages indicate synchronous sea level rise, salinity changes, and perhaps storm activity changes across the event. Similar to the New Jersey and North Sea records, the inception of dominant subtropical dinocysts (Apectodinium) preceded the onset of the carbon isotope excursion in the Southern Ocean. This indicates that anomalous environmental changes preceded the massive input of 13C-depleted carbon. Additionally, we generated high-resolution benthic stable isotope data of ETM2 and H2 from the Southeast Atlantic and the Southern Ocean and compared them in detail with PETM data from the same sites. The magnitudes of the ?13C and ?18O excursions of the ETM2 and H2 events are significantly smaller than those during the PETM, but the ?13C and ?18O excursions are scaled identically for all three hyperthermals. This indicates that the ?13C change of the exogenic carbon pool was similarly related to warming during these events.

Sluijs, A.; Bijl, P.; Stap, L.; van Roij, L.; Bohaty, S. M.; Brinkhuis, H.; Harrington, G. J.; Lourens, L. J.; Reichart, G.; Roehl, U.; Schneider, L. J.; Sessa, J.; Thomas, E.; Schouten, S.; Zachos, J. C.



Self-replicating colloidal clusters  

PubMed Central

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.



Major palaeoenvironmental perturbation in an Early Aptian carbonate platform: Prelude of the Oceanic Anoxic Event 1a?  

NASA Astrophysics Data System (ADS)

The Early Aptian Oceanic Anoxic Event (OAE 1a) was characterized by intensified greenhouse climate conditions, widespread accumulation of organic deposits in open-marine settings, major perturbations in the C cycle and a generalized increase in terrestrial runoff. Sedimentological, diagenetic and chemostratigraphic analyses of Lower Aptian platform carbonates from the North Cantabrian basin (N Spain) illustrate the regional impact and effects of those global conditions on shallow marine environments. The studied interval outlines four stages of platform evolution. Stage 1 (earliest Bedoulian) is defined by an initial rapid marine transgression that led to deposition of shallow water oligotrophic photozoan skeletal assemblages, and by a later interval of subaerial exposure. Stage 2 (early Bedoulian) starts with a rapid transgression followed by deposition of grainstones that yield heterozoan assemblages, more typical of mesotrophic conditions, along with ferruginized oolites. Stage 3 (early Bedoulian) is defined by the drowning of the carbonate platform and subsequent deposition of open-marine marls, which are thought to represent the local expression of the OAE 1a. Finally, stage 4 shows the return of shallow water photozoan carbonate sedimentation. The carbonate O and C stable isotope records have revealed prominent negative excursions during deposition of the marly interval of the stage 3, which may be associated with the important global changes that occurred at the onset of the OAE 1a. The change in skeletal assemblages that preceded the isotopic excursions and the platform drowning documents conditions of environmental stress caused by a combination of local and global factors. The global change, coupled with increased basin subsidence, triggered the drowning of the platform by progressive reduction of the growth potential of the carbonate factory.

Najarro, María; Rosales, Idoia; Martín-Chivelet, Javier



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.


A Novel DDB2-ATM Feedback Loop Regulates Human Cytomegalovirus Replication  

PubMed Central

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

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



Rapid changes in the redox conditions of the western Tethys Ocean during the early Aptian oceanic anoxic event  

NASA Astrophysics Data System (ADS)

The early Aptian (125 to 121 Ma) records an episode of severe environmental change including a major perturbation of the carbon cycle, an oceanic anoxic event (OAE 1a, 122.5 Ma), a platform drowning episode and a biocalcification crisis. We propose to trace changes in the oxygenation state of the ocean during the early Aptian anoxic event using the redox-sensitive trace-element (RSTE) distribution, phosphorus accumulation rates (PARs) and organic-matter characterization in three different basins of the western Tethys. The following sections have been investigated: Gorgo a Cerbara (central Italy) in the Umbria Marche basin, Glaise (SE France) in the Vocontian basin and Cassis/La Bédoule (SE France) located in the Provencal basin. In the Gorgo a Cerbara section, RSTE distributions show a low background level along the main part of the section, contrasted by different maxima in concentrations within the Selli level. In the Glaise section, the Goguel level displays a weak increase in RSTE contents coeval with moderate TOC values. At Cassis/La Bédoule, no significant RSTE enrichments have been observed in sediments equivalent to the Selli level. These differences in the records of the geochemical proxies of the Selli level or its equivalent indicate the deposition under different redox conditions, probably related to the paleogeography. Our data indicate the development of anoxic-euxinic conditions in the deeper part of the Tethys during OAE 1a, whereas in the shallower environments, conditions were less reducing. Moreover, at Gorgo a Cerbara, the Selli level is characterized by rapid changes in the intensity of reducing conditions in the water column. Ocean eutrophication seems to be a major factor in the development and the persistence of anoxia as suggested by the PAR evolution. Higher PAR values at the onset of OAE 1a suggest an increase in nutrient input, whereas the return to lower values through the first part of the OAE 1a interval may be related to the weakened capacity to retain P in the sedimentary reservoir due to bottom-water oxygen depletion. This general pattern is contrasted by the data of Gorgo a Cerbara, where the sediments deposited during the OAE 1a interval show P-enrichments (mainly authigenic P). This is associated with maxima in TOC values and Corg:Ptot ratios, suggesting that a part of the remobilized P was trapped in the sediments and as such prevented from returning to the water column.

Westermann, Stéphane; Stein, Melody; Matera, Virginie; Fiet, Nicolas; Fleitmann, Dominik; Adatte, Thierry; Föllmi, Karl B.



Defects of mitochondrial DNA replication.  


Mitochondrial DNA is replicated by DNA polymerase ? in concert with accessory proteins such as the mitochondrial DNA helicase, single-stranded DNA binding protein, topoisomerase, and initiating factors. Defects in mitochondrial DNA replication or nucleotide metabolism can cause mitochondrial genetic diseases due to mitochondrial DNA deletions, point mutations, or depletion, which ultimately cause loss of oxidative phosphorylation. These genetic diseases include mitochondrial DNA depletion syndromes such as Alpers or early infantile hepatocerebral syndromes, and mitochondrial DNA deletion disorders, such as progressive external ophthalmoplegia, ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy. This review focuses on our current knowledge of genetic defects of mitochondrial DNA replication (POLG, POLG2, C10orf2, and MGME1) that cause instability of mitochondrial DNA and mitochondrial disease. PMID:24985751

Copeland, William C



Postweaning exposure to dietary zearalenone, a mycotoxin, promotes premature onset of puberty and disrupts early pregnancy events in female mice.  


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

Zhao, Fei; Li, Rong; Xiao, Shuo; Diao, Honglu; Viveiros, Maria M; Song, Xiao; Ye, Xiaoqin



Promoter hypermethylation of CDH13 is a common, early event in human esophageal adenocarcinogenesis and correlates with clinical risk factors.  


Although the CDH13 gene has been shown to undergo epigenetic silencing by promoter methylation in many types of tumors, hypermethylation of this gene in Barrett's-associated esophageal adenocarcinogenesis has not been studied. Two hundred fifty-nine human esophageal tissues were therefore examined for CDH13 promoter hypermethylation by real-time methylation-specific PCR. CDH13 hypermethylation showed discriminative receiver-operator characteristic curve profiles, sharply demarcating esophageal adenocarcinoma (EAC) from esophageal squamous cell carcinoma (ESCC) and normal esophagus (NE) (p < 0.0001). CDH13 normalized methylation values (NMV) were significantly higher in Barrett's esophagus (BE), dysplastic BE (D) and EAC than in NE (p < 0.0000001). CDH13 hypermethylation frequency was 0% in NE but increased early during neoplastic progression, rising to 70% in BE, 77.5% in D and 76.1% in EAC. Both CDH13 hypermethylation frequency and its mean NMV were significantly higher in BE with than without accompanying EAC. In contrast, only 5 (19.2%) of 26 ESCCs exhibited CDH13 hypermethylation. Furthermore, both CDH13 hypermethylation frequency and its mean NMV were significantly higher in EAC than in ESCC, as well as in BE or D vs. ESCC. Interestingly, mean CDH13 NMV was significantly lower in short-segment than in long-segment BE, a known clinical risk factor for neoplastic progression. Similarly, BE segment length was significantly lower in specimens with unmethylated than with methylated CDH13 promoters. 5-aza-2'-deoxycytidine treatment of OE33 EAC and KYSE220 ESCC cells reduced CDH13 methylation and increased CDH13 mRNA expression. These findings suggest that hypermethylation of CDH13 is a common, tissue-specific event in human EAC, occurs early during BE-associated neoplastic progression, and correlates with known clinical neoplastic progression risk factors. PMID:18729198

Jin, Zhe; Cheng, Yulan; Olaru, Alexandru; Kan, Takatsugu; Yang, Jian; Paun, Bogdan; Ito, Tetsuo; Hamilton, James P; David, Stefan; Agarwal, Rachana; Selaru, Florin M; Sato, Fumiaki; Abraham, John M; Beer, David G; Mori, Yuriko; Shimada, Yutaka; Meltzer, Stephen J



Modulation of HCV replication after combination antiretroviral therapy in HCV/HIV co-infected patients.  


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

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



Early Life Events Carry Over to Influence Pre-Migratory Condition in a Free-Living Songbird  

PubMed Central

Conditions experienced during development can have long-term consequences for individual success. In migratory songbirds, the proximate mechanisms linking early life events and survival are not well understood because tracking individuals across stages of the annual cycle can be extremely challenging. In this paper, we first use a 13 year dataset to demonstrate a positive relationship between 1st year survival and nestling mass in migratory Savannah sparrows (Passerculus sandwichensis). We also use a brood manipulation experiment to show that nestlings from smaller broods have higher mass in the nest relative to individuals from larger broods. Having established these relationships, we then use three years of field data involving multiple captures of individuals throughout the pre-migratory period and a multi-level path model to examine the hypothesis that conditions during development limit survival during migration by affecting an individual's ability to accumulate sufficient lean tissue and fat mass prior to migration. We found a positive relationship between fat mass during the pre-migratory period (Sept–Oct) and nestling mass and a negative indirect relationship between pre-migratory fat mass and fledging date. Our results provide the first evidence that conditions during development limit survival during migration through their effect on fat stores. These results are particularly important given recent evidence showing that body condition of songbirds at fledging is affected by climate change and anthropogenic changes to landscape structure. PMID:22194925

Mitchell, Greg W.; Guglielmo, Christopher G.; Wheelwright, Nathaniel T.; Freeman-Gallant, Corey R.; Norris, D. Ryan



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

NASA Astrophysics Data System (ADS)

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

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



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. PMID:24783209

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



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. PMID:22037588

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



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. PMID:24766462

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



Phosphorylated Serine Residues and an Arginine-Rich Domain of the Moloney Murine Leukemia Virus p12 Protein Are Required for Early Events of Viral Infection  

Microsoft Academic Search

Mutational analyses of the p12 Gag phosphoprotein of Moloney murine leukemia virus have demonstrated its participation in both virus assembly and the early stages of infection. The molecular mechanisms by which p12 functions in these events are still poorly understood. We performed studies to examine the significance of p12 phosphorylation in the viral life cycle. Alanine substitutions were introduced at

Andrew Yueh; Stephen P. Goff



Early Life Events and Health Outcomes in Late Life in Developing Countries—Evidence from the Mexican Health and Aging Study (MHAS)  

Microsoft Academic Search

In this paper, we focus on the interplay between early life events, socioeco- nomic conditions throughout the life course, and health outcomes at old ages in Mexico. We investigate how the eect of education on health changes as individuals age. We analyze whether the process of accumulation of endur- ing disease states over the life span diers between old Mexicans

Iliana Kohler; Beth J. Soldo


Early Events in Xenograft Development from the Human Embryonic Stem Cell Line HS181 - Resemblance with an Initial Multiple Epiblast Formation  

Microsoft Academic Search

Xenografting is widely used for assessing in vivo pluripotency of human stem cell populations. Here, we report on early to late events in the development of mature experimental teratoma from a well-characterized human embryonic stem cell (HESC) line, HS181. The results show an embryonic process, increasingly chaotic. Active proliferation of the stem cell derived cellular progeny was detected already at

Karin Gertow; Jessica Cedervall; Seema Jamil; Rouknuddin Ali; Marta P. Imreh; Miklos Gulyas; Bengt Sandstedt; Lars Ährlund-Richter



PriA-directed replication fork restart in Escherichia coli  

Microsoft Academic Search

The encounter of a replication fork with either a damaged DNA template, a nick in the template strand or a ‘frozen’ protein–DNA complex can stall the replisome and cause it to fall apart. Such an event generates a requirement for replication fork restart if the cell is going to survive. Recent evidence shows that replication fork restart is effected by

Kenneth J Marians



Replication of hepatitis C virus  

Microsoft Academic Search

Exciting progress has recently been made in understanding the replication of hepatitis C virus, a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. The development of complete cell-culture systems should now enable the systematic dissection of the entire viral lifecycle, providing insights into the hitherto difficult-to-study early and late steps. These efforts have already translated into the

François Penin; Charles M. Rice; Darius Moradpour



DNA replication and chromatin  

Microsoft Academic Search

The study of DNA replication in eukaryotic chromosomes has revealed a multitude of different regulatory levels. Nuclear and chromosomal location as well as chromatin structure may affect the activity of replication origins and their modulation during development.

Susan A Gerbi; Anja-Katrin Bielinsky



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

PubMed Central

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

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



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. PMID:24210825

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



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



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



HARP: A Hierarchical Asynchronous Replication Protocol for Massively Replicated Systems  

E-print Network

HARP: A Hierarchical Asynchronous Replication Protocol for Massively Replicated Systems Noha Adly a Hierarchical Asynchronous Replication Protocol (HARP) that scales well for thousands of replicas while ensuring

Haddadi, Hamed


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.



Dose-response modeling of early molecular and cellular key events in the CAR-mediated hepatocarcinogenesis pathway.  


Low-dose extrapolation and dose-related transitions are paramount in the ongoing debate regarding the quantification of cancer risks for nongenotoxic carcinogens. Phenobarbital (PB) is a prototypical nongenotoxic carcinogen that activates the constitutive androstane receptor (CAR) resulting in rodent liver tumors. In this study, male and female CD-1 mice administered dietary PB at 0, 0.15, 1.5, 15, 75, or 150 mg/kg-day for 2 or 7 days to characterize multiple apical and molecular endpoints below, at (?75 mg/kg-day), and above the carcinogenic dose level of PB and examine these responses using benchmark dose modeling. Linear toxicokinetics were observed for all doses. Increased liver weight, hepatocellular hypertrophy, and mitotic figures were seen at 75 and 150 mg/kg-day. CAR activation, based on Cyp2b qPCR and pentoxyresorufin dealkylase activity, occurred at doses ? 1.5 mg/kg-day. The no-observable transcriptional effect level for global gene expression was 15 mg/kg-day. At 2 days, several xenobiotic metabolism and cell protective pathways were activated at lower doses and to a greater degree in females. However, hepatocellular proliferation, quantified by bromodeoxyuridine immunohistochemistry, was the most sensitive indicator of PB exposure with female mice more sensitive than males, contrary to sex-specific differences in sensitivity to hepatocarcinogenesis. Taken together, the identification of low-dose cellular and molecular transitions in the subtumorigenic dose range aids the understanding of early key events in CAR-mediated hepatocarcinogenesis. PMID:24449422

Geter, David R; Bhat, Virunya S; Gollapudi, B Bhaskar; Sura, Radhakrishna; Hester, Susan D



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

E-print Network

for Early Diagnosis of Alzheimer's Disease Nicholas Stepenosky1 , Deborah Green2 , John Kounios2. Furthermore, considering that most people can live up to 8 ­ 20 years with early intervention, a reliable early diagnosis can not only add years to patient's life, but can significantly increase the quality

Polikar, Robi


Replication in prevention science.  


Replication research is essential for the advancement of any scientific field. In this paper, we argue that prevention science will be better positioned to help improve public health if (a) more replications are conducted; (b) those replications are systematic, thoughtful, and conducted with full knowledge of the trials that have preceded them; and (c) state-of-the art techniques are used to summarize the body of evidence on the effects of the interventions. Under real-world demands it is often not feasible to wait for multiple replications to accumulate before making decisions about intervention adoption. To help individuals and agencies make better decisions about intervention utility, we outline strategies that can be used to help understand the likely direction, size, and range of intervention effects as suggested by the current knowledge base. We also suggest structural changes that could increase the amount and quality of replication research, such as the provision of incentives and a more vigorous pursuit of prospective research registers. Finally, we discuss methods for integrating replications into the roll-out of a program and suggest that strong partnerships with local decision makers are a key component of success in replication research. Our hope is that this paper can highlight the importance of replication and stimulate more discussion of the important elements of the replication process. We are confident that, armed with more and better replications and state-of-the-art review methods, prevention science will be in a better position to positively impact public health. PMID:21541692

Valentine, Jeffrey C; Biglan, Anthony; Boruch, Robert F; Castro, Felipe González; Collins, Linda M; Flay, Brian R; Kellam, Sheppard; Mo?cicki, Eve K; Schinke, Steven P



Iron deficiency anemia as a risk factor for cerebrovascular events in early childhood: a case-control study.  


In recent years, iron-deficiency anemia (IDA) has been suggested to have an association with childhood-onset ischemic stroke in otherwise healthy children, but few cases have proven it thus far. In this study, we aimed to investigate whether iron-deficiency anemia is a risk factor for cerebrovascular events and childhood-onset ischemic stroke in previously healthy children. This was a case-control study that included 21 stroke cases with patients who had previously been generally healthy, and matched with age and gender of 100 healthy control subjects. Patients were included if a diagnosis of definite stroke had been made and other known etiologies of childhood onset stroke were excluded. For all subjects, iron parameters including serum iron, ferritin, transferrin, total iron binding capacity, and transferrin saturation were assessed. We screened all case patients for prothrombotic factors including level of hemoglobin S, protein C, protein S, antithrombin III, lupus anticoagulant, factor V Leiden, and prothrombin gene mutation (G20210A). Brain magnetic resonance images (MRI), magnetic resonance angiography (MRA), and magnetic resonance venography (MRV) were performed to all case patients. All case patients have normal results regarding functional, immunological, and molecular assay for prothrombotic factors screening. Our results showed that IDA was disclosed in 57.1 % of stroke cases with no identified cause, as compared to 26 % of controls. Our study suggest that previously healthy children who developed stroke are 3.8 times more likely to have IDA than healthy children, who do not develop stroke (OR, 3.8; 95 % CI:1.3-11.2 P?=?0.005). In addition, there was significant interaction between IDA and thrombocytosis among studied cases (OR, 10.5; 95 % CI, 1.0-152 P?=?0.02). There were nonsignificant differences between stroke patients with IDA and those with normal iron parameters regarding stroke subtype (P?>?0.05). Public health messages on the importance of early detection of iron-deficiency anemia in young children, especially in our developing countries so that it can be treated before a life-threatening complication like stroke develops. PMID:24141332

Azab, Seham F A; Abdelsalam, Sanaa M; Saleh, Safaa H A; Elbehedy, Rabab M; Lotfy, Sabah M; Esh, Asmaa M H; Srea, Mona A; Aziz, Khalid A



Evolution of GHF5 endoglucanase gene structure in plant-parasitic nematodes: no evidence for an early domain shuffling event  

PubMed Central

Background Endo-1,4-beta-glucanases or cellulases from the glycosyl hydrolase family 5 (GHF5) have been found in numerous bacteria and fungi, and recently also in higher eukaryotes, particularly in plant-parasitic nematodes (PPN). The origin of these genes has been attributed to horizontal gene transfer from bacteria, although there still is a lot of uncertainty about the origin and structure of the ancestral GHF5 PPN endoglucanase. It is not clear whether this ancestral endoglucanase consisted of the whole gene cassette, containing a catalytic domain and a carbohydrate-binding module (CBM, type 2 in PPN and bacteria) or only of the catalytic domain while the CBM2 was retrieved by domain shuffling later in evolution. Previous studies on the evolution of these genes have focused primarily on data of sedentary nematodes, while in this study, extra data from migratory nematodes were included. Results Two new endoglucanases from the migratory nematodes Pratylenchus coffeae and Ditylenchus africanus were included in this study. The latter one is the first gene isolated from a PPN of a different superfamily (Sphaerularioidea); all previously known nematode endoglucanases belong to the superfamily Tylenchoidea (order Rhabditida). Phylogenetic analyses were conducted with the PPN GHF5 endoglucanases and homologous endoglucanases from bacterial and other eukaryotic lineages such as beetles, fungi and plants. No statistical incongruence between the phylogenetic trees deduced from the catalytic domain and the CBM2 was found, which could suggest that both domains have evolved together. Furthermore, based on gene structure data, we inferred a model for the evolution of the GHF5 endoglucanase gene structure in plant-parasitic nematodes. Our data confirm a close relationship between Pratylenchus spp. and the root knot nematodes, while some Radopholus similis endoglucanases are more similar to cyst nematode genes. Conclusion We conclude that the ancestral PPN GHF5 endoglucanase gene most probably consisted of the whole gene cassette, i.e. the GHF5 catalytic domain and the CBM2, rather than that it evolved by domain shuffling. Our evolutionary model for the gene structure in PPN GHF5 endoglucanases implies the occurrence of an early duplication event, and more recent gene duplications at genus or species level. PMID:18980666



Carbon-isotope record of the Early Jurassic (Toarcian) Oceanic Anoxic Event from fossil wood and marine carbonate (Lusitanian Basin, Portugal)  

Microsoft Academic Search

The Toarcian Oceanic Anoxic Event (OAE) in the Early Jurassic (?183 Ma ago) was characterized by widespread near-synchronous deposition of organic-rich shales in marine settings, as well as perturbations to several isotopic systems. Characteristically, two positive carbon-isotope excursions in a range of materials are separated by an abrupt negative shift. Carbon-isotope profiles from Toarcian fossil wood collected in England and Denmark

Stephen P. Hesselbo; Hugh C. Jenkyns; Luis V. Duarte; Luiz C. V. Oliveira



Carbon-isotope record of the Early Jurassic (Toarcian) Oceanic Anoxic Event from fossil wood and marine carbonate (Lusitanian Basin, Portugal)  

Microsoft Academic Search

The Toarcian Oceanic Anoxic Event (OAE) in the Early Jurassic (˜ 183 Ma ago) was characterized by widespread near-synchronous deposition of organic-rich shales in marine settings, as well as perturbations to several isotopic systems. Characteristically, two positive carbon-isotope excursions in a range of materials are separated by an abrupt negative shift. Carbon-isotope profiles from Toarcian fossil wood collected in England

Stephen P. Hesselbo; Hugh C. Jenkyns; Luis V. Duarte; Luiz C. V. Oliveira



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. PMID:20962406

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



Fragile Site Instability in Saccharomyces cerevisiae Causes Loss of Heterozygosity by Mitotic Crossovers and Break-Induced Replication  

PubMed Central

Loss of heterozygosity (LOH) at tumor suppressor loci is a major contributor to cancer initiation and progression. Both deletions and mitotic recombination can lead to LOH. Certain chromosomal loci known as common fragile sites are susceptible to DNA lesions under replication stress, and replication stress is prevalent in early stage tumor cells. There is extensive evidence for deletions stimulated by common fragile sites in tumors, but the role of fragile sites in stimulating mitotic recombination that causes LOH is unknown. Here, we have used the yeast model system to study the relationship between fragile site instability and mitotic recombination that results in LOH. A naturally occurring fragile site, FS2, exists on the right arm of yeast chromosome III, and we have analyzed LOH on this chromosome. We report that the frequency of spontaneous mitotic BIR events resulting in LOH on the right arm of yeast chromosome III is higher than expected, and that replication stress by low levels of polymerase alpha increases mitotic recombination 12-fold. Using single-nucleotide polymorphisms between the two chromosome III homologs, we mapped the locations of recombination events and determined that FS2 is a strong hotspot for both mitotic reciprocal crossovers and break-induced replication events under conditions of replication stress. PMID:24068975

Miller, Shaylynn D.; Casper, Anne M.



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


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



Ostracods and facies of the Early and Middle Frasnian at Devils Gate in Nevada: Relationship to the Alamo Event  

USGS Publications Warehouse

In order to document the Alamo Event and to investigate its influence on shallow-marine environments, we undertook a study of ostracods, conodonts, and analysis of the sedimentology of the lower member of the type Devils Gate Limestone, Six major carbonate microfacies (MF1-MF6) ranging from open-marine environments below storm wave base to pre-evaporitic supratidal lagoons were recognized. The sedimentological study detected no important sedimentological changes during the Alamo Event; only an influx of detrital material and lithoclasts indicate that an unusual event had occurred. Ostracods are generally rare or absent in the lower member of the Devils Gate Limestone, and only 2,000 carapaces, valves and fragments were extracted; from these some 26 taxa were identified. Two new species, Voronina? eureka and Serenida dorsoplicata are proposed. The ostracods belong to the Eifelian Mega-Assemblage and their distribution was influenced by strong salinity variations. Because of the rarity and low diversity of ostracods and conodonts in samples collected from the lower part of the lower member of the Devils Gate Limestone it is not adequate to demonstrate conclusively an extinction event close to the Alamo Event Bed. Nevertheless the greater abundance and diversity of ostracods above this bed seems to indicate that the Alamo Event did not result in significant extinction of ostracod taxa in this shallow water setting. The ostracod fauna present in the lower member of the Devils Gate Limestone suggests faunal exchanges between Nevada and the Russian Platform via the Western Canadian platform.

Casier, J.-G.; Berra, I.; Olempska, E.; Sandberg, C.; Preat, A.



Best practices for mapping replication origins in eukaryotic chromosomes.  


Understanding the regulatory principles ensuring complete DNA replication in each cell division is critical for deciphering the mechanisms that maintain genomic stability. Recent advances in genome sequencing technology facilitated complete mapping of DNA replication sites and helped move the field from observing replication patterns at a handful of single loci to analyzing replication patterns genome-wide. These advances address issues, such as the relationship between replication initiation events, transcription, and chromatin modifications, and identify potential replication origin consensus sequences. This unit summarizes the technological and fundamental aspects of replication profiling and briefly discusses novel insights emerging from mining large datasets, published in the last 3 years, and also describes DNA replication dynamics on a whole-genome scale. Curr. Protoc. Cell Biol. 64:22.18.1-22.18.13. © 2014 by John Wiley & Sons, Inc. PMID:25181303

Besnard, Emilie; Desprat, Romain; Ryan, Michael; Kahli, Malik; Aladjem, Mirit I; Lemaitre, Jean-Marc



Replication Initiation Point Mapping  

Microsoft Academic Search

Replication in eukaryotes is bidirectional and semi-discontinuous. This asymmetry provides the basis for mapping the origin of bidirectional replication (OBR), which is the transition point from discontinuous to continuous synthesis. The regions of each DNA strand complementary to the leading strand or lagging strand can be measured by the methods of imbalanced DNA synthesis or Okazaki fragment distribution, respectively. The

Susan A. Gerbi; Anja-Katrin Bielinsky



Replication in Field Research.  

ERIC Educational Resources Information Center

Suggests the routine use of replications in field studies, pointing out that it is usually possible to synthesize replications quantitatively using meta-analysis. Makes the c ase that this is especially attractive for investigators whose research paradigm choices are limited in the field environment. (SLD)

Schafer, William D.



State-Machine Replication  

E-print Network

State-Machine Replication #12;The Problem Clients Server #12;The Problem Clients Server #12;The (state machine) #12;The Solution 1. Make server deterministic (state machine) State machine #12;The Solution 1. Make server deterministic (state machine) 2. Replicate server State machines #12;The Solution 1

Venkataramani, Arun


Replicative intermediates of maize streak virus found during leaf development.  


Geminiviruses of the genera Begomovirus and Curtovirus utilize three replication modes: complementary-strand replication (CSR), rolling-circle replication (RCR) and recombination-dependent replication (RDR). Using two-dimensional gel electrophoresis, we now show for the first time that maize streak virus (MSV), the type member of the most divergent geminivirus genus, Mastrevirus, does the same. Although mastreviruses have fewer regulatory genes than other geminiviruses and uniquely express their replication-associated protein (Rep) from a spliced transcript, the replicative intermediates of CSR, RCR and RDR could be detected unequivocally within infected maize tissues. All replicative intermediates accumulated early and, to varying degrees, were already present in the shoot apex and leaves at different maturation stages. Relative to other replicative intermediates, those associated with RCR increased in prevalence during leaf maturation. Interestingly, in addition to RCR-associated DNA forms seen in other geminiviruses, MSV also apparently uses dimeric open circular DNA as a template for RCR. PMID:20032206

Erdmann, Julia B; Shepherd, Dionne N; Martin, Darren P; Varsani, Arvind; Rybicki, Edward P; Jeske, Holger



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

NASA Astrophysics Data System (ADS)

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

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



A major Late Devonian-Early Carboniferous (Hercynian) Thermotectonic event at the NW Margin of the Arabian-Nubian Shield: Evidence from zircon fission track dating  

NASA Astrophysics Data System (ADS)

Zircon fission track (ZFT) ages of 17 Precambrian samples from deep boreholes and outcrops in southern Israel and Sinai fall within the range 328-373 Ma (Late Devonian-Early Carboniferous). Single zircon grain age distributions are unimodal with a high chi-square probability. The age data indicate total resetting of the ZFT clocks but only partial resetting of coexisting sphenes, constraining the temperatures attained to about 225° ± 50°C, followed by relatively rapid regional cooling at the times indicated. In the study area, the lower Paleozoic section presently overlying Precambrian rocks is limited to Cambrian strata, up to 300 m thick. Further, stratigraphic evidence for sub-Carboniferous erosion is preserved only in SW Sinai. To the east, in southern Jordan, a 2-2.5 km thick lower Paleozoic succession is reported. Despite the lack of stratigraphic evidence in the study area, the ZFT data (1) strongly suggest that an equivalent or thicker section also existed, (2) constrain the timing of the erosion to Late Devonian-Early Carboniferous (Hercynian), and (3) indicate that thermal gradients may have reached ?50°C/km prior to the uplift/erosion event. Regional stratigraphic evidence indicates that the Late Devonian-Early Carboniferous event was confined to a relatively narrow belt extending from the Gulf of Suez area to the vicinity of NE Syria and SE Turkey.

Kohn, B. P.; Eyal, M.; Feinstein, S.



Inhibition of Influenza Virus Replication by Targeting Broad Host Cell Pathways  

PubMed Central

Antivirals that are currently used to treat influenza virus infections target components of the virus which can mutate rapidly. Consequently, there has been an increase in the number of resistant strains to one or many antivirals in recent years. Here we compared the antiviral effects of lysosomotropic alkalinizing agents (LAAs) and calcium modulators (CMs), which interfere with crucial events in the influenza virus replication cycle, against avian, swine, and human viruses of different subtypes in MDCK cells. We observed that treatment with LAAs, CMs, or a combination of both, significantly inhibited viral replication. Moreover, the drugs were effective even when they were administered 8 h after infection. Finally, analysis of the expression of viral acidic polymerase (PA) revealed that both drugs classes interfered with early events in the viral replication cycle. This study demonstrates that targeting broad host cellular pathways can be an efficient strategy to inhibit influenza replication. Furthermore, it provides an interesting avenue for drug development where resistance by the virus might be reduced since the virus is not targeted directly. PMID:25333287

Marois, Isabelle; Cloutier, Alexandre; Meunier, Isabelle; Weingartl, Hana M.; Cantin, Andre M.; Richter, Martin V.



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


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

Mansilla, Sabrina F; Soria, Gastón; Vallerga, María Belén; Habif, Martín; Martínez-López, Wilner; Prives, Carol; Gottifredi, Vanesa



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

E-print Network

Neuquén Basin carbon isotopes tuff layers zircon U­Pb dating Karoo Basin New data from a Lower Jurassic mechanism for the Toarcian Oceanic Anoxic Event (TOAE) and the associated negative carbon isotope excursion discovered in the section. Dating by ID-TIMS of zircons from two tuff beds located within the carbon isotope

Svensen, Henrik


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

Microsoft Academic Search

We explore the hypothesis that the abrupt drainage of Laurentide lakes and associated rapid switch of the North Atlantic thermohaline circulation 8200 yr ago had a catastrophic influence on Neolithic civilisation in large parts of southeastern Europe, Anatolia, Cyprus, and the Near East. The event at 8200 cal yr BP is observed in a large number of high-resolution climate proxies in the

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



Developmental events in differentiating floral buds of four olive ( Olea europaea L.) cultivars during late winter to early spring  

Microsoft Academic Search

The olive tree (Olea europaea L.) is a very important evergreen fruit tree because of the high interest of olive oil and table olives in the human diet. Differentiation of olive floral buds during winter is strictly related to flowering during spring and finally to fruit production during autumn–winter. In order to determine which are the developmental events in differentiating

Christina K. Kitsaki; Evagelos Andreadis; Dimitris L. Bouranis



Collapse of mitochondrial membrane potential and caspases activation are early events in okadaic acid-treated Caco-2 cells  

Microsoft Academic Search

Diarrhetic Shellfish Poisoning (DSP) results from the consumption of shellfish contaminated with okadaic acid (OA) or one of the dinophysistoxins (DTX). It has been reported that this toxin induces apoptosis in several cell models, but the molecular events involved in this process have not been clarified. In this report we studied intracellular signals induced by OA in Caco-2 cells: mitochondrial

Jorge Lago; Francisco Santaclara; Juan M. Vieites; Ana G. Cabado



Cognitive testing in early phase clinical trials: outcome according to adverse event profile in a Phase I studyy  

Microsoft Academic Search

Background It has been proposed that objective cognitive testing provides additional information to that collected via adverse event (AE) recordings. However, in clinical trials of compounds with potentially negative effects on cognition, the results of cognitive testing may overlap with AE recordings. Aims To examine cognitive function in subjects who do and do not report sedation-related AEs in a Phase

Alex Collie; Paul Maruff; Peter J. Snyder; Amanda Darekar; John P. Huggins


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



Effects of adverse early-life events on aggression and anti-social behaviours in animals and humans.  


We review the impact of early adversities on the development of violence and antisocial behaviour in humans, and present three aetiological animal models of escalated rodent aggression, each disentangling the consequences of one particular adverse early-life factor. A review of the human data, as well as those obtained with the animal models of repeated maternal separation, post-weaning social isolation and peripubertal stress, clearly shows that adverse developmental conditions strongly affect aggressive behaviour displayed in adulthood, the emotional responses to social challenges and the neuronal mechanisms activated by conflict. Although similarities between models are evident, important differences were also noted, demonstrating that the behavioural, emotional and neuronal consequences of early adversities are to a large extent dependent on aetiological factors. These findings support recent theories on human aggression, which suggest that particular developmental trajectories lead to specific forms of aggressive behaviour and brain dysfunctions. However, dissecting the roles of particular aetiological factors in humans is difficult because these occur in various combinations; in addition, the neuroscientific tools employed in humans still lack the depth of analysis of those used in animal research. We suggest that the analytical approach of the rodent models presented here may be successfully used to complement human findings and to develop integrative models of the complex relationship between early adversity, brain development and aggressive behaviour. PMID:25059307

Haller, J; Harold, G; Sandi, C; Neumann, I D



Mid-Cimmerian, Early Alpine and Late Cenozoic orogenic events in the Shotur Kuh metamorphic complex, Great Kavir block, NE Iran  

NASA Astrophysics Data System (ADS)

The Shotur Kuh complex, exposed in the NE part of the Great Kavir block, is composed of amphibolite facies metaigneous rocks and micaschist, and of lower-grade Permian-Miocene cover sequences that experienced four main deformation phases and at least two metamorphic events. The D1 deformation phase is associated with a prograde metamorphism that in the basement reached amphibolite facies conditions. This Barrovian-type metamorphism with field gradient of 20-22 °C/km was related to collision-induced crustal thickening. The D2 event corresponds to post-collisional exhumational upflow of middle crust, resulting in updoming of the basement core and its top-to-the-Northwest unroofing along a low-angle detachment shear zone at the basement/cover boundary. The D1 and D2 events are considered as Mid-Cimmerian in age because they also affected the Upper Triassic-Lower Jurassic Shemshak Formation and are sealed by the Middle Jurassic conglomerates. The D3 folding event, characterised by NE-SW shortening, also affected the Cretaceous limestones, and it is sealed by Paleocene conglomerates. Considering the Late Cretaceous age of this deformation, it is related to the Late Cimmerian-Early Alpine orogeny that resulted from the Cenozoic closure of the Neo-Tethys oceanic tract(s) and convergence between the Arabian and Eurasian plates. The D4 folding event, characterised by NW-SE shortening, also affected the Miocene conglomerates, suggesting its Miocene or post-Miocene age. This deformation event is associated with Late Cenozoic convergence between Arabia and Eurasia, and it could be combined with a left-lateral activity along the Great Kavir fault-bounding system.

Rahmati-Ilkhchi, Mahmoud; Je?ábek, Petr; Faryad, Shah Wali; Koyi, Hemin A.



Rumination as a mechanism linking stressful life events to symptoms of depression and anxiety: longitudinal evidence in early adolescents and adults.  


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

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



Evaluation of early healing events around mesenchymal stem cell-seeded collagen–glycosaminoglycan scaffold. An experimental study in Wistar rats  

Microsoft Academic Search

Purpose  Tissue engineering using cell-seeded biodegradable scaffolds offers a new bone regenerative approach that might circumvent\\u000a many of the limitations of current therapeutic modalities. The aim of this experiment was to study the early healing events\\u000a around mesenchymal stem cell-seeded collagen–glycosaminoglycan scaffolds.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  The 5-mm critical size defects were created in the calvarial bones of 41 Wistar rats. The defects were either

Mohamed Alhag; Eric Farrell; Mary Toner; Noel Claffey; T. Clive Lee; Fergal O’Brien



The critical early proinflammatory events associated with idiopathic pneumonia syndrome in irradiated murine allogeneic recipients are due to donor T cell infusion and potentiated by cyclophosphamide.  

PubMed Central

We have hypothesized that lung damage occurring in the peri-bone marrow transplant (BMT) period is critical for the subsequent generation of idiopathic pneumonia syndrome (IPS), a major complication following human BMT. The proinflammatory events induced by a common pre-BMT conditioning regimen, cyclophosphamide (Cytoxan(R)) (Cy) and total body irradiation, were analyzed in a murine BMT model. Electron microscopy indicated that Cy exacerbated irradiation-induced epithelial cell injury as early as day 3 after BMT. Allogenicity was an important contributing factor to lung injury as measured by lung wet and dry weights and decreased specific lung compliance. The most significant pulmonary dysfunction was seen in mice receiving both allogeneic T cells and Cy conditioning. IPS was associated with an influx of T cells, macrophages, and neutrophils early post-BMT. Hydroxyproline levels were not increased, indicating that the injury was not fibrotic early post-BMT. As early as 2 h after chemoradiation, host macrophages increased in number in the lung parenchyma. Continued increases in macrophages occurred if splenic T cells were administered with the donor graft. The expression of costimulatory B7 molecules correlated with macrophage numbers. Frequencies of cells expressing mRNA for the inflammatory proteins TNF-alpha, IL-1beta, and TGFbeta were increased. Cy accelerated the upregulation of TGFbeta and increase in host macrophages. The exacerbation of macrophage activation and severity of IPS was dependent on allogeneic T cells, implicating immune-mediated mechanisms as critical to the outcome of IPS. This demonstration of early injury after BMT indicates the need for very early therapeutic intervention before lung damage becomes profound and irreversible. PMID:9276718

Panoskaltsis-Mortari, A; Taylor, P A; Yaeger, T M; Wangensteen, O D; Bitterman, P B; Ingbar, D H; Vallera, D A; Blazar, B R



Survivin-Responsive Conditionally Replicating Adenovirus Exhibits Cancer-Specific and Efficient Viral Replication  

Microsoft Academic Search

Although a conditionally replicating adenovirus (CRA) exhibiting cancer-selective replication and induction of cell death is an innovative potential anticancer agent, current imperfections in cancer specificity and efficient viral replica- tion limit the usefulness of this technique. Here, we cons- tructed survivin-responsive CRAs (Surv.CRAs), in which expression of the wild-type or mutant adenoviral early region 1A (E1A) gene is regulated by

Junichi Kamizono; Satoshi Nagano; Yoshiteru Murofushi; Setsuro Komiya; Hisayoshi Fujiwara; Toyojiro Matsuishi; Ken-ichiro Kosai



Early events in xenograft development from the human embryonic stem cell line HS181--resemblance with an initial multiple epiblast formation.  


Xenografting is widely used for assessing in vivo pluripotency of human stem cell populations. Here, we report on early to late events in the development of mature experimental teratoma from a well-characterized human embryonic stem cell (HESC) line, HS181. The results show an embryonic process, increasingly chaotic. Active proliferation of the stem cell derived cellular progeny was detected already at day 5, and characterized by the appearance of multiple sites of engraftment, with structures of single or pseudostratified columnar epithelium surrounding small cavities. The striking histological resemblance to developing embryonic ectoderm, and the formation of epiblast-like structures was supported by the expression of the markers OCT4, NANOG, SSEA-4 and KLF4, but a lack of REX1. The early neural marker NESTIN was uniformly expressed, while markers linked to gastrulation, such as BMP-4, NODAL or BRACHYURY were not detected. Thus, observations on day 5 indicated differentiation comparable to the most early transient cell populations in human post implantation development. Confirming and expanding on previous findings from HS181 xenografts, these early events were followed by an increasingly chaotic development, incorporated in the formation of a benign teratoma with complex embryonic components. In the mature HS181 teratomas not all types of organs/tissues were detected, indicating a restricted differentiation, and a lack of adequate spatial developmental cues during the further teratoma formation. Uniquely, a kinetic alignment of rare complex structures was made to human embryos at diagnosed gestation stages, showing minor kinetic deviations between HS181 teratoma and the human counterpart. PMID:22140465

Gertow, Karin; Cedervall, Jessica; Jamil, Seema; Ali, Rouknuddin; Imreh, Marta P; Gulyas, Miklos; Sandstedt, Bengt; Ahrlund-Richter, Lars



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

Microsoft Academic Search

This study modeled children’s trajectories of teacher rated aggressive-disruptive behavior problems assessed at six time points\\u000a between the ages of 6 and 11 and explored the likelihood of being exposed to DSM-IV qualifying traumatic events and posttraumatic\\u000a stress disorder (PTSD) in 837 urban first graders (71% African American) followed-up for 15 years. Childhood trajectories\\u000a of chronic high or increasing aggressive-disruptive behavior

Carla L. Storr; Cindy M. Schaeffer; Hanno Petras; Nicholas S. Ialongo; Naomi Breslau



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. PMID:22664974

Stefanidou, Martha; Herrera, Carolina; Armanasco, Naomi



Early holocene high magnitude debris flow events and environmental change as illustrated by the Moxi Platform, Hengduan Mountains, SW China  

Microsoft Academic Search

Thick debris flow deposits in the Hengduan Mountains of southwestern China record landscape instability at the close of the\\u000a last glaciation and in the early Holocene. The deposits, ranging in thickness from 100 to 200 m, are common and in high magnitude\\u000a in the valleys of this region. They are products of large debris flows induced by glacier and enabled

Junyan Zhang; Genwei Cheng; Yongfei Li



Reduction in Mitochondrial Membrane Potential Is an Early Event in Fas-Independent CTL-Mediated Apoptosis  

Microsoft Academic Search

Cytotoxic T lymphocytes (CTL) can destroy target cells via the Fas-mediated pathway or the granule-mediated pathway. We used Fas-negative target cells to examine for target-cell reduction in mitochondrial membrane potential (??m) induced by intact CTL via the granule-mediated pathway. We find that reduction in ??m is an early step in Fas-independent CTL killing of target cells that precedes phosphatidyl serine

Dan Hu; Thomas J. Kipps



Time-Resolved Human Kinome RNAi Screen Identifies a Network Regulating Mitotic-Events as Early Regulators of Cell Proliferation  

Microsoft Academic Search

Analysis of biological processes is frequently performed with the help of phenotypic assays where data is mostly acquired in single end-point analysis. Alternative phenotypic profiling techniques are desired where time-series information is essential to the biological question, for instance to differentiate early and late regulators of cell proliferation in loss-of-function studies. So far there is no study addressing this question

Jitao David Zhang; Cindy Koerner; Stephanie Bechtel; Christian Bender; Ioanna Keklikoglou; Christian Schmidt; Anja Irsigler; Ute Ernst; Özgür Sahin; Stefan Wiemann; Ulrich Tschulena



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


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 Ca(2+) concentration ([Ca(2+)]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 [Ca(2+)]cyt increase and singlet oxygen production, do not seem to be involved in PCD. PMID:24420571

Monetti, Emanuela; Kadono, Takashi; Tran, Daniel; Azzarello, Elisa; Arbelet-Bonnin, Delphine; Biligui, Bernadette; Briand, Joël; Kawano, Tomonori; Mancuso, Stefano; Bouteau, François



Analysis of Different Device-Based Intrathoracic Impedance Vectors for Detection of Heart Failure Events (from the Detect Fluid Early from Intrathoracic Impedance Monitoring Study).  


Detect Fluid Early from Intrathoracic Impedance Monitoring (DEFEAT-PE) is a prospective, multicenter study of multiple intrathoracic impedance vectors to detect pulmonary congestion (PC) events. Changes in intrathoracic impedance between the right ventricular (RV) coil and device can (RVcoil?Can) of implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy ICDs (CRT-Ds) are used clinically for the detection of PC events, but other impedance vectors and algorithms have not been studied prospectively. An initial 75-patient study was used to derive optimal impedance vectors to detect PC events, with 2 vector combinations selected for prospective analysis in DEFEAT-PE (ICD vectors: RVring?Can + RVcoil?Can, detection threshold 13 days; CRT-D vectors: left ventricular ring?Can + RVcoil?Can, detection threshold 14 days). Impedance changes were considered true positive if detected <30 days before an adjudicated PC event. One hundred sixty-two patients were enrolled (80 with ICDs and 82 with CRT-Ds), all with ?1 previous PC event. One hundred forty-four patients provided study data, with 214 patient-years of follow-up and 139 PC events. Sensitivity for PC events of the prespecified algorithms was as follows: ICD: sensitivity 32.3%, false-positive rate 1.28 per patient-year; CRT-D: sensitivity 32.4%, false-positive rate 1.66 per patient-year. An alternative algorithm, ultimately approved by the US Food and Drug Administration (RVring?Can + RVcoil?Can, detection threshold 14 days), resulted in (for all patients) sensitivity of 21.6% and a false-positive rate of 0.9 per patient-year. The CRT-D thoracic impedance vector algorithm selected in the derivation study was not superior to the ICD algorithm RVring?Can + RVcoil?Can when studied prospectively. In conclusion, to achieve an acceptably low false-positive rate, the intrathoracic impedance algorithms studied in DEFEAT-PE resulted in low sensitivity for the prediction of heart failure events. PMID:25150135

Heist, E Kevin; Herre, John M; Binkley, Philip F; Van Bakel, Adrian B; Porterfield, James G; Porterfield, Linda M; Qu, Fujian; Turkel, Melanie; Pavri, Behzad B



Functional interactions of DNA topoisomerases with a human replication origin  

Microsoft Academic Search

The human DNA replication origin, located in the lamin B2 gene, interacts with the DNA topoisomerases I and II in a cell cycle-modulated manner. The topoisomerases inter- act in vivo and in vitro with precise bonds ahead of the start sites of bidirectional replication, within the pre- replicative complex region; topoisomerase I is bound in M, early G1 and G1\\/S

Gulnara Abdurashidova; Sorina Radulescu; Oscar Sandoval; Sotir Zahariev; Miltcho B Danailov; Alexander Demidovich; Laura Santamaria; Giuseppe Biamonti; Silvano Riva; Arturo Falaschi



Stringent control of replication of plasmids derived from coliphage ?  

Microsoft Academic Search

The first events of ? plasmid replication in vivo, which probably regulate this process, are the transcriptional activation of the origin of replication by RNA polymerase and the binding of the initiator protein, ?O, to this nucleotide sequence. The ?O protein is known for its rapid proteolytic degradation; hence amino acid starvation of Escherichia coli should result in inhibiton of

Grzegorz Wegrzyn; Peter Neubauer; Steffen Krueger; Michael Hecker; Karol Taylor



A porin-like protein from oral secretions of Spodoptera littoralis larvae induces defense-related early events in plant leaves.  


Insect herbivory on plants is a complex incident consisting of at least two different aspects, namely mechanical damage and chemical challenge, as feeding insects introduce oral secretions (OS) into the wounded tissue of the attacked plant. Mechanical wounding alone is sufficient to induce a set of defense-related reactions in host plants, but some early events such as membrane potential (Vm) changes and cytosolic Ca²?-elevations can be triggered only by herbivores suggesting that OS-derived molecules are involved in those processes. Following an assay-guided purification based on planar lipid bilayer membrane technique in combination with proteomic analysis, a porin-like protein (PLP) of most likely bacterial origin was determined from collected OS of Spodoptera littoralis larvae. PLP exhibited channel-forming activity. Further, early defense-related events in plant-insect interaction were evaluated by using a purified fraction and ?-hemolysin (?-HL) as a commercial pore-forming compound. Both up-regulated the calmodulin-like CML42 in Arabidopsis thaliana, which only responds to oral secretion and not to wounding. An elevation of in vivo [Ca²?](cyt) was not observed. Because membrane channel formation is a widespread phenomenon in plant-insect interactions, this PLP might represent an example for microbial compounds from the insect gut which are initially involved in plant-insect interactions. PMID:23845235

Guo, Huijuan; Wielsch, Natalie; Hafke, Jens B; Svatoš, Aleš; Mithöfer, Axel; Boland, Wilhelm



Physical activity, additional breast cancer events, and mortality among early-stage breast cancer survivors: findings from the WHEL Study  

Microsoft Academic Search

Objective  Research suggests that physical activity is associated with improved breast cancer survival, yet no studies have examined\\u000a the association between post-diagnosis changes in physical activity and breast cancer outcomes. The aim of this study was\\u000a to determine whether baseline activity and 1-year change in activity are associated with breast cancer events or mortality.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  A total of 2,361 post-treatment breast cancer

Lisa A. Cadmus Bertram; Marcia L. Stefanick; Nazmus Saquib; Loki Natarajan; Ruth E. Patterson; Wayne Bardwell; Shirley W. Flatt; Vicky A. Newman; Cheryl L. Rock; Cynthia A. Thomson; John P. Pierce



Modeling DNA Replication Intermediates  

SciTech Connect

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

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



Alterations in fatty acid utilization and an impaired antioxidant defense mechanism are early events in podocyte injury: a proteomic analysis.  


Ultrastructural alterations of podocytes are closely associated with loss of glomerular filtration function. In the present study, we explored changes at the proteome level that paralleled the disturbances of podocyte architecture in the early stages of puromycin aminonucleoside (PA) nephrosis in vivo. Using two-dimensional fluorescence difference gel electrophoresis and vacuum matrix-assisted laser desorption/ionization mass spectrometry combined with postsource decay fragment ion analysis and high-energy collision-induced dissociation tandem mass spectrometry, 23 differentially expressed protein spots, corresponding to 16 glomerular proteins that are involved in various cellular functions, were unambiguously identified, and a subset was corroborated by Western blot analysis. The majority of these proteins were primarily related to fatty acid metabolism and redox regulation. Key enzymes of the mitochondrial beta-oxidation pathway and antioxidant enzymes were consistently down-regulated in PA nephrosis. These changes were paralleled by increased expression levels of CD36. PA treatment of murine podocytes in culture resembled these specific protein changes in vitro. In this cell system, the modulatory effects of albumin-bound fatty acids on the expression levels of Mn-superoxide dismutase in response to PA were demonstrated as well. Taken together, these results indicate that a disrupted fatty acid metabolism in concert with an impaired antioxidant defense mechanism in podocytes may play a role in the early stages of PA-induced lesions in podocytes. PMID:19264907

Mayrhofer, Corina; Krieger, Sigurd; Huttary, Nicole; Chang, Martina Wei-Fen; Grillari, Johannes; Allmaier, Günter; Kerjaschki, Dontscho



More evidence for a glacial world prior to the middle Miocene oxygen-isotope enrichment event: resolution of early Miocene glacioeustatic sea-level cyclicity from North Carolina  

SciTech Connect

Benthic delta/sup 18/O analyses from DSDP sites worldwide have documented a positive excursion (similarly ordered + 1.5%) through the early-middle Miocene. These data are traditionally interpreted as marking the transition from an ice-free world to one that was extensively glaciated. Recently, however, this doctrine has been challenged, and an alternative hypothesis suggests the benthic delta/sup 18/O excursion primarily reflects a temperature drop within a previously glaciated world. Within the North Carolina continental margin, a chronostratigraphic framework consisting of 6 discrete early Miocene depositional sequences was established via stratigraphic interpretations from over 21,000 Km of high-resolution seismic reflection profiles. Each sequence is bound by unconformities which were mapped throughout the continental margin. Biostratigraphic analyses of 140 vibracores penetrating these sequences demonstrate that each sequence is a consequence of 4th-order (10/sup 5/yrs) sea-level cyclicity, similar in duration (100-300 Ka) and amplitude (100-150 m) to the glacioeustatic sea-level fluctuations of the Quaternary Epoch. Recognition of late Burdigalian high-frequency (4th-order) sea-level cyclicity demonstrates that continental ice-sheets were large enough during the early Miocene to drive eustatic sea-level fluctuations with Milankovitch-type periodicities. This further supports Matthews (1984) hypothesis that continental ice-caps existed on Antarctica PRIOR to the well-documented middle Miocene benthic delta/sup 18/O global enrichment event.

Synder, S.W.; Synder, S.W.; Waters, V.J.; Steinmetz, J.C.; Hine, A.C.; Riggs, S.R.



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. PMID:22489141

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



Replicated Composite Optics Development  

NASA Technical Reports Server (NTRS)

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

Engelhaupt, Darell



Replication of the Baculovirus Genome  

Microsoft Academic Search

The review describes the current state of studying the baculovirus DNA replication. The structural organization of replication initiation sites and replication intermediates are considered. Attention is focused on virus replication factors, including DNA polymerase, helicase, IE-1, LEF-1, LEF-2, and LEF-3.

V. S. Mikhailov



BRCA1 Promotes Unloading of the CMG Helicase from a Stalled DNA Replication Fork.  


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

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



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


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



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


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



The Significance of Replication  

Microsoft Academic Search

Much has been made of an apparent lack of reproducibility in so called ``cold fusion'' experiments. In this paper we will demonstrate that this failure, while real, was the result of inability to meet critical threshold criteria: a thermodynamic loading, dynamic flux and disequilibrium trigger. Recent experiments, performed independently at SRI and ENEA, have successfully replicated powerful excess heat results

Michael C. H. McKrubre; Francis L. Tanzella; Vittorio Violante



SIMS Replications in Ontario.  

ERIC Educational Resources Information Center

Replication of the Second International Mathematics Study (SIMS) in Ontario, Canada, is described and assessed. The curriculum and testing program covers numerical methods, geometry, and algebra. Whereas classical studies focused on mean scores of a system's students and on percentages of teachers for opportunity to learn (OTL), SIMS aggregates…

Russell, Howard


How telomeres are replicated  

Microsoft Academic Search

The replication of the ends of linear chromosomes, or telomeres, poses unique problems, which must be solved to maintain genome integrity and to allow cell division to occur. Here, we describe and compare the timing and specific mechanisms that are required to initiate, control and coordinate synthesis of the leading and lagging strands at telomeres in yeasts, ciliates and mammals.

Eric Gilson; Vincent Géli



Replicated spectrographs in astronomy  

NASA Astrophysics Data System (ADS)

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

Hill, Gary J.



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



Replicative DNA polymerases.  


In 1959, Arthur Kornberg was awarded the Nobel Prize for his work on the principles by which DNA is duplicated by DNA polymerases. Since then, it has been confirmed in all branches of life that replicative DNA polymerases require a single-stranded template to build a complementary strand, but they cannot start a new DNA strand de novo. Thus, they also depend on a primase, which generally assembles a short RNA primer to provide a 3'-OH that can be extended by the replicative DNA polymerase. The general principles that (1) a helicase unwinds the double-stranded DNA, (2) single-stranded DNA-binding proteins stabilize the single-stranded DNA, (3) a primase builds a short RNA primer, and (4) a clamp loader loads a clamp to (5) facilitate the loading and processivity of the replicative polymerase, are well conserved among all species. Replication of the genome is remarkably robust and is performed with high fidelity even in extreme environments. Work over the last decade or so has confirmed (6) that a common two-metal ion-promoted mechanism exists for the nucleotidyltransferase reaction that builds DNA strands, and (7) that the replicative DNA polymerases always act as a key component of larger multiprotein assemblies, termed replisomes. Furthermore (8), the integrity of replisomes is maintained by multiple protein-protein and protein-DNA interactions, many of which are inherently weak. This enables large conformational changes to occur without dissociation of replisome components, and also means that in general replisomes cannot be isolated intact. PMID:23732474

Johansson, Erik; Dixon, Nicholas



Multifaceted Regulation of Translational Readthrough by RNA Replication Elements in a Tombusvirus  

PubMed Central

Translational readthrough of stop codons by ribosomes is a recoding event used by a variety of viruses, including plus-strand RNA tombusviruses. Translation of the viral RNA-dependent RNA polymerase (RdRp) in tombusviruses is mediated using this strategy and we have investigated this process using a variety of in vitro and in vivo approaches. Our results indicate that readthrough generating the RdRp requires a novel long-range RNA-RNA interaction, spanning a distance of ?3.5 kb, which occurs between a large RNA stem-loop located 3'-proximal to the stop codon and an RNA replication structure termed RIV at the 3'-end of the viral genome. Interestingly, this long-distance RNA-RNA interaction is modulated by mutually-exclusive RNA structures in RIV that represent a type of RNA switch. Moreover, a different long-range RNA-RNA interaction that was previously shown to be necessary for viral RNA replicase assembly was also required for efficient readthrough production of the RdRp. Accordingly, multiple replication-associated RNA elements are involved in modulating the readthrough event in tombusviruses and we propose an integrated mechanistic model to describe how this regulatory network could be advantageous by (i) providing a quality control system for culling truncated viral genomes at an early stage in the replication process, (ii) mediating cis-preferential replication of viral genomes, and (iii) coordinating translational readthrough of the RdRp with viral genome replication. Based on comparative sequence analysis and experimental data, basic elements of this regulatory model extend to other members of Tombusviridae, as well as to viruses outside of this family. PMID:22174683

Cimino, Peter A.; Nicholson, Beth L.; Wu, Baodong; Xu, Wei; White, K. Andrew



Evidence for Proterozoic and late Cretaceous-early Tertiary ore-forming events in the Coeur d'Alene district, Idaho and Montana  

USGS Publications Warehouse

New 40Ar/39Ar age spectra on sericite and lead isotope data on tetrahedrite, siderite, galena, bournonite, and stibnite, together with previously published isotopic, geochemical, and geologic studies provide evidence for two major vein-forming events in the Coeur d'Alene district and surrounding area of the Belt basin. The data suggest that the zinc- and lead-rich veins (e.g., Bunker Hill and Star-Morning mines) formed in the Proterozoic (1.0 Ga), whereas the silver-rich veins (e.g., Silver belt mines), antimony veins (e.g., US Antimony mine), and gold-bearing quartz veins (Murry subdistrict) formed in Late Cretaceous to early Tertiary time.

Leach, D. L.; Hofstra, A. H.; Church, S. E.; Snee, L. W.; Vaughn, R. B.; Zartman, R. E.



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

SciTech Connect

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

Trompezinski, Sandra; Migdal, Camille [EA 41-69, Universite Lyon 1, Pavillon R, Hopital Edouard Herriot, Lyon (France); Tailhardat, Magalie; Le Varlet, Beatrice; Courtellemont, Pascal [LVMH Recherche, St Jean de Braye (France); Haftek, Marek [EA 41-69, Universite Lyon 1, Pavillon R, Hopital Edouard Herriot, Lyon (France); Serres, Mireille [EA 41-69, Universite Lyon 1, Pavillon R, Hopital Edouard Herriot, Lyon (France)], E-mail:



Defective Mitochondrial Dynamics Is an Early Event in Skeletal Muscle of an Amyotrophic Lateral Sclerosis Mouse Model  

PubMed Central

Mitochondria are dynamic organelles that constantly undergo fusion and fission to maintain their normal functionality. Impairment of mitochondrial dynamics is implicated in various neurodegenerative disorders. Amyotrophic lateral sclerosis (ALS) is an adult-onset neuromuscular degenerative disorder characterized by motor neuron death and muscle atrophy. ALS onset and progression clearly involve motor neuron degeneration but accumulating evidence suggests primary muscle pathology may also be involved. Here, we examined mitochondrial dynamics in live skeletal muscle of an ALS mouse model (G93A) harboring a superoxide dismutase mutation (SOD1G93A). Using confocal microscopy combined with overexpression of mitochondria-targeted photoactivatable fluorescent proteins, we discovered abnormal mitochondrial dynamics in skeletal muscle of young G93A mice before disease onset. We further demonstrated that similar abnormalities in mitochondrial dynamics were induced by overexpression of mutant SOD1G93A in skeletal muscle of normal mice, indicating the SOD1 mutation drives ALS-like muscle pathology in the absence of motor neuron degeneration. Mutant SOD1G93A forms aggregates inside muscle mitochondria and leads to fragmentation of the mitochondrial network as well as mitochondrial depolarization. Partial depolarization of mitochondrial membrane potential in normal muscle by carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) caused abnormalities in mitochondrial dynamics similar to that in the SOD1G93A model muscle. A specific mitochondrial fission inhibitor (Mdivi-1) reversed the SOD1G93A action on mitochondrial dynamics, indicating SOD1G93A likely promotes mitochondrial fission process. Our results suggest that accumulation of mutant SOD1G93A inside mitochondria, depolarization of mitochondrial membrane potential and abnormal mitochondrial dynamics are causally linked and cause intrinsic muscle pathology, which occurs early in the course of ALS and may actively promote ALS progression. PMID:24324755

Luo, Guo; Yi, Jianxun; Ma, Changling; Xiao, Yajuan; Yi, Frank; Yu, Tian; Zhou, Jingsong



Carcinogen exposure differentially modulates RAR-beta promoter hypermethylation, an early and frequent event in mouse lung carcinogenesis.  


The retinoic acid receptor beta (RAR-beta) gene encodes one of the primary receptors for retinoic acid, an important signaling molecule in lung growth, differentiation and carcinogenesis. RAR-beta has been shown to be down-regulated by methylation in human lung cancer. We have used previously lung tumors induced in mice to evaluate the timing and effect of specific carcinogen exposures on targeting genes altered in human lung cancer. These studies were extended to characterize the role of methylation of the RAR-beta gene in murine lung cancers. After treatment with the demethylating agent 5-aza-2'-deoxycytidine (DAC), RAR-beta was re-expressed in silenced cell lines or expressed at a higher rate than without DAC, supporting methylation as the inactivating mechanism. Bisulfite sequencing detected dense methylation in the area of the CpG island that contained the 5' untranslated region and the first translated exon in non-expressing cell lines, compared with minimal and heterogeneous methylation in normal mouse lung. Methylation-specific PCR revealed that this gene is targeted differentially by carcinogen exposures with the detection of methylated alleles in virtually all primary tumors associated with cigarette smoke or 4-methylnitrosamino-1-(3-pyridyl)-butanone (NNK) in contrast to half of tumors induced by methylene chloride or vinyl carbamate. RAR-beta methylation was also detected in 54% of preneoplastic hyperplasias induced by treatment with NNK. Bisulfite sequencing of both premalignant and malignant lesions detected dense methylation in the same area observed in cell lines, substantiating that this gene is functionally inactivated at the earliest histologic stage of adenocarcinoma development. These studies demonstrate that aberrant methylation of RAR-beta is an early and common alteration in murine lung tumors induced by several environmentally relevant exposures. PMID:14656941

Vuillemenot, Brian R; Pulling, Leah C; Palmisano, William A; Hutt, Julie A; Belinsky, Steven A



Limiting replication initiation factors execute the temporal programme of origin firing in budding yeast  

PubMed Central

Eukaryotic chromosomes are replicated from multiple origins that initiate throughout the S-phase of the cell cycle. Why all origins do not fire simultaneously at the beginning of S-phase is not known, but two kinase activities, cyclin-dependent kinase (CDK) and Dbf4-dependent kinase (DDK), are continually required throughout the S-phase for all replication initiation events. Here, we show that the two CDK substrates Sld3 and Sld2 and their binding partner Dpb11, together with the DDK subunit Dbf4 are in low abundance in the budding yeast, Saccharomyces cerevisiae. Over-expression of these factors is sufficient to allow late firing origins of replication to initiate early and together with deletion of the histone deacetylase RPD3, promotes the firing of heterochromatic, dormant origins. We demonstrate that the normal programme of origin firing prevents inappropriate checkpoint activation and controls S-phase length in budding yeast. These results explain how the competition for limiting DDK kinase and CDK targets at origins regulates replication initiation kinetics during S-phase and establishes a unique system with which to investigate the biological roles of the temporal programme of origin firing. PMID:22081107

Mantiero, Davide; Mackenzie, Amanda; Donaldson, Anne; Zegerman, Philip



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

PubMed Central

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

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



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

SciTech Connect

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

Rosso, A.



Molecular evolution of glutamine synthetase II: Phylogenetic evidence of a non-endosymbiotic gene transfer event early in plant evolution  

PubMed Central

Background Glutamine synthetase (GS) is essential for ammonium assimilation and the biosynthesis of glutamine. The three GS gene families (GSI, GSII, and GSIII) are represented in both prokaryotic and eukaryotic organisms. In this study, we examined the evolutionary relationship of GSII from eubacterial and eukaryotic lineages and present robust phylogenetic evidence that GSII was transferred from ?-Proteobacteria (Eubacteria) to the Chloroplastida. Results GSII sequences were isolated from four species of green algae (Trebouxiophyceae), and additional green algal (Chlorophyceae and Prasinophytae) and streptophyte (Charales, Desmidiales, Bryophyta, Marchantiophyta, Lycopodiophyta and Tracheophyta) sequences were obtained from public databases. In Bayesian and maximum likelihood analyses, eubacterial (GSIIB) and eukaryotic (GSIIE) GSII sequences formed distinct clades. Both GSIIB and GSIIE were found in chlorophytes and early-diverging streptophytes. The GSIIB enzymes from these groups formed a well-supported sister clade with the ?-Proteobacteria, providing evidence that GSIIB in the Chloroplastida arose by horizontal gene transfer (HGT). Bayesian relaxed molecular clock analyses suggest that GSIIB and GSIIE coexisted for an extended period of time but it is unclear whether the proposed HGT happened prior to or after the divergence of the primary endosymbiotic lineages (the Archaeplastida). However, GSIIB genes have not been identified in glaucophytes or red algae, favoring the hypothesis that GSIIB was gained after the divergence of the primary endosymbiotic lineages. Duplicate copies of the GSIIB gene were present in Chlamydomonas reinhardtii, Volvox carteri f. nagariensis, and Physcomitrella patens. Both GSIIB proteins in C. reinhardtii and V. carteri f. nagariensis had N-terminal transit sequences, indicating they are targeted to the chloroplast or mitochondrion. In contrast, GSIIB proteins of P. patens lacked transit sequences, suggesting a cytosolic function. GSIIB sequences were absent in vascular plants where the duplication of GSIIE replaced the function of GSIIB. Conclusions Phylogenetic evidence suggests GSIIB in Chloroplastida evolved by HGT, possibly after the divergence of the primary endosymbiotic lineages. Thus while multiple GS isoenzymes are common among members of the Chloroplastida, the isoenzymes may have evolved via different evolutionary processes. The acquisition of essential enzymes by HGT may provide rapid changes in biochemical capacity and therefore be favored by natural selection. PMID:20579371



Early healing events in a porcine model of contaminated wounds: effects of nanocrystalline silver on matrix metalloproteinases, cell apoptosis, and healing.  


A porcine model of wound healing was employed to examine the impact of nanocrystalline silver-coated dressings on specific wound healing events. Full-thickness wounds were created on the backs of pigs, contaminated with an experimental inoculum containing Pseudomonas aeruginosa, Fusobacterium sp., and coagulase-negative staphylococci, and covered with dressing products either containing silver or not. Nanocrystalline silver-coated dressings promoted rapid wound healing, particularly during the first several days post-injury. Healing was characterized by rapid development of well vascularized granulation tissue that supported tissue grafting 4 days post-injury, unlike control dressed wounds. The proteolytic environment of wounds treated with nanocrystalline silver was characterized by reduced levels of matrix metalloproteinases. Matrix metalloproteinases have been shown to be present in chronic ulcers at abnormally high levels, as compared with acute wounds, and may contribute to the nonhealing nature of these wounds. Cellular apoptosis occurred at a higher frequency in the nanocrystalline silver-treated wounds than in wounds dressed with other products. The results suggest that nanocrystalline silver may play a role in altering or compressing the inflammatory events in wounds and facilitating the early phases of wound healing. These benefits are associated with reduced local matrix metalloproteinase levels and enhanced cellular apoptosis. PMID:12100375

Wright, J Barry; Lam, Kan; Buret, Andre G; Olson, Merle E; Burrell, Robert E



Late, not early mismatch responses to changes in frequency are reduced or deviant in children with dyslexia: an event-related potential study  

PubMed Central

Background Developmental disorders of oral and written language have been linked to deficits in the processing of auditory information. However, findings have been inconsistent, both for behavioural and electrophysiological measures. Methods In this study, we examined event-related potentials (ERPs) in 20 6- to 14-year-old children with developmental dyslexia and 20 age-matched controls, divided into younger (6–11 years, n?=?10) and older (11–14 years, n?=?10) age bands. We focused on early (mismatch negativity; MMN) and late (late discriminative negativity; LDN) conventional mismatch responses and associated measures derived from time-frequency analysis (inter-trial coherence and event-related spectral perturbation). Responses were elicited using an auditory oddball task, whereby a stream of 1000-Hz standards was interspersed with rare large (1,200 Hz) and small (1,030 Hz) frequency deviants. Results Conventional analyses revealed no significant differences between groups in the size of the MMN to either large or small frequency deviants. However, the younger age band of children with dyslexia showed an enhanced inter-trial coherence in the theta frequency band over the time window corresponding to the MMN to small deviants. By contrast, these same children showed a reduced-amplitude LDN for the small deviants relative to their age-matched controls, whilst the older children with dyslexia showed a shorter and less intense period of event-related desynchronization over this time window. Conclusions Initial detection and discrimination of auditory frequency change appears normal or even enhanced in children with dyslexia. Rather, deficits in late-stage auditory processing appear to be a feature of this population. PMID:25110526



The Combined Effect of Nursing Support and Adverse Event Mitigation on Adherence to Interferon Beta-1b Therapy in Early Multiple Sclerosis  

PubMed Central

There is limited clinical evidence on the impact of nurse support and adverse event (AE) mitigation techniques on adherence to interferon beta-1b (IFN?-1b) therapy in multiple sclerosis (MS) in a real-world setting. The aim of the Success of Titration, analgesics, and BETA nurse support on Acceptance Rates in MS Treatment (START) trial was to assess the combined effect of titration, analgesics, and BETA (Betaseron Education, Training, Assistance) nurse support on adherence to IFN?-1b therapy in patients with early-onset MS and to evaluate safety. Participants were instructed to titrate IFN?-1b and use analgesics to minimize flu-like symptoms. All received BETA nurse follow-up at frequent intervals: live training, two telephone calls during the first month of therapy, and monthly calls thereafter. Participants were considered adherent if they took at least 75% of the total prescribed doses over 12 months (?75% compliance). Safety was monitored via reported AEs and laboratory test results. Participants who took at least one IFN?-1b dose over 12 months were analyzed (N = 104); 73.8% of participants completed the study. The mean age of participants was 37.2 years; 72.1% were women and 78.8% were white. Ninety participants had relapsing-remitting MS and 14 had clinically isolated syndrome. The mean compliance rate, reported for 96 participants with complete dose interruption records, was 84.4%. At 12 months, 78.1% of participants were considered adherent. The serious adverse event rate was 9.6%; most events were unrelated to therapy. Thus in the START study, in which participants received nursing support combined with dose titration and use of analgesics, the majority of participants were adherent to therapy. PMID:24453752

Markowitz, Clyde; Patel, Payal; Boateng, Francis; Rametta, Mark



Inhomogeneous DNA replication kinetics is associated with immune system response  

NASA Astrophysics Data System (ADS)

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

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



Sequential analysis of multistage hepatocarcinogenesis reveals that miR-100 and PLK1 dysregulation is an early event maintained along tumor progression.  


MicroRNAs (miRNAs) have an important role in a wide range of physiological and pathological processes, and their dysregulation has been reported to affect the development and progression of cancers, including hepatocellular carcinoma (HCC). However, in the plethora of dysregulated miRNAs, it is largely unknown which of them have a causative role in the hepatocarcinogenic process. In the present study, we first aimed to determine changes in the expression profile of miRNAs in human HCCs and to compare them with liver tumors generated in a rat model of chemically induced HCC. We found that members of the miR-100 family (miR-100, miR-99a) were downregulated in human HCCs; a similar downregulation was also observed in rat HCCs. Their reduction was paralleled by an increased expression of polo like kinase 1 (PLK1), a target of these miRNAs. The introduction of miR-100 in HCC cells impaired their growth ability and their capability to form colonies in soft agar. Next, we aimed at investigating, in the same animal model, if dysregulation of miR-100 and PLK1 is an early or late event along the multistep process of hepatocarcinogenesis. The obtained results showed that miR-100 downregulation (i) is already evident in very early preneoplastic lesions generated 9 weeks after carcinogenic treatment; (ii) is also observed in adenomas and early HCCs; and (iii) is not simply a marker of proliferating hepatocytes. To our knowledge, this is the first work unveiling the role of a miRNA family along HCC progression. PMID:22249248

Petrelli, A; Perra, A; Schernhuber, K; Cargnelutti, M; Salvi, A; Migliore, C; Ghiso, E; Benetti, A; Barlati, S; Ledda-Columbano, G M; Portolani, N; De Petro, G; Columbano, A; Giordano, S



Telomere Replication: Poised but Puzzling  

PubMed Central

Faithful replication of chromosomes is essential for maintaining genome stability. Telomeres, the chromosomal termini, pose quite a challenge to replication machinery due to the complexity in their structures and sequences. Efficient and complete replication of chromosomes is critical to prevent aberrant telomeres as well as to avoid unnecessary loss of telomere DNA. Compelling evidence supports the emerging picture of synergistic actions between DNA replication proteins and telomere protective components in telomere synthesis. This review discusses the actions of various replication and telomere-specific binding proteins that ensure accurate telomere replication and their roles in telomere maintenance and protection. PMID:21122064

Sampathi, Shilpa; Chai, Weihang



DNA Replicating Itself  

NSDL National Science Digital Library

A simplified representation of a DNA molecule separating to form two new molecules.   To reproduce, a cell must copy and transmit its genetic information (DNA) to all of its progeny. To do so, DNA replicates, following the process of semiconservative replication. Each strand of the original molecule acts as a template for the synthesis of a new complementary DNA molecule. The two strands of the double helix are first separated by enzymes. With the assistance of other enzymes, spare parts available inside the cell are bound to the individual strands following the rules of complementary base pairing: adenine (A) to thymine (T) and guanine (G) to cytosine (C). Two strands of DNA are obtained from one, having produced two daughter molecules which are identical to one another and to the parent molecule.

Excellence, Access



Aluminum-26 in H4 chondrites: Implications for its production and its usefulness as a fine-scale chronometer for early solar system events  

NASA Astrophysics Data System (ADS)

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 (CAIs). For Ste. Marguerite (SM) and Forest Vale (FV) Pb/Pb and Mn-Cr ages have previously been determined (Göpel et al., 1994; Polnau et al., 2000; Polnau and Lugmair, 2001). Plagioclase grains from these two meteorites show clear excesses of 26Mg. The 26Al/27Al ratios inferred from these excesses and from isotopically normal Mg in pyroxene and olivine are (2.87+/-0.64)x10-7 for SM and (1.52+/-0.52)x10-7 for FV. The differences between these ratios and the ratio of 5x10-5 in CAIs indicate time differences of 5.4+/-0.1 Ma and 6.1+/-0.2 Ma for SM and FV, respectively. These differences are in agreement with the absolute Pb/Pb ages for CAIs and SM and FV phosphates but there are large discrepancies between the U-Pb and Mn-Cr system for the relative ages for CAIs, SM and FV. For example, Mn-Cr ages of carbonates from Kaidun are older than the Pb/Pb age of CAIs. However, even if we require that CAIs are older than these carbonates, the time difference between this "adjusted" CAI age and the Mn-Cr ages of SM and FV require that 26Al was widely distributed in the early solar system at the time of CAI formation and was not mostly present in CAIs, a feature of the X-wind model proposed by Shu and collaborators (Gounelle et al., 2001; Shu et al., 2001). From this we conclude that there was enough 26Al to melt small planetary bodies as long as they formed within 2 Ma of CAIs, and that 26Al can serve as a fine-scale chronometer for early solar system events.

Zinner, Ernst; Göpel, Christa



A New Replicator: A theoretical framework for analysing replication  

Microsoft Academic Search

BACKGROUND: Replicators are the crucial entities in evolution. The notion of a replicator, however, is far less exact than the weight of its importance. Without identifying and classifying multiplying entities exactly, their dynamics cannot be determined appropriately. Therefore, it is importance to decide the nature and characteristics of any multiplying entity, in a detailed and formal way. RESULTS: Replication is

István Zachar; Eörs Szathmáry



Inhibition of Gammaherpesvirus Replication by RNA Interference  

Microsoft Academic Search

RNA interference (RNAi) is a conserved mechanism in which double-stranded, small interfering RNAs (siRNAs) trigger a sequence-specific gene-silencing process. Here we describe the inhibition of murine her- pesvirus 68 replication by siRNAs targeted to sequences encoding Rta, an immediate-early protein known as an initiator of the lytic viral gene expression program, and open reading frame 45 (ORF 45), a conserved

Qingmei Jia; Ren Sun



Inhibition of the Ubiquitin-Proteasome System Prevents Vaccinia Virus DNA Replication and Expression of Intermediate and Late Genes?  

PubMed Central

The ubiquitin-proteasome system has a central role in the degradation of intracellular proteins and regulates a variety of functions. Viruses belonging to several different families utilize or modulate the system for their advantage. Here we showed that the proteasome inhibitors MG132 and epoxomicin blocked a postentry step in vaccinia virus (VACV) replication. When proteasome inhibitors were added after virus attachment, early gene expression was prolonged and the expression of intermediate and late genes was almost undetectable. By varying the time of the removal and addition of MG132, the adverse effect of the proteasome inhibitors was narrowly focused on events occurring 2 to 4 h after infection, the time of the onset of viral DNA synthesis. Further analyses confirmed that genome replication was inhibited by both MG132 and epoxomicin, which would account for the effect on intermediate and late gene expression. The virus-induced replication of a transfected plasmid was also inhibited, indicating that the block was not at the step of viral DNA uncoating. UBEI-41, an inhibitor of the ubiquitin-activating enzyme E1, also prevented late gene expression, supporting the role of the ubiquitin-proteasome system in VACV replication. Neither the overexpression of ubiquitin nor the addition of an autophagy inhibitor was able to counter the inhibitory effects of MG132. Further studies of the role of the ubiquitin-proteasome system for VACV replication may provide new insights into virus-host interactions and suggest potential antipoxviral drugs. PMID:19129442

Satheshkumar, P. S.; Anton, Luis C.; Sanz, Patrick; Moss, Bernard



doi:10.1128/mBio.00330-10. 2(1): .mBio.Expression and Replication  

E-print Network

doi:10.1128/mBio.00330-10. 2(1): .mBio.Expression and Replication Promotes Herpes Simplex Virus 1 and David M. Knipe and Replication 1 Immediate-Early Gene Expression Factor Promotes Herpes Simplex Virus Herpes Simplex Virus 1 Immediate-Early Gene Expression and Replication Kevin F. Bryant, Robert C

Knipe, David M.


Tel1ATM dictates the replication timing of short yeast telomeres.  


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

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



Evaluation of Epidemic Intelligence Systems Integrated in the Early Alerting and Reporting Project for the Detection of A/H5N1 Influenza Events  

PubMed Central

The objective of Web-based expert epidemic intelligence systems is to detect health threats. The Global Health Security Initiative (GHSI) Early Alerting and Reporting (EAR) project was launched to assess the feasibility and opportunity for pooling epidemic intelligence data from seven expert systems. EAR participants completed a qualitative survey to document epidemic intelligence strategies and to assess perceptions regarding the systems performance. Timeliness and sensitivity were rated highly illustrating the value of the systems for epidemic intelligence. Weaknesses identified included representativeness, completeness and flexibility. These findings were corroborated by the quantitative analysis performed on signals potentially related to influenza A/H5N1 events occurring in March 2010. For the six systems for which this information was available, the detection rate ranged from 31% to 38%, and increased to 72% when considering the virtual combined system. The effective positive predictive values ranged from 3% to 24% and F1-scores ranged from 6% to 27%. System sensitivity ranged from 38% to 72%. An average difference of 23% was observed between the sensitivities calculated for human cases and epizootics, underlining the difficulties in developing an efficient algorithm for a single pathology. However, the sensitivity increased to 93% when the virtual combined system was considered, clearly illustrating complementarities between individual systems. The average delay between the detection of A/H5N1 events by the systems and their official reporting by WHO or OIE was 10.2 days (95% CI: 6.7–13.8). This work illustrates the diversity in implemented epidemic intelligence activities, differences in system's designs, and the potential added values and opportunities for synergy between systems, between users and between systems and users. PMID:23472077

Barboza, Philippe; Vaillant, Laetitia; Mawudeku, Abla; Nelson, Noele P.; Hartley, David M.; Madoff, Lawrence C.; Linge, Jens P.; Collier, Nigel; Brownstein, John S.; Yangarber, Roman; Astagneau, Pascal; on behalf of the Early Alerting, Reporting Project of the Global Health Security Initiative



The functional organization of trial-related activity in lexical processing after early left hemispheric brain lesions: An event-related fMRI study  

PubMed Central

Children with congenital left hemisphere damage due to perinatal stroke are capable of acquiring relatively normal language functions despite experiencing a cortical insult that in adults often leads to devastating lifetime disabilities. Although this observed phenomenon accepted, its neurobiological mechanisms are not well characterized. In this paper we examined the functional neuroanatomy of lexical processing in 13 children/adolescents with perinatal left hemispheric damage. In contrast to many previous perinatal infarct fMRI studies, we use an event-related design, which allowed us to isolate trial related activity and examine correct and error trials separately. Using both group and single subject analysis techniques we attempt to address several methodological factors that may contribute to some discrepancies in the perinatal lesion literature. These methodological factors include making direct statistical comparisons, using common stereotactic space, using both single-subject and group analyses, and accounting for performance differences. Our group analysis, investigating correct trial related activity (separately from error trials), showed very few statistical differences in the non-involved right hemisphere between patients and performance matched controls. The single subject analysis revealed atypical regional activation patterns in several patients; however, the location of these regions identified in individual patients often varied across subjects. These results are consistent with the idea that alternative functional organization of trial-related activity after left hemisphere lesions is in large part unique to the individual. In addition, reported differences between results obtained with event-related designs and blocked designs may suggest diverging organizing principles for sustained and trial-related activity after early childhood brain injuries. PMID:19819000

Fair, Damien A.; Choi, Alexander H.; Dosenbach, Yannic B.L.; Coalson, Rebecca S.; Miezin, Francis M.; Petersen, Steven E.; Schlaggar, Bradley L.



Replication of damaged genomes.  


Cellular DNA is continuously assaulted by chemical and physical agents that arise from both endogenous metabolic processes as well as exogenous insults. Commonly encountered environmental agents include polyaromatic hydrocarbons, polycyclic aromatic amines, the ultraviolet component of sunlight, and ionizing radiation, among many others. Although the kinds of damages and the mechanisms involved in their interaction with DNA vary widely, genotoxic agents alter the structure of DNA in ways that may result in permanent alterations in the DNA sequence or in cell death. To avoid these consequences, cells have evolved countermeasures to reduce the biological consequences of DNA damage. These mechanisms are highly conserved and are present in all eukaryotic cells. In general, cellular responses include the detection of damage, signal transduction to halt cell cycle progression, and the recruitment of repair mechanisms that are tailored to the specific kind of damage. If replication-blocking damage remains when cells enter S-phase, then tolerance mechanisms in the form of complex recombination mechanisms or translesion DNA synthesis using accessory DNA polymerases exist. These mechanisms complete the replication of damaged genomes and suppress cytotoxicity, but at the potential cost of mutagenesis and genomic instability. This review focuses on error-prone mechanisms, including a discussion of the Y-family of DNA polymerases, current concepts of DNA polymerase switching mechanisms, and their relevance to cancer and cancer prevention. PMID:22181702

Klarer, Alden C; McGregor, W



Replication fork recovery and regulation of common fragile sites stability.  


The acquisition of genomic instability is a triggering factor in cancer development, and common fragile sites (CFS) are the preferential target of chromosomal instability under conditions of replicative stress in the human genome. Although the mechanisms leading to CFS expression and the cellular factors required to suppress CFS instability remain largely undefined, it is clear that DNA becomes more susceptible to breakage when replication is impaired. The models proposed so far to explain how CFS instability arises imply that replication fork progression along these regions is perturbed due to intrinsic features of fragile sites and events that directly affect DNA replication. The observation that proteins implicated in the safe recovery of stalled forks or in engaging recombination at collapsed forks increase CFS expression when downregulated or mutated suggests that the stabilization and recovery of perturbed replication forks are crucial to guarantee CFS integrity. PMID:25216703

Franchitto, Annapaola; Pichierri, Pietro



Relationship between C-reactive protein and early activation of leukocytes indicated by leukocyte antisedimentation rate (LAR) in patients with acute cerebrovascular events.  


The purpose of this study was to determine the relationship between high-sensitive C-reactive protein (hsCRP) and leukocyte antisedimentation rate (LAR) as a specific test to detect early activation of leukocytes providing the first line of defence against infections in ischemic stroke. In 49 patients with acute ischemic events and 61 healthy subjects (HS), we examined LAR, astroglia specific S100B indicating the extent of brain tissue damage and hsCRP within 6 hours, as well as 24 and 72 hours after onset of symptoms. Serum levels of hsCRP on admission was significantly higher in patients with acute ischemic stroke (AIS) compared to HS and were higher in patients with recurrent to first ever ischemic stroke. Increased basal levels of hsCRP also correlated with severity of stroke and extent of infarct reflected by S100B levels in sera, but did not correlate with post-stroke infections. However, a higher rate of infection was observed among patients, in whom hsCRP was elevated at 72 hours but LAR did not increase. Therefore, such late elevation of hsCRP may indicate pre-clinical infections due to deficient leukocyte activation. Simple tests like LAR and hsCRP may help in predicting outcome and high risk of infectious complications. PMID:20364064

Molnar, Tihamer; Papp, Viktoria; Banati, Miklos; Szereday, Laszlo; Pusch, Gabriella; Szapary, Laszlo; Bogar, Lajos; Illes, Zsolt



Apoptosis as a mechanism of skin renewal: Le(y)-antigen expression is involved in an early event of a cell's commitment to apoptosis.  


Skin renewal is a typical example of the active participation of a cell in its own death process. Cells arising from mitotic activity in the stratum germinativum of the epidermis continuously migrate upwards to the stratum corneum, where dead cells are eventually desquamated. Recent studies have suggested that apoptosis is involved in the dynamic process of skin renewal. However, this still remains to be further elucidated. In this paper, we investigated the involvement of apoptosis in the skin renewal process. Changes in the morphology of cells in different epidermal layers were compared with histochemical analyses of the extent of DNA fragmentation, as determined by nick end-labelling, and of the reactivities to a monoclonal antibody directed to Le(y)-antigen, difucosylated type 2 chain determinant, which has a close association with apoptosis, and to a monoclonal antibody directed to the proliferating cell nuclear antigen. The results show that apoptosis proceeds concomitantly with cell movement in the epidermis. It seems likely that commitment of a cell to death by apoptosis occurs in the epidermal tissue immediately after completion of cell proliferation, and that Le(y)-antigen expression may be involved in the entire apoptotic process including this early event. PMID:7543813

Minamide, S; Naora, H; Adachi, M; Okano, A; Naora, H



Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer  

PubMed Central

Germline mutations in CDKN2A and/or red hair color variants in MC1R genes are associated with an increased susceptibility to develop cutaneous melanoma or non melanoma skin cancer. We studied the impact of the CDKN2A germinal mutation p.G101W and MC1R variants on gene expression and transcription profiles associated with skin cancer. To this end we set-up primary skin cell co-cultures from siblings of melanoma prone-families that were later analyzed using the expression array approach. As a result, we found that 1535 transcripts were deregulated in CDKN2A mutated cells, with over-expression of immunity-related genes (HLA-DPB1, CLEC2B, IFI44, IFI44L, IFI27, IFIT1, IFIT2, SP110 and IFNK) and down-regulation of genes playing a role in the Notch signaling pathway. 3570 transcripts were deregulated in MC1R variant carriers. In particular, genes related to oxidative stress and DNA damage pathways were up-regulated as well as genes associated with neurodegenerative diseases such as Parkinson’s, Alzheimer and Huntington. Finally, we observed that the expression signatures indentified in phenotypically normal cells carrying CDKN2A mutations or MC1R variants are maintained in skin cancer tumors (melanoma and squamous cell carcinoma). These results indicate that transcriptome deregulation represents an early event critical for skin cancer development. PMID:24742402

Puig-Butille, Joan Anton; Escamez, Maria Jose; Garcia-Garcia, Francisco; Tell-Marti, Gemma; Fabra, Angels; Martinez-Santamaria, Lucia; Badenas, Celia; Aguilera, Paula; Pevida, Marta; Dopazo, Joaquin; del Rio, Marcela; Puig, Susana



Genetic and functional analysis of DD44, a sex-linked gene from the dioecious plant Silene latifolia, provides clues to early events in sex chromosome evolution.  

PubMed Central

Silene latifolia is a dioecious plant with heteromorphic sex chromosomes. The sex chromosomes of S. latifolia provide an opportunity to study the early events in sex chromosome evolution because of their relatively recent emergence. In this article, we present the genetic and physical mapping, expression analysis, and molecular evolutionary analysis of a sex-linked gene from S. latifolia, DD44 (Differential Display 44). DD44 is homologous to the oligomycin sensitivity-conferring protein, an essential component of the mitochondrial ATP synthase, and is ubiquitously expressed in both sexes. We have been able to genetically map DD44 to a region of the Y chromosome that is genetically linked to the carpel-suppressing locus. Although we have physically mapped DD44 to the distal end of the long arm of the X chromosome using fluorescence in situ hybridization (FISH), DD44 maps to the opposite arm of the Y chromosome as determined by our genetic map. These data suggest that chromosomal rearrangements have occurred on the Y chromosome, which may have contributed to the genetic isolation of the Y chromosome. We discuss the implications of these results with respect to the structural and functional evolution of the S. latifolia Y chromosome. PMID:12586719

Moore, Richard C; Kozyreva, Olga; Lebel-Hardenack, Sabine; Siroky, Jiri; Hobza, Roman; Vyskot, Boris; Grant, Sarah R



The DNA Replication Stress Hypothesis of Alzheimer's Disease  

PubMed Central

A well-recognized theory of Alzheimer's disease (AD) pathogenesis suggests ectopic cell cycle events to mediate neurodegeneration. Vulnerable neurons of the AD brain exhibit biomarkers of cell cycle progression and DNA replication suggesting a reentry into the cell cycle. Chromosome reduplication without proper cell cycle completion and mitotic division probably causes neuronal cell dysfunction and death. However, this theory seems to require some inputs in accordance with the generally recognized amyloid cascade theory as well as to explain causes and consequences of genomic instability (aneuploidy) in the AD brain. We propose that unscheduled and incomplete DNA replication (replication stress) destabilizes (epi)genomic landscape in the brain and leads to DNA replication “catastrophe” causing cell death during the S phase (replicative cell death). DNA replication stress can be a key element of the pathogenetic cascade explaining the interplay between ectopic cell cycle events and genetic instabilities in the AD brain. Abnormal cell cycle reentry and somatic genome variations can be used for updating the cell cycle theory introducing replication stress as a missing link between cell genetics and neurobiology of AD. PMID:22262948

Yurov, Yuri B.; Vorsanova, Svetlana G.; Iourov, Ivan Y.



Regulation of DNA replication on subchromosomal units of mammalian cells  

PubMed Central

The regulation of DNA replication at a subchromosomal level in mammalian cells has been investigated. DNA fiber autoradiographs were prepared from mouse L-929 cells pulse labeled with (3H)thymidine. Initiation events and subsequent chain growth occurring over short stretches (up to three replication units in length) of chromosomal DNA were analyzed. The results show that adjacent units usually initiate replication synchronously and that this synchrony is related to the proximity of initiation sites. In addition, adjacent units are of similar size and the rates of replication fork progression within units and on adjacent units are similar. The rate of fork progression increases with increasing replication unit size. Finally, no evidence for fixed termination sites for the units has been found. These observations suggest that despite large variations in size of replication units, timing of initiation events, and rates of fork progression found in chromosomal DNA as a whole, these processes are closely regulated within subchromosomal clusters of active replication units. PMID:1167322



Replication of Sugarscape Using MASON  

Microsoft Academic Search

The purpose of this research was to replicate the Sugarscape model (Eptstein and Axtell 1996) and simulation outcomes as described\\u000a in Growing Artificial Societies (GAS). Sugarscape is a classic agent-based model and contemporary simulation toolkits usually only have a very simple replication\\u000a of a few core rules. There is scant evidence of significant replication of the rules and simulation outcomes;

Anthony Bigbee; Claudio Cioffi-Revilla; Sean Luke


Universal Temporal Profile of Replication Origin Activation in Eukaryotes  

NASA Astrophysics Data System (ADS)

The complete and faithful transmission of eukaryotic genome to daughter cells involves the timely duplication of mother cell's DNA. DNA replication starts at multiple chromosomal positions called replication origin. From each activated replication origin two replication forks progress in opposite direction and duplicate the mother cell's DNA. While it is widely accepted that in eukaryotic organisms replication origins are activated in a stochastic manner, little is known on the sources of the observed stochasticity. It is often associated to the population variability to enter S phase. We extract from a growing Saccharomyces cerevisiae population the average rate of origin activation in a single cell by combining single molecule measurements and a numerical deconvolution technique. We show that the temporal profile of the rate of origin activation in a single cell is similar to the one extracted from a replicating cell population. Taking into account this observation we exclude the population variability as the origin of observed stochasticity in origin activation. We confirm that the rate of origin activation increases in the early stage of S phase and decreases at the latter stage. The population average activation rate extracted from single molecule analysis is in prefect accordance with the activation rate extracted from published micro-array data, confirming therefore the homogeneity and genome scale invariance of dynamic of replication process. All these observations point toward a possible role of replication fork to control the rate of origin activation.

Goldar, Arach




E-print Network

In Euglena gracilis the synthesis of the chloroplast from its precursor, the proplastid, is separated in time from the division or replication of the organelle which occurs just prior to cell division (10, 12). The proplastids are only found in darkgrown cells and rapidly form chloroplasts when such cells are exposed to light. The proplastids divide during dark growth. Ultraviolet irradiation inhibits proplastid division or replication but does not interfere with the proplastid's ability to synthesize chloroplasts (12). Chloroplast replication is also inhibited by ultraviolet irradiation (8). Euglena, then, is an excellent organism for the study of chloroplast synthesis and replication. Nalidixic acid (-ethyl 1-4 dihydro-7-methyl-

In Euglena; Nalidixic Acid


Fragmentation of perfluorinated membranes used in fuel cells: detecting very early events by selective encapsulation of short-lived fragments in ?-cyclodextrin.  


The fragmentation of perfluorinated ionomeric membranes during fuel cell (FC) operation is studied in our laboratory by direct electron spin resonance (ESR) and by spin trapping ESR, and interpretation of the results is facilitated by the study of model compounds (MCs). The advantage of this approach is the ability to detect and identify "early events" in the fragmentation process, before the appearance of stable species that can be detected by NMR and other methods. We report a spin trapping ESR study of the fragmentation of Nafion, Aquivion, and 3M membranes in their water dispersions and of the corresponding model compounds in the presence of HO•, using 2-methyl-2-nitrosopropane (MNP) as a spin trap. Hydroxyl radicals were generated by UV irradiation of hydrogen peroxide. In the MCs the presence of both oxygen-centered radicals (OCRs) and carbon-centered radicals (CCRs) adducts as well as di-tert-butyl nitroxide radicals (DTBN, from spin trap decomposition) were detected. The presence of both OCR and CCR adducts is rationalized by the initial generation of OCRs with low stability and their transformation into the more stable CCRs. Addition of ?-cyclodextrin (?-CD) led to a significant increase of the intensity of the MNP/OCR adducts and in one system also to the complete disappearance of the MNP/CCR adduct, results that we assign to the fast selective encapsulation of OCR adducts in the hydrophobic ?-CD host. In the membrane dispersions the presence of oxygen-centered radical (OCR) adducts and DTBN radicals have been detected; this result is rationalized by the slower rate of transformation of OCR adducts to CCR adducts in the membrane systems. PMID:21923141

Spulber, Mariana; Schlick, Shulamith



Rapid mold replication  

SciTech Connect

The desire to reduce tooling costs have driven manufacturers to investigate new manufacturing methods and materials. In the plastics injection molding industry replicating molds to meet production needs is time consuming (up to 6 months) and costly in terms of lost business. We have recently completed a feasibility study demonstrating the capability of high rate Electron Beam Physical Vapor Deposition (EBPVD) in producing mold inserts in days, not months. In the current practice a graphite mandrel, in the shape of the insert`s negative image, was exposed to a jet of metal vapor atoms emanating from an electron beam heated source of an aluminum-bronze alloy. The condensation rate of the metal atoms on the mandrel was sufficient to allow the deposit to grow at over 30 {mu}m/min or 1.2 mils per minute. The vaporization process continued for approximately 14 hours after which the mandrel and deposit were removed from the EBPVD vacuum chamber. The mandrel and condensate were easily separated resulting in a fully dense aluminum-bronze mold insert about 2.5 cm or one inch thick. This mold was subsequently cleaned and drilled for water cooling passages and mounted on a fixture for operation in an actual injection molding machine. Results of the mold`s operation were extremely successful showing great promise for this technique. This paper describes the EBPVD feasibility demonstration in more detail and discusses future development work needed to bring this technique into practice.

Heestand, G.M.; Beeler, R.G. Jr.; Brown, D.L. [and others



Ultima Replicated Optics Research  

NASA Technical Reports Server (NTRS)

Designs are reviewed incorporating processes suitable for replication of precision spherical segments of very large (greater than 20 meter diameter) telescopes combining ultra-lightweight and high precision. These designs must be amenable to assembly and alignment after deployment . The methods considered lie outside the present scope of fabrication, deployment and alignment considered to date. Design guidelines for reducing the weight and low frequency resonance in low G environment were given by The Serius Group, Dr. Glenn Zeiders, and are considered baseline for this activity. The goal of a rigid design of 10 Kg/sq M is being persued for the Next Generation Space Telescope (NGST) and is not likely adequate for advanced efforts. Flexures have been considered for maintaining the figure of many lightweight structures by control loop processes. This adds to the complexity and weight to the extent that it becomes difficult to recover the benefits. Two fabrication guidelines lead to a stiffer and concurrently lighter structure. First the use of thin vertical wall triangular structural reinforcements to increase the resistance to bending is preferred over hexagonal or square similar sections. Secondly, the incorporation of a similar back sheet on a cellular structure markedly improves the geometric stiffness. Neither improves the short range stiffness. Also often overlooked is that selected material properties must include high microyield and low hysteresis in addition to high elastic modulus to weight (stiffness). The fabrication steps can easily exceed the strain requirement.

Hadaway, James; Engelhaupt, Darell



Weighted voting for replicated data  

Microsoft Academic Search

In a new algorithm for maintaining replicated data, every copy of a replicated file is assigned some number of votes. Every transaction collects a read quorum of rvotes to read a file, and a write quorum of wvotes to write a file, such that r+w is greater than the total number of votes assigned to the file. This ensures that

David K. Gifford



Local Utility Aware Content Replication  

Microsoft Academic Search

A commonly employed abstraction for studying the object place- ment problem for the purpose of Internet content distribution is that of a distributed replication group. In this work the initial model of distributed replication group of Leff, Wolf, and Yu (IEEE TPDS '93) is extended to the case that individual nodes act selfishly, i.e., cater to the optimization of their

Nikolaos Laoutaris; Orestis Telelis; Vassilios Zissimopoulos; Ioannis Stavrakakis



Replication of coliphage lambda DNA  

Microsoft Academic Search

A general scheme of ? phage and plasmid DNA replication in Escherichia coli is presented, and results of in vivo experiments from the authors' laboratory are superimposed. The initiator ?O functions in the assembly of the replication complex (RC) at ori?, making it a stable component of this structure. ClpP \\/ ClpX protease-specific action on ?O does not affect the

Karol Taylor; Grzegorz W?grzyn



LHCb experience with LFC replication  

NASA Astrophysics Data System (ADS)

Database replication is a key topic in the framework of the LHC Computing Grid to allow processing of data in a distributed environment. In particular, the LHCb computing model relies on the LHC File Catalog, i.e. a database which stores information about files spread across the GRID, their logical names and the physical locations of all the replicas. The LHCb computing model requires the LFC to be replicated at Tier-1s. The LCG 3D project deals with the database replication issue and provides a replication service based on Oracle Streams technology. This paper describes the deployment of the LHC File Catalog replication to the INFN National Center for Telematics and Informatics (CNAF) and to other LHCb Tier-1 sites. We performed stress tests designed to evaluate any delay in the propagation of the streams and the scalability of the system. The tests show the robustness of the replica implementation with performance going much beyond the LHCb requirements.

Bonifazi, F.; Carbone, A.; Perez, E. D.; D'Apice, A.; dell'Agnello, L.; Duellmann, D.; Girone, M.; Re, G. L.; Martelli, B.; Peco, G.; Ricci, P. P.; Sapunenko, V.; Vagnoni, V.; Vitlacil, D.



Regulating DNA Replication in Plants  

PubMed Central

Chromosomal DNA replication in plants has requirements and constraints similar to those in other eukaryotes. However, some aspects are plant-specific. Studies of DNA replication control in plants, which have unique developmental strategies, can offer unparalleled opportunities of comparing regulatory processes with yeast and, particularly, metazoa to identify common trends and basic rules. In addition to the comparative molecular and biochemical studies, genomic studies in plants that started with Arabidopsis thaliana in the year 2000 have now expanded to several dozens of species. This, together with the applicability of genomic approaches and the availability of a large collection of mutants, underscores the enormous potential to study DNA replication control in a whole developing organism. Recent advances in this field with particular focus on the DNA replication proteins, the nature of replication origins and their epigenetic landscape, and the control of endoreplication will be reviewed. PMID:23209151

Sanchez, Maria de la Paz; Costas, Celina; Sequeira-Mendes, Joana; Gutierrez, Crisanto



Patterns of DNA replication of human chromosomes. II. Replication map and replication model.  

PubMed Central

Combining higher resolution chromosome analysis and bromodeoxyuridine (BrdU) incorporation, our study demonstrates that: (1) Human chromosomes synthesize DNA in a segmental but highly coordinated fashion. Each chromosome replicates according to its innate pattern of chromosome structure (banding). (2) R-positive bands are demonstrated as the initiation sites of DNA synthesis in all human chromosomes, including late-replicating chromosomes such as the LX and Y. (3) Replication is clearly biphasic in the sense that late-replicating elements, such as G-bands, the Yh, C-bands, and the entire LX, initiate replication after it has been completed in the autosomal R-bands (euchromatin) with minimal or no overlap. The chronological priority of R-band replication followed by G-bands is also retained in the facultative heterochromatin or late-replicating X chromosome (LX). Therefore, the inclusion of G-bands as a truly late-replicating chromatin type or G(Q)-heterochromatin is suggested. (4) Lateral asymmetry (LA) in the Y chromosome can be detected after less than half-cycle in 5-bromodeoxyuridine (BrdUrd), and the presence of at least two regions of LA in this chromosome is confirmed. (5) Finally, the replicational map of human chromosomes is presented, and a model of replication chronology is suggested. Based on this model, a system of nomenclature is proposed to place individual mitoses (or chromosomes) within S-phase, according to their pattern of replication banding. Potential applications of this methodology in clinical and theoretical cytogenetics are suggested. Images Fig. 4 Fig. 4 Fig. 1 Fig. 3 Fig. 1 Fig. 2 Fig. 4 Fig. 4 PMID:7124731

Camargo, M; Cervenka, J



Emerging players in the initiation of eukaryotic DNA replication  

PubMed Central

Faithful duplication of the genome in eukaryotes requires ordered assembly of a multi-protein complex called the pre-replicative complex (pre-RC) prior to S phase; transition to the pre-initiation complex (pre-IC) at the beginning of DNA replication; coordinated progression of the replisome during S phase; and well-controlled regulation of replication licensing to prevent re-replication. These events are achieved by the formation of distinct protein complexes that form in a cell cycle-dependent manner. Several components of the pre-RC and pre-IC are highly conserved across all examined eukaryotic species. Many of these proteins, in addition to their bona fide roles in DNA replication are also required for other cell cycle events including heterochromatin organization, chromosome segregation and centrosome biology. As the complexity of the genome increases dramatically from yeast to human, additional proteins have been identified in higher eukaryotes that dictate replication initiation, progression and licensing. In this review, we discuss the newly discovered components and their roles in cell cycle progression. PMID:23075259



Early signalling events implicated in leukotriene B4-induced activation of the NADPH oxidase in eosinophils: role of Ca2+, protein kinase C and phospholipases C and D.  

PubMed Central

The early signalling events that may ultimately contribute to the assembly and subsequent activation of the NADPH oxidase in guinea-pig peritoneal eosinophils were investigated in response to leukotriene B4 (LTB4). LTB4 promoted a rapid, transient and receptor-mediated increase in the rate of H2O2 generation that was potentiated by R 59 022, a diradylglycerol (DRG) kinase inhibitor, implicating protein kinase C (PKC) in the genesis of this response. This conclusion was supported by the finding that the PKC inhibitor, Ro 31-8220, attenuated (by about 30%) the peak rate of LTB4-induced H2O2 generation under conditions where the same response evoked by 4 beta-phorbol 12,13-dibutyrate (PDBu) was inhibited by more than 90%. Paradoxically, Ro 31-8220 doubled the amount of H2O2 produced by LTB4 which may relate to the ability of PKC to inhibit cell signalling through phospholipase C (PLC). Indeed, Ro 31-8220 significantly enhanced LTB4-induced Ins(1,4,5)P3 accumulation and the duration of the Ca2+ transient in eosinophils. Experiments designed to assess the relative importance of DRG-mobilizing phospholipases in LTB4-induced oxidase activation indicated that phospholipase D (PLD) did not play a major role. Thus, although H2O2 generation was abolished by butan-1-ol, this was apparently unrelated to the inhibition of PLD, as LTB4 failed to stimulate the formation of Ptd[3H]BuOH in [3H]butan-1-ol-treated eosinophils. Rather, the inhibition was probably due to the ability of butan-1-ol to increase the eosinophil cyclic AMP content. In contrast, Ca(2+)- and PLC-driven mechanisms were implicated in H2O2 generation, as LTB4 elevated the Ins(1,4,5)P3 content and intracellular free Ca2+ concentration in intact cells, and cochelation of extracellular and intracellular Ca2+ significantly attenuated LTB4-induced H2O2 generation. Pretreatment of eosinophils with wortmannin did not affect LTB4-induced H2O2 production at concentrations at which it abolished the respiratory burst evoked by formylmethionyl-leucylphenylalanine in human neutrophils. Collectively, these data suggest that LTB4 activates the NADPH oxidase in eosinophils by PLD- and PtdIns 3-kinase-independent mechanisms that involve Ca2+, PLC and PKC. Furthermore, the activation of additional pathways that do not require Ca2+ is also suggested by the finding that LTB4 evoked a significant respiratory burst in Ca(2+)-depleted cells. PMID:7575412

Perkins, R S; Lindsay, M A; Barnes, P J; Giembycz, M A



Carbon-isotope record of the Early Jurassic (Toarcian) Oceanic Anoxic Event from fossil wood and marine carbonate (Lusitanian Basin, Portugal)  

NASA Astrophysics Data System (ADS)

The Toarcian Oceanic Anoxic Event (OAE) in the Early Jurassic (˜ 183 Ma ago) was characterized by widespread near-synchronous deposition of organic-rich shales in marine settings, as well as perturbations to several isotopic systems. Characteristically, two positive carbon-isotope excursions in a range of materials are separated by an abrupt negative shift. Carbon-isotope profiles from Toarcian fossil wood collected in England and Denmark have previously been shown to exhibit this large drop (˜ - 7‰) in ?13C values, interpreted as due to an injection of isotopically light CO 2 into the ocean-atmosphere system. However, the global nature of this excursion has been challenged on the basis of carbon-isotope data from nektonic marine molluscs (belemnites), which exhibit heavier than expected carbon-isotope values. Here we present new data, principally from fossil wood and bulk carbonate collected at centimetre scale from a hemipelagic section at Peniche, coastal Portugal. This section is low in organic carbon (average TOC = ˜ 0.5%), and the samples should not have suffered significant diagenetic contamination by organic carbon of marine origin. The carbon-isotope profile based on wood shows two positive excursions separated by a large and abrupt negative excursion, which parallels exactly the profile based on bulk carbonate samples from the same section, albeit with approximately twice the amplitude (˜ - 8‰ in wood versus ˜ - 3.5‰ in carbonate). These data indicate that the negative carbon-isotope excursion affected the atmosphere and, by implication, the global ocean as well. The difference in amplitude between terrestrial organic and marine carbonate curves can be explained by greater water availability in the terrestrial environment during the negative excursion, for which there is independent evidence from marine osmium-isotope records and, plausibly, changes in atmospheric CO 2 content, for which independent evidence is also available. The Peniche succession is also notable for the occurrence of re-deposited sediments: their lowest occurrence coincides with the base of the negative excursion and their highest occurrence coincides with its top. Thus, slope instability and sediment supply could have been strongly linked to the global environmental perturbation, an association that may misleadingly simulate the effects of sea-level fall.

Hesselbo, Stephen P.; Jenkyns, Hugh C.; Duarte, Luis V.; Oliveira, Luiz C. V.



Template Role of Double-Stranded RNA in Tombusvirus Replication  

PubMed Central

ABSTRACT Replication of plus-strand RNA [(+)RNA] viruses of plants is a relatively simple process that involves complementary minus-strand RNA [(?)RNA] synthesis and subsequent (+)RNA synthesis. However, the actual replicative form of the (?)RNA template in the case of plant (+)RNA viruses is not yet established unambiguously. In this paper, using a cell-free replication assay supporting a full cycle of viral replication, we show that replication of Tomato bushy stunt virus (TBSV) leads to the formation of double-stranded RNA (dsRNA). Using RNase digestion, DNAzyme, and RNA mobility shift assays, we demonstrate the absence of naked (?)RNA templates during replication. Time course experiments showed the rapid appearance of dsRNA earlier than the bulk production of new (+)RNAs, suggesting an active role for dsRNA in replication. Radioactive nucleotide chase experiments showed that the mechanism of TBSV replication involves the use of dsRNA templates in strand displacement reactions, where the newly synthesized plus strand replaces the original (+)RNA in the dsRNA. We propose that the use of dsRNA as a template for (+)RNA synthesis by the viral replicase is facilitated by recruited host DEAD box helicases and the viral p33 RNA chaperone protein. Altogether, this replication strategy allows TBSV to separate minus- and plus-strand syntheses in time and regulate asymmetrical RNA replication that leads to abundant (+)RNA progeny. IMPORTANCE Positive-stranded RNA viruses of plants use their RNAs as the templates for replication. First, the minus strand is synthesized by the viral replicase complex (VRC), which then serves as a template for new plus-strand synthesis. To characterize the nature of the (?)RNA in the membrane-bound viral replicase, we performed complete RNA replication of Tomato bushy stunt virus (TBSV) in yeast cell-free extracts and in plant extracts. The experiments demonstrated that the TBSV (?)RNA is present as a double-stranded RNA that serves as the template for TBSV replication. During the production of new plus strands, the viral replicase displaces the old plus strand in the dsRNA template, leading to asymmetrical RNA synthesis. The presented data are in agreement with the model that the dsRNA is present in nuclease-resistant membranous VRCs. This strategy likely allows TBSV to protect the replicating viral RNA from degradation as well as to evade the early detection of viral dsRNAs by the host surveillance system. PMID:24600009

Kovalev, Nikolay; Pogany, Judit



Pathological replication in cells lacking RecG DNA translocase.  


Little is known about what happens when forks meet to complete DNA replication in any organism. In this study we present data suggesting that the collision of replication forks is a potential threat to genomic stability. We demonstrate that Escherichia coli cells lacking RecG helicase suffer major defects in chromosome replication following UV irradiation, and that this is associated with high levels of DNA synthesis initiated independently of the initiator protein DnaA. This UV-induced stable DNA replication is dependent on PriA helicase and continues long after UV-induced lesions have been excised. We suggest UV irradiation triggers the assembly of new replication forks, leading to multiple fork collisions outside the terminus area. Such collisions may generate branched DNAs that serve to establish further new forks, resulting in uncontrolled DNA amplification. We propose that RecG reduces the likelihood of this pathological cascade being set in motion by reducing initiation of replication at D- and R-loops, and other structures generated as a result of fork collisions. Our results shed light on why replication initiation in bacteria is limited to a single origin and why termination is carefully orchestrated to a single event within a restricted area each cell cycle. PMID:19538444

Rudolph, Christian J; Upton, Amy L; Harris, Lynda; Lloyd, Robert G



Inhibitors of nucleotidyltransferase superfamily enzymes suppress herpes simplex virus replication.  


Herpesviruses are large double-stranded DNA viruses that cause serious human diseases. Herpesvirus DNA replication depends on multiple processes typically catalyzed by nucleotidyltransferase superfamily (NTS) enzymes. Therefore, we investigated whether inhibitors of NTS enzymes would suppress replication of herpes simplex virus 1 (HSV-1) and HSV-2. Eight of 42 NTS inhibitors suppressed HSV-1 and/or HSV-2 replication by >10-fold at 5 ?M, with suppression at 50 ?M reaching ?1 million-fold. Five compounds in two chemical families inhibited HSV replication in Vero and human foreskin fibroblast cells as well as the approved drug acyclovir did. The compounds had 50% effective concentration values as low as 0.22 ?M with negligible cytotoxicity in the assays employed. The inhibitors suppressed accumulation of viral genomes and infectious particles and blocked events in the viral replication cycle before and during viral DNA replication. Acyclovir-resistant mutants of HSV-1 and HSV-2 remained highly sensitive to the NTS inhibitors. Five of six NTS inhibitors of the HSVs also blocked replication of another herpesvirus pathogen, human cytomegalovirus. Therefore, NTS enzyme inhibitors are promising candidates for new herpesvirus treatments that may have broad efficacy against members of the herpesvirus family. PMID:25267681

Tavis, John E; Wang, Hong; Tollefson, Ann E; Ying, Baoling; Korom, Maria; Cheng, Xiaohong; Cao, Feng; Davis, Katie L; Wold, William S M; Morrison, Lynda A



Enigmatic roles of Mcm10 in DNA replication  

PubMed Central

Mcm10 is required for DNA replication in all eukaryotes. While the exact contribution of Mcm10 to genome replication remains heavily debated, early reports suggested that it promotes DNA unwinding and origin firing. These ideas have been solidified by recent studies that propose a role for Mcm10 in helicase activation. Although the molecular underpinnings of this activation step have yet to be revealed, structural data on Mcm10 provide further insight into a possible mechanism of action. The essential role in DNA replication initiation is not mutually exclusive with additional functions that Mcm10 may have as part of the elongation machinery. Here, we review the recent findings regarding the role of Mcm10 in DNA replication and discuss existing controversies. PMID:23332289

Thu, Yee Mon; Bielinsky, Anja-Katrin



Cancer Centers Program - News & Events

Cancer Centers Program - News & Events Home > News & Events > Recent Communications > Archives Communications Archives PLCO Etiology and Early Marker Studies (EEMS) To: Potential EEMS Investigator From: EEMS Coordinating Center Regarding:


Early bioenergetic evolution  

PubMed Central

Life is the harnessing of chemical energy in such a way that the energy-harnessing device makes a copy of itself. This paper outlines an energetically feasible path from a particular inorganic setting for the origin of life to the first free-living cells. The sources of energy available to early organic synthesis, early evolving systems and early cells stand in the foreground, as do the possible mechanisms of their conversion into harnessable chemical energy for synthetic reactions. With regard to the possible temporal sequence of events, we focus on: (i) alkaline hydrothermal vents as the far-from-equilibrium setting, (ii) the Wood–Ljungdahl (acetyl-CoA) pathway as the route that could have underpinned carbon assimilation for these processes, (iii) biochemical divergence, within the naturally formed inorganic compartments at a hydrothermal mound, of geochemically confined replicating entities with a complexity below that of free-living prokaryotes, and (iv) acetogenesis and methanogenesis as the ancestral forms of carbon and energy metabolism in the first free-living ancestors of the eubacteria and archaebacteria, respectively. In terms of the main evolutionary transitions in early bioenergetic evolution, we focus on: (i) thioester-dependent substrate-level phosphorylations, (ii) harnessing of naturally existing proton gradients at the vent–ocean interface via the ATP synthase, (iii) harnessing of Na+ gradients generated by H+/Na+ antiporters, (iv) flavin-based bifurcation-dependent gradient generation, and finally (v) quinone-based (and Q-cycle-dependent) proton gradient generation. Of those five transitions, the first four are posited to have taken place at the vent. Ultimately, all of these bioenergetic processes depend, even today, upon CO2 reduction with low-potential ferredoxin (Fd), generated either chemosynthetically or photosynthetically, suggesting a reaction of the type ‘reduced iron ? reduced carbon’ at the beginning of bioenergetic evolution. PMID:23754820

Sousa, Filipa L.; Thiergart, Thorsten; Landan, Giddy; Nelson-Sathi, Shijulal; Pereira, Ines A. C.; Allen, John F.; Lane, Nick; Martin, William F.



DNA replication and transcription programs respond to the same chromatin cues.  


DNA replication is a dynamic process that occurs in a temporal order along each of the chromosomes. A consequence of the temporally coordinated activation of replication origins is the establishment of broad domains (>100 kb) that replicate either early or late in S phase. This partitioning of the genome into early and late replication domains is important for maintaining genome stability, gene dosage, and epigenetic inheritance; however, the molecular mechanisms that define and establish these domains are poorly understood. The modENCODE Project provided an opportunity to investigate the chromatin features that define the Drosophila replication timing program in multiple cell lines. The majority of early and late replicating domains in the Drosophila genome were static across all cell lines; however, a small subset of domains was dynamic and exhibited differences in replication timing between the cell lines. Both origin selection and activation contribute to defining the DNA replication program. Our results suggest that static early and late replicating domains were defined at the level of origin selection (ORC binding) and likely mediated by chromatin accessibility. In contrast, dynamic domains exhibited low ORC densities in both cell types, suggesting that origin activation and not origin selection governs the plasticity of the DNA replication program. Finally, we show that the male-specific early replication of the X chromosome is dependent on the dosage compensation complex (DCC), suggesting that the transcription and replication programs respond to the same chromatin cues. Specifically, MOF-mediated hyperacetylation of H4K16 on the X chromosome promotes both the up-regulation of male-specific transcription and origin activation. PMID:24985913

Lubelsky, Yoav; Prinz, Joseph A; DeNapoli, Leyna; Li, Yulong; Belsky, Jason A; MacAlpine, David M



Aurora-A controls pre-replicative complex assembly and DNA replication by stabilizing geminin in mitosis  

PubMed Central

Geminin, an essential factor for DNA replication, directly binds to the licensing factor Cdt1 and inhibits pre-replicative complex formation to prevent re-replication. In G1, geminin levels are controlled by the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase complex, which targets geminin for proteasomal degradation to allow pre-replicative complex formation. Conversely, from S to G2, geminin is stabilized due to APC/C ubiquitin ligase complex inhibition, ensuring the inhibition of pre-replicative complex formation. However, mitotic regulation of geminin has hitherto not been described. Here we show that Aurora-A phosphorylates geminin on Thr25 during M phase, and this event induces geminin stabilization by preventing its APC/C ubiquitin ligase complex-mediated degradation during mitosis. In turn, stabilized geminin inhibits SCFSkp2-mediated degradation of Cdt1 to ensure pre-replicative complex formation in the ensuing S phase. The Aurora-A–geminin–Cdt1 axis therefore represents a critical regulator of proper DNA replication. PMID:23695679

Tsunematsu, Takaaki; Takihara, Yoshihiro; Ishimaru, Naozumi; Pagano, Michele; Takata, Takashi; Kudo, Yasusei



Coronavirus Replicase-Reporter Fusions Provide Quantitative Analysis of Replication and Replication Complex Formation  

PubMed Central

ABSTRACT The replication of coronaviruses occurs in association with multiple virus-induced membrane structures that evolve during the course of infection; however, the dynamics of this process remain poorly understood. Previous studies of coronavirus replication complex organization and protein interactions have utilized protein overexpression studies and immunofluorescence of fixed cells. Additionally, live-imaging studies of coronavirus replicase proteins have used fluorescent reporter molecules fused to replicase proteins, but expressed from nonnative locations, mostly late-transcribed subgenomic mRNAs, in the presence or absence of the native protein. Thus, the timing and targeting of native replicase proteins expressed in real time from native locations in the genome remain unknown. In this study, we tested whether reporter molecules could be expressed from the replicase polyprotein of murine hepatitis virus as fusions with nonstructural protein 2 or 3 and whether such reporters could define the targeting and activity of replicase proteins during infection. We demonstrate that the fusion of green fluorescent protein and firefly luciferase with either nonstructural protein 2 or 3 is tolerated and that these reporter-replicase fusions can be used to quantitate replication complex formation and virus replication. The results show that the replicase gene has flexibility to accommodate a foreign gene addition and can be used directly to study replicase complex formation and evolution during infection as well as to provide highly sensitive and specific markers for protein translation and genome replication. IMPORTANCE Coronaviruses are a family of enveloped, positive-sense RNA viruses that are important agents of disease, including severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus. Replication is associated with multiple virus-induced membrane structures that evolve during infection; however, the dynamics of this process remain poorly understood. In this study, we tested whether reporter molecules expressed from native locations within the replicase polyprotein of murine hepatitis virus as fusions with nonstructural proteins could define the expression and targeting of replicase proteins during infection in live cells. We demonstrate that the replicase gene tolerates the introduction of green fluorescent protein or firefly luciferase as fusions with replicase proteins. These viruses allow early quantitation of virus replication as well as real-time measurement of replication complexes. PMID:24623413

Freeman, Megan Culler; Graham, Rachel L.; Lu, Xiaotao; Peek, Christopher T.



Endoplasmic reticulum stress causes EBV lytic replication.  


Endoplasmic reticulum (ER) stress triggers a homeostatic cellular response in mammalian cells to ensure efficient folding, sorting, and processing of client proteins. In lytic-permissive lymphoblastoid cell lines (LCLs), pulse exposure to the chemical ER-stress inducer thapsigargin (TG) followed by recovery resulted in the activation of the EBV immediate-early (BRLF1, BZLF1), early (BMRF1), and late (gp350) genes, gp350 surface expression, and virus release. The protein phosphatase 1 a (PP1a)-specific phosphatase inhibitor Salubrinal (SAL) synergized with TG to induce EBV lytic genes; however, TG treatment alone was sufficient to activate EBV lytic replication. SAL showed ER-stress-dependent and -independent antiviral effects, preventing virus release in human LCLs and abrogating gp350 expression in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated B95-8 cells. TG resulted in sustained BCL6 but not BLIMP1 or CD138 expression, which is consistent with maintenance of a germinal center B-cell, rather than plasma-cell, phenotype. Microarray analysis identified candidate genes governing lytic replication in LCLs undergoing ER stress. PMID:21849482

Taylor, Gwen Marie; Raghuwanshi, Sandeep K; Rowe, David T; Wadowsky, Robert M; Rosendorff, Adam



Possible Models for DNA Replication  

NSDL National Science Digital Library

Three possible ways in which DNA can replicate are illustrated. The two original strands of DNA are shown in yellow (light); newly synthesized DNA is blue (dark). To explain the phenomenon of heredity, biological information must be accurately copied and transmitted from each cell to all of its progeny. Three ways for DNA molecules to replicate may be considered, each obeying the rules of complementary base pairing. Conservative replication would leave intact the original DNA molecule and generate a completely new molecule. Dispersive replication would produce two DNA molecules with sections of both old and new DNA interspersed along each strand. Semiconservative replication would produce molecules with both old and new DNA, but each molecule would be composed of one old strand and one new one. The replication is semiconservative. Each strand acts as a template for the synthesis of a new DNA molecule by the sequential addition of complementary base pairs, thereby generating a new DNA strand that is the complementary sequence to the parental DNA. Each daughter DNA molecule ends up with one of the original strands and one newly synthesized strand.

BEGIN:VCARD VERSION:2.1 FN:Access Excellence N:Excellence;Access REV:2005-03-12 END:VCARD



Real-time single-molecule observation of rolling-circle DNA replication  

PubMed Central

We present a simple technique for visualizing replication of individual DNA molecules in real time. By attaching a rolling-circle substrate to a TIRF microscope-mounted flow chamber, we are able to monitor the progression of single-DNA synthesis events and accurately measure rates and processivities of single T7 and Escherichia coli replisomes as they replicate DNA. This method allows for rapid and precise characterization of the kinetics of DNA synthesis and the effects of replication inhibitors. PMID:19155275

Tanner, Nathan A.; Loparo, Joseph J.; Hamdan, Samir M.; Jergic, Slobodan; Dixon, Nicholas E.; van Oijen, Antoine M.



Domain-wide regulation of DNA replication timing during mammalian development  

Microsoft Academic Search

Studies of replication timing provide a handle into previously impenetrable higher-order levels of chromosome organization\\u000a and their plasticity during development. Although mechanisms regulating replication timing are not clear, novel genome-wide\\u000a studies provide a thorough survey of the extent to which replication timing is regulated during most of the early cell fate\\u000a transitions in mammals, revealing coordinated changes of a defined

Benjamin D. Pope; Ichiro Hiratani; David M. Gilbert



Self-assembly and Self-replication of Short Amphiphilic ?-sheet Peptides  

NASA Astrophysics Data System (ADS)

Most self-replicating peptide systems are made of ?-helix forming sequences. However, it has been postulated that shorter and simpler peptides may also serve as templates for replication when arranged into well-defined structures. We describe here the design and characterization of new peptides that form soluble ?-sheet aggregates that serve to significantly accelerate their ligation and self-replication. We then discuss the relevance of these phenomena to early molecular evolution, in light of additional functionality associated with ?-sheet assemblies.

Bourbo, Valery; Matmor, Maayan; Shtelman, Elina; Rubinov, Boris; Ashkenasy, Nurit; Ashkenasy, Gonen



Differences in the epigenetic and reprogramming properties of pluripotent and extra-embryonic stem cells implicate chromatin remodelling as an important early event in the developing mouse embryo  

Microsoft Academic Search

BACKGROUND: During early mouse development, two extra-embryonic lineages form alongside the future embryo: the trophectoderm (TE) and the primitive endoderm (PrE). Epigenetic changes known to take place during these early stages include changes in DNA methylation and modified histones, as well as dynamic changes in gene expression. RESULTS: In order to understand the role and extent of chromatin-based changes for

Joana Santos; C Filipe Pereira; Aida Di-Gregorio; Thomas Spruce; Olivia Alder; Tristan Rodriguez; Véronique Azuara; Matthias Merkenschlager; Amanda G Fisher



Cdc45 Is a Critical Effector of Myc-Dependent DNA Replication Stress  

PubMed Central

SUMMARY c-Myc oncogenic activity is thought to be mediated in part by its ability to generate DNA replication stress and subsequent genomic instability when deregulated. Previous studies have demonstrated a nontranscriptional role for c-Myc in regulating DNA replication. Here, we analyze the mechanisms by which c-Myc deregulation generates DNA replication stress. We find that overexpression of c-Myc alters the spatiotemporal program of replication initiation by increasing the density of early-replicating origins. We further show that c-Myc deregulation results in elevated replication-fork stalling or collapse and subsequent DNA damage. Notably, these phenotypes are independent of RNA transcription. Finally, we demonstrate that overexpression of Cdc45 recapitulates all c-Myc-induced replication and damage phenotypes and that Cdc45 and GINS function downstream of Myc. PMID:23643534

Srinivasan, Seetha V.; Dominguez-Sola, David; Wang, Lily C.; Hyrien, Olivier; Gautier, Jean



Problems in studying and defining pubertal events  

Microsoft Academic Search

Problems in studying and defining pubertal events during early adolescence are examined in this paper. Whether puberty is best characterized as a social construction or as a physical event and whether early adolescence is best considered a transitional or distinct life period are discussed. Then, the markers or life events associated with puberty and possible boundaries of early adolescence are

Jeanne Brooks-Gunn; Anne C. Petersen



Timing of Early Proterozoic collisional and extensional events in the granulite-gneiss-charnockite-granite complex, Lake Baikal, USSR: A U-Pb, Rb-Sr, and Sm-Nd isotopic study  

SciTech Connect

In the Sharyzhalgay Complex of the Lake Baikal region in eastern Siberia Early Proterozoic collisional and extensional events were separated by ca. 100 m.yr. The earlier collisional event, associated with the development of granulites and gneisses as the result of high-grade dynamothermal metamorphism, took place close to 1965 {plus minus} 4 Ma. A {sup 207}Pb/{sup 204}Pb vs. {sup 206}Pb/{sup 204}Pb isochron for zircon from five size fractions and a six point Rb-Sr whole-rock errorchron give generally corresponding ages of 1956 {plus minus} 8 and 1963 {plus minus} 163 Ma, respectively. The later extensional event, associated with charnockitization due to the uprise of fluids and heat in a regime corresponding to the middle to upper crustal levels of a Basin and Range-type province, was initiated in the 1880-1860 Ma period. The event was continued with magmatic emplacement of granitic masses into the deep levels of caldera-like structures, possibly during the upper time range of lower concordia intercept ages of 1817 +30/{minus}32 and 1797 +40/{minus}44 Ma for two distinctly different zircon populations in a pyroxene-bearing granodiorite interpreted as an evolved (and contaminated) product of the mantle-derived magma that was the source of CO{sub 2} involved in the charnockitization. Upper intercept ages of 2784 +48/{minus}45 and 2775 +61/{minus}55 Ma indicate late Archean crust at depth as the source region of the incorporated zircon. T{sub DM} ages from Sm-Nd isotopic data show that the protolith of the lithologically layered supracrustal assemblage, subsequently polyphase deformed and polymetamorphosed in Early Proterozoic times, was also formed in Early Proterozoic (not Archean) times.

Aftalion, M. (Scottish Univ. Research and Reactor Centre, Glasgow (United Kingdom)); Bibikova, E.V. (Vernadsky Inst. of Geochemistry and Analytical Chemistry, Moscow (USSR)); Bowes, D.R. (Univ. of Glasgow (United Kingdom)); Hopwood, A.M. (Univ. of St. Andrews, Fife (United Kingdom)); Perchuk, L.L. (Inst. of Experimental Mineralogy, Moscow (USSR))



Segregation of Replicative DNA Polymerases during S Phase  

PubMed Central

DNA polymerases (Pol) ?, ?, and ? replicate the bulk of chromosomal DNA in eukaryotic cells, Pol ? being the main leading strand and Pol ? the lagging strand DNA polymerase. By applying chromatin immunoprecipitation (ChIP) and quantitative PCR we found that at G1/S arrest, all three DNA polymerases were enriched with DNA containing the early firing lamin B2 origin of replication and, 2 h after release from the block, with DNA containing the origin at the upstream promoter region of the MCM4 gene. Pol ?, ?, and ? were released from these origins upon firing. All three DNA polymerases, Mcm3 and Cdc45, but not Orc2, still formed complexes in late S phase. Reciprocal ChIP of the three DNA polymerases revealed that at G1/S arrest and early in S phase, Pol ?, ?, and ? were associated with the same nucleoprotein complexes, whereas in late S phase Pol ? and Pol ?/? were largely associated with distinct complexes. At G1/S arrest, the replicative DNA polymerases were associated with lamins, but in late S phase only Pol ?, not Pol ?/?, remained associated with lamins. Consistently, Pol ?, but not Pol ?, was found in nuclear matrix fraction throughout the cell cycle. Therefore, Pol ? and Pol ?/? seem to pursue their functions at least in part independently in late S phase, either by physical uncoupling of lagging strand maturation from the fork progression, or by recruitment of Pol ?, but not Pol ?, to post-replicative processes such as translesion synthesis or post-replicative repair. PMID:22887995

Vaara, Markku; Itkonen, Harri; Hillukkala, Tomi; Liu, Zhe; Nasheuer, Heinz-Peter; Schaarschmidt, Daniel; Pospiech, Helmut; Syvaoja, Juhani E.



Multiple roles of the replication initiation protein Cdtl during helicase loading in S. cerevisiae  

E-print Network

The faithful transmission of genetic information is critical for the events of cell division and propagation. In eukaryotic cells, chromosomal replication is carefully coordinated with the cell cycle to ensure that the ...

Takara, Thomas J. (Thomas Joji)



Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells  

Microsoft Academic Search

The immune system is central in the pathogenesis of scrapie and other transmissible spongiform encephalopathies (TSEs) or 'prion' diseases. After infecting by peripheral (intraperitoneal or oral) routes, most TSE agents replicate in spleen and lymph nodes before neuroinvasion. Characterization of the cells supporting replication in these tissues is essential to understanding early pathogenesis and may indicate potential targets for therapy,

K. L. Brown; K. Stewart; D. L. Ritchie; N. A. Mabbott; A. Williams; H. Fraser; W. I. Morrison; M. E. Bruce



The co-chaperone BAG3 regulates Herpes Simplex Virus replication  

E-print Network

The co-chaperone BAG3 regulates Herpes Simplex Virus replication Christos A. Kyratsous and Saul J-chaperone, as a regulator of herpes virus immediate early gene expression. We report that a herpes simplex virus lacking of promyelocytic leukemia to increase herpes simplex virus replication. Hsc70 HSV ICP0 VZV Productive infection

Symington, Lorraine S.


Topologically associating domains are stable units of replication-timing regulation.  


Eukaryotic chromosomes replicate in a temporal order known as the replication-timing program. In mammals, replication timing is cell-type-specific with at least half the genome switching replication timing during development, primarily in units of 400-800 kilobases ('replication domains'), whose positions are preserved in different cell types, conserved between species, and appear to confine long-range effects of chromosome rearrangements. Early and late replication correlate, respectively, with open and closed three-dimensional chromatin compartments identified by high-resolution chromosome conformation capture (Hi-C), and, to a lesser extent, late replication correlates with lamina-associated domains (LADs). Recent Hi-C mapping has unveiled substructure within chromatin compartments called topologically associating domains (TADs) that are largely conserved in their positions between cell types and are similar in size to replication domains. However, TADs can be further sub-stratified into smaller domains, challenging the significance of structures at any particular scale. Moreover, attempts to reconcile TADs and LADs to replication-timing data have not revealed a common, underlying domain structure. Here we localize boundaries of replication domains to the early-replicating border of replication-timing transitions and map their positions in 18 human and 13 mouse cell types. We demonstrate that, collectively, replication domain boundaries share a near one-to-one correlation with TAD boundaries, whereas within a cell type, adjacent TADs that replicate at similar times obscure replication domain boundaries, largely accounting for the previously reported lack of alignment. Moreover, cell-type-specific replication timing of TADs partitions the genome into two large-scale sub-nuclear compartments revealing that replication-timing transitions are indistinguishable from late-replicating regions in chromatin composition and lamina association and accounting for the reduced correlation of replication timing to LADs and heterochromatin. Our results reconcile cell-type-specific sub-nuclear compartmentalization and replication timing with developmentally stable structural domains and offer a unified model for large-scale chromosome structure and function. PMID:25409831

Pope, Benjamin D; Ryba, Tyrone; Dileep, Vishnu; Yue, Feng; Wu, Weisheng; Denas, Olgert; Vera, Daniel L; Wang, Yanli; Hansen, R Scott; Canfield, Theresa K; Thurman, Robert E; Cheng, Yong; Gülsoy, Günhan; Dennis, Jonathan H; Snyder, Michael P; Stamatoyannopoulos, John A; Taylor, James; Hardison, Ross C; Kahveci, Tamer; Ren, Bing; Gilbert, David M



Snake pictures draw more early attention than spider pictures in non-phobic women: evidence from event-related brain potentials.  


Snakes were probably the first predators of mammals and may have been important agents of evolutionary changes in the primate visual system allowing rapid visual detection of fearful stimuli (Isbell, 2006). By means of early and late attention-related brain potentials, we examined the hypothesis that more early visual attention is automatically allocated to snakes than to spiders. To measure the early posterior negativity (EPN), 24 healthy, non-phobic women watched the random rapid serial presentation of 600 snake pictures, 600 spider pictures, and 600 bird pictures (three pictures per second). To measure the late positive potential (LPP), they also watched similar pictures (30 pictures per stimulus category) in a non-speeded presentation. The EPN amplitude was largest for snake pictures, intermediate for spider pictures and smallest for bird pictures. The LPP was significantly larger for both snake and spider pictures when compared to bird pictures. Interestingly, spider fear (as measured by a questionnaire) was associated with EPN amplitude for spider pictures, whereas snake fear was not associated with EPN amplitude for snake pictures. The results suggest that ancestral priorities modulate the early capture of visual attention and that early attention to snakes is more innate and independent of reported fear. PMID:24374241

Van Strien, J W; Eijlers, R; Franken, I H A; Huijding, J



Trapping DNA Replication Origins from the Human Genome  

PubMed Central

Synthesis of chromosomal DNA is initiated from multiple origins of replication in higher eukaryotes; however, little is known about these origins’ structures. We isolated the origin-derived nascent DNAs from a human repair-deficient cell line by blocking the replication forks near the origins using two different origin-trapping methods (i.e., UV- or chemical crosslinker-treatment and cell synchronization in early S phase using DNA replication inhibitors). Single-stranded DNAs (of 0.5–3 kb) that accumulated after such treatments were labeled with bromodeoxyuridine (BrdU). BrdU-labeled DNA was immunopurified after fractionation by alkaline sucrose density gradient centrifugation and cloned by complementary-strand synthesis and PCR amplification. Competitive PCR revealed an increased abundance of DNA derived from known replication origins (c-myc and lamin B2 genes) in the nascent DNA fractions from the UV-treated or crosslinked cells. Nucleotide sequences of 85 and 208 kb were obtained from the two libraries (I and II) prepared from the UV-treated log-phase cells and early S phase arrested cells, respectively. The libraries differed from each other in their G+C composition and replication-related motif contents, suggesting that differences existed between the origin fragments isolated by the two different origin-trapping methods. The replication activities for seven out of 12 putative origin loci from the early-S phase cells were shown by competitive PCR. We mapped 117 (library I) and 172 (library II) putative origin loci to the human genome; approximately 60% and 50% of these loci were assigned to the G-band and intragenic regions, respectively. Analyses of the flanking sequences of the mapped loci suggested that the putative origin loci tended to associate with genes (including conserved sites) and DNase I hypersensitive sites; however, poor correlations were found between such loci and the CpG islands, transcription start sites, and K27-acetylated histone H3 peaks. PMID:24705160

Eki, Toshihiko; Murakami, Yasufumi; Hanaoka, Fumio



The effect of Ku on telomere replication time is mediated by telomere length but is independent of histone tail acetylation  

PubMed Central

DNA replication in Saccharomyces cerevisiae proceeds according to a temporal program. We have investigated the role of the telomere-binding Ku complex in specifying late replication of telomere-proximal sequences. Genome-wide analysis shows that regions extending up to 80 kb from telomeres replicate abnormally early in a yku70 mutant. We find that Ku does not appear to regulate replication time by binding replication origins directly, nor is its effect on telomere replication timing mediated by histone tail acetylation. We show that Ku instead regulates replication timing through its effect on telomere length, because deletion of the telomerase regulator Pif1 largely reverses the short telomere defect of a yku70 mutant and simultaneously rescues its replication timing defect. Consistent with this conclusion, deleting the genome integrity component Elg1 partially rescued both length and replication timing of yku70 telomeres. Telomere length–mediated control of replication timing requires the TG1–3 repeat-counting component Rif1, because a rif1 mutant replicates telomeric regions early, despite having extended TG1–3 tracts. Overall, our results suggest that the effect of Ku on telomere replication timing results from its impact on TG1–3 repeat length and support a model in which Rif1 measures telomere repeat length to ensure that telomere replication timing is correctly programmed. PMID:21441303

Lian, Hui-Yong; Robertson, E. Douglas; Hiraga, Shin-ichiro; Alvino, Gina M.; Collingwood, David; McCune, Heather J.; Sridhar, Akila; Brewer, Bonita J.; Raghuraman, M. K.; Donaldson, Anne D.



A distinct first replication cycle of DNA introduced in mammalian cells  

PubMed Central

Many mutation events in microsatellite DNA sequences were traced to the first embryonic divisions. It was not known what makes the first replication cycles of embryonic DNA different from subsequent replication cycles. Here we demonstrate that an unusual replication mode is involved in the first cycle of replication of DNA introduced in mammalian cells. This alternative replication starts at random positions, and occurs before the chromatin is fully assembled. It is detected in various cell lines and primary cells. The presence of single-stranded regions increases the efficiency of this alternative replication mode. The alternative replication cannot progress through the A/T-rich FRA16B fragile site, while the regular replication mode is not affected by it. A/T-rich microsatellites are associated with the majority of chromosomal breakpoints in cancer. We suggest that the alternative replication mode may be initiated at the regions with immature chromatin structure in embryonic and cancer cells resulting in increased genomic instability. This work demonstrates, for the first time, differences in the replication progression during the first and subsequent replication cycles in mammalian cells. PMID:21062817

Chandok, Gurangad S.; Kapoor, Kalvin K.; Brick, Rachel M.; Sidorova, Julia M.; Krasilnikova, Maria M.



The Role of Sulfur in Regulating the Exogenic Cycles of Carbon and Oxygen on Early Earth: Lessons Learned From Modern Lakes and Cretaceous Oceanic Anoxic Event 2  

Microsoft Academic Search

Several lines of evidence suggest that sulfate concentrations were low in the Archean and rose during the ``Great Oxidation Event.'' Importantly, in low sulfate systems, sulfate concentrations strongly influence the efficiency of nutrient recycling and therefore primary production, by affecting phosphorus (P) availability. For example, empirical evidence has shown that sulfate concentrations in modern lakes (<1 mM) are inversely correlated

M. T. Hurtgen; D. D. Adams; B. B. Sageman; M. L. Gomes



Systematic surgical closure of patent foramen ovale in selected patients with cerebrovascular events due to paradoxical embolism. Early results of a preliminary study1,2  

Microsoft Academic Search

Objective: To define therapeutic strategy for management of patients with ischemic stroke due to a high probability of paradoxical embolism through a Patent Foramen Ovale (PFO). Methods: Since 1988 all consecutive patients with cerebrovascular events and PFO from the Stroke Registry of our population-based primary-care center are prospectively studied and followed. Since 1992, among 118 patients with cryptogenic embolic brain

P. Ruchat; J. Bogousslavsky; M. Hurni; A. P. Fischer; X. Jeanrenaud; L. K. von Segesser


The Impact of Early Institutional Rearing on the Ability to Discriminate Facial Expressions of Emotion: An Event-Related Potential Study  

ERIC Educational Resources Information Center

Event-related potentials (ERPs), in response to 4 facial expressions of fear, angry, happy, and sad, were collected from 72 institutionalized children (IG), ages 7 to 32 months, in Bucharest, Romania, and compared with ERPs from 33 children, ages 8 to 32 months, who had never been institutionalized (NIG). The NIG and IG exhibited different…

Parker, Susan W.; Nelson, Charles A.



Development of a Systems Computational Model to Investigate Early Biological Events in Hepatic Activation of Constitutive Androstane Receptor (CAR) by Phenobarbital  

EPA Science Inventory

Activation of the nuclear receptor CAR (constitutive active/androstane receptor) is implicated in the control several key biological events such as metabolic pathways. Here, we combined data from literature with information obtained from in vitro assays in the US EPA ToxCast dat...


DNA Replication with Codon Bingo  

NSDL National Science Digital Library

This DNA Replication Lesson Plan incorporates several types of instructional strategies to reach all students. These strategies include: Demonstrations Discussions Cooperative learning Brainstorming Stimulations Inquiry Based activity Projects Game Cooperative Learning Self assessment The students will: Describe the process of DNA replication and/or its role in the transmission and conservation of genetic information. Explain the basic processes of transcription and/or translation, and their roles in the expression of genes. Clarify the basic components of DNA by constructing an advanced organizer.

Arnel Dela Cruz, Miraflor Buscaino, Marilyn Samson, Larie Laudato



CELL CYCLE: Replication Meets Cohesion  

NSDL National Science Digital Library

Access to the article is free, however registration and sign-in are required. When a cell replicates its DNA during S phase of the cell cycle, the sister chromatid pairs must stick together like glue until they are separated to opposite ends of the cell (and hence into separate daughter cells) at anaphase. How the cell achieves this is still unclear but, as Takahashi and Yanagida explain in their Perspective, new findings in yeast have identified one molecule, Trf4p, that may be involved both in DNA replication and sister chromatid cohesion (Wang et al.).

Kohta Takahashi (Kyoto University;Department of Gene Mechanisms, Graduate School of Biostudies); Mitsuhiro Yanagida (Kyoto University;Department of Gene Mechanisms, Graduate School of Biostudies)



Exploiting replication in distributed systems  

NASA Technical Reports Server (NTRS)

Techniques are examined for replicating data and execution in directly distributed systems: systems in which multiple processes interact directly with one another while continuously respecting constraints on their joint behavior. Directly distributed systems are often required to solve difficult problems, ranging from management of replicat