bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of Function of the Tumor Suppressor DKC1 Perturbs p27 Translation Control and Contributes to Pituitary Tumorigenesis
Authors: Bellodi Cristian , Krasnykh Olya , Haynes Nikesha , Theodoropoulou Marily , Peng Guang , Montanaro Lorenzo , Ruggero Davide 
Published: June 2010

Abstract
Mutations in DKC1, encoding for dyskerin, a pseudouridine synthase that modifies rRNA and regulates telomerase activity, are associated with ribosomal dysfunction and increased cancer susceptibility in the human syndrome, X-linked dyskeratosis congenita (X-DC). In a mouse model for X-DC, impairments in DKC1 function affected the translation of specific mRNAs harboring internal ribosomal entry site (IRES) elements, including the tumor suppressor, p27. However, how this translational deregulation contributes to tumor initiation and progression remains poorly understood. Here, we report that impairment in p27 IRES-mediated translation due to decreased levels of DKC1 activity markedly increases spontaneous pituitary tumorigenesis in p27 heterozygous mice. Using a new bioluminescent mouse model, we monitored p27 translation in vivo and show that p27 IRES-mediated translation is reduced in the pituitary of DKC1 hypomorphic mice (DKC1m). Furthermore, we show that DKC1 has a critical role in regulating the assembly of the 48S translational preinitiation complex mediated by the p27 IRES element. An analysis of human tumors identified a novel mutation of DKC1 (DKC1S485G) in a human pituitary adenoma. We show that this specific amino acid substitution significantly alters DKC1 stability/pseudouridylation activity, and this correlates with reductions in p27 protein levels. Furthermore, DKC1S485G mutation does not alter telomerase RNA levels. Altogether, these findings show that genetic alterations in DKC1 could contribute to tumorigenesis associated with somatic cancers and establish a critical role for DKC1 in tumor suppression, at least in part, through translational control of p27. Cancer Res; 70(14); 6026–35. ©2010 AACR.
Targeting Epidermal Growth Factor Receptor–Associated Signaling Pathways in Non–Small Cell Lung Cancer Cells: Implication in Radiation Response
Authors: Choi Eun Jung , Ryu Yun Kyeong , Kim So Yeon , Wu Hong Gyun , Kim Jae Sung , Kim Il Han , Kim In Ah 
Published: June 2010

AbstractSeveral studies have shown solid evidence for the potential value of targeting epidermal growth factor receptor (EGFR) signaling to enhance the antitumor activity of radiation. However, therapeutic resistance has emerged as an important clinical issue. Here, we investigated whether strategies for targeting EGFR-associated downstream signaling would radiosensitize a panel of non–small cell lung cancer cell lines. Inhibition of K-RAS using RNA interference attenuated downstream signaling and increased radiosensitivity of A549 and H460 cells, whereas inhibition of EGFR did not. A549 cells harboring a K-RAS mutation at codon V12 were radiosensitized by small interfering RNA (siRNA) targeting this codon. H460 cells having mutation at codon V61 was radiosensitized by siRNA targeting of this mutation. K-RAS siRNA did not radiosensitize H1299 cells possessing wild-type K-RAS. Inhibition of the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin pathway led to significant radiosensitization of the two cell lines, whereas selective inhibition of extracellular signal-regulated kinase signaling did not. Inhibitors targeting the PI3K-AKT-mTOR pathway also abrogated G2 arrest following irradiation and induced γH2AX foci formation. A dual inhibitor of class I PI3K and mammalian target of rapamycin effectively increased the radiosensitivity of A549 and H460 cells. Inhibition of PI3K-AKT signaling was associated with the downregulation of DNA-PKs. Although apoptosis was the primary mode of cell death when cells were pretreated with LY294002 or AKT inhibitor VIII, cells pretreated with rapamycin or PI-103 showed mixed modes of cell death, including apoptosis and autophagy. Our results suggest possible mechanisms for counteracting EGFR prosurvival signaling implicated in radioresistance and offer an alternative strategy for overcoming resistance to EGFR inhibitors used in combination with irradiation. Mol Cancer Res; 8(7); 1027–36. ©2010 AACR.
Functional Characterization of a Cancer Causing Mutation in Human Replication Protein A
Authors: Hass Cathy S. , Gakhar Lokesh , Wold Marc S. 
Published: June 2010

Abstract
Replication protein A (RPA) is the primary ssDNA-binding protein in eukaryotes. RPA is essential for DNA replication, repair, and recombination. Mutation of a conserved leucine residue to proline in the high-affinity DNA binding site of RPA (residue L221 in human RPA) has been shown to have defects in DNA repair and a high rate of chromosomal rearrangements in yeast. The homologous mutation in mice was found to be lethal when homozygous and to cause high rates of cancer when heterozygous. To understand the molecular defect causing these phenotypes, we created the homologous mutation in the human RPA1 gene (L221P) and analyzed its properties in cells and in vitro. RPA1(L221P) does not support cell cycle progression when it is the only form of RPA1 in HeLa cells. This phenotype is caused by defects in DNA replication and repair. No phenotype is observed when cells contain both wild-type and L221P forms of RPA1, indicating that L221P is not dominant. Recombinant L221P polypeptide forms a stable complex with the other subunits of RPA, indicating that the mutation does not destabilize the protein; however, the resulting complex has dramatically reduced ssDNA binding activity and cannot support SV40 DNA replication in vitro. These findings indicate that in mammals, the L221P mutation causes a defect in ssDNA binding and a nonfunctional protein complex. This suggests that haploinsufficiency of RPA causes an increase in the levels of DNA damage and in the incidence of cancer. Mol Cancer Res; 8(7); 1017–26. ©2010 AACR.
In vitro effects of human neutrophil cathepsin G on thrombin generation: Both acceleration and decreased potential
Authors: Lecompte Thomas , Tournier Agnès , Morlon Lise , Marchand-Arvier Monique , Vigneron Claude , Perrin Julien 
Published: June 2010

SummaryCathepsin G (Cath G), a serine-protease found in neutrophils, has been reported to have effects that could either facilitate or impede coagulation. Thrombin generation (CAT method) was chosen to study its overall effect on the process, at a plasma concentration (240 nM) observed after neutrophil activation. Coagulation was triggered by tissue factor in the presence of platelets or phospholipid vesicles. To help identify potential targets of Cath G, plasma depleted of clotting factors or of inhibitors was used. Cath G induced a puzzling combination of two diverging effects of varying intensities depending on the phospholipid surface provided: accelerating the process under the three conditions (shortened clotting time by up to 30%), and impeding the process during the same thrombin generation time-course since thrombin peak and ETP (total thrombin potential) were decreased, up to 45% and 12%, respectively, suggestive of deficient prothrombinase. This is consistent with Cath G working on at least two targets in the coagulation cascade. Our data indicate that coagulation acceleration can be attributed neither to platelet activation and nor to activation of a clotting factor. When TFPI (tissue factor pathway inhibitor) was absent, no effect on lag time was observed and the anticoagulant activity of TFPI was decreased in the presence of Cath G. Consistent with the literature and the hypothesis of deficient prothrombinase, experiments using Russel’s Viper Venom indicate that the anticoagulant effect can be attributed to a deleterious effect on factor V. The clinical relevance of these findings deserves to be studied.
Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement
Authors: Cohen Alexander , Eriksson Bengt , Puskas David , Shi Minggao , Bocanegra Tomas , Weitz Jeffrey , Raskob Gary 
Published: June 2010

SummaryEdoxaban is a new oral direct factor Xa inhibitor. The purpose of this study was to evaluate the efficacy and safety of different doses of edoxaban for the prevention of venous thromboembolism (VTE) in patients undergoing elective total hip replacement. A total of 903 patients were randomised to oral edoxaban 15, 30, 60 or 90 mg once daily or subcutaneous dalteparin once daily (initial dose 2,500 IU, subsequent doses 5,000 IU). Both drugs were begun 6–8 hours postoperatively and continued for 7–10 days, when bilateral venography was performed. The primary efficacy endpoint was the incidence of total VTE, which included proximal and/or distal deep-vein thrombosis (DVT) by venography or symptomatic, objectively confirmed DVT or pulmonary embolism during the treatment period. The primary safety outcome was the incidence of the composite of major and clinically relevant non-major bleeding. All venograms and bleeding events were reviewed by a central independent adjudication committee blinded as to treatment allocation. Of the 903 patients randomised, 776 were evaluable for the primary efficacy analysis. The incidences of VTE were 28.2%, 21.2%, 15.2%, and 10.6% in patients receiving edoxaban 15, 30, 60 and 90 mg, respectively, compared with 43.8% in the dalteparin group (p<0.005 ). There was a statistically significant (p<0.001) dose-response for efficacy across the edoxaban dose groups for total VTE and for major VTE. The incidence of clinically relevant bleeding was low and similar across the groups. Oral edoxaban once daily is effective for preventing VTE after total hip replacement.
The Prefrontal Cortex Modulates Category Selectivity in Human Extrastriate Cortex
Authors: Miller Brian T. , Vytlacil Jason , Fegen David , Pradhan Suraj , D'Esposito Mark 
Published: June 2010

Abstract
Different categories of visual objects evoke distinct stimulus-evoked sensory responses in extrastriate visual cortex. Although numerous lines of evidence support a distinct representational neural architecture, the mechanisms underlying the modulation of the category selectivity by top–down influences remains uncertain. In this study, we investigate the causal role of the PFC in the modulation of evoked activity to face and scene stimuli in the extrastriate cortex. We used two experimental approaches to disrupt prefrontal cortical function—repetitive TMS to PFC in healthy participants (Experiment 1) and focal PFC lesions in stroke patients (Experiment 2). After these perturbations to normal PFC function (pre- vs. post-TMS and lesion vs. intact hemisphere), stimulus-evoked activity in extrastriate cortex exhibited less distinct category selectivity to faces and scenes. These two experiments provide convergent evidence highlighting a direct role of PFC in the top–down modulation of bottom–up visual signals.
Regional Patterns of Sea Level Change Related to Interannual Variability and Multidecadal Trends in the Atlantic Meridional Overturning Circulation*
Authors: Lorbacher K. , Dengg J. , Böning C. W. , Biastoch A. 
Published: June 2010

Abstract
Some studies of ocean climate model experiments suggest that regional changes in dynamic sea level could provide a valuable indicator of trends in the strength of the Atlantic meridional overturning circulation (MOC). This paper describes the use of a sequence of global ocean–ice model experiments to show that the diagnosed patterns of sea surface height (SSH) anomalies associated with changes in the MOC in the North Atlantic (NA) depend critically on the time scales of interest. Model hindcast simulations for 1958–2004 reproduce the observed pattern of SSH variability with extrema occurring along the Gulf Stream (GS) and in the subpolar gyre (SPG), but they also show that the pattern is primarily related to the wind-driven variability of MOC and gyre circulation on interannual time scales; it is reflected also in the leading EOF of SSH variability over the NA Ocean, as described in previous studies. The pattern, however, is not useful as a “fingerprint” of longer-term changes in the MOC: as shown with a companion experiment, a multidecadal, gradual decline in the MOC [of 5 Sv (1 Sv ≡ 106 m3 s−1) over 5 decades] induces a much broader, basin-scale SSH rise over the mid-to-high-latitude NA, with amplitudes of 20 cm. The detectability of such a trend is low along the GS since low-frequency SSH changes are effectively masked here by strong variability on shorter time scales. More favorable signal-to-noise ratios are found in the SPG and the eastern NA, where a MOC trend of 0.1 Sv yr−1 would leave a significant imprint in SSH already after about 20 years.
Dust Aerosol Important for Snowball Earth Deglaciation
Authors: Abbot Dorian S. , Halevy Itay 
Published: June 2010

Abstract
Most previous global climate model simulations could only produce the termination of Snowball Earth episodes at CO2 partial pressures of several tenths of a bar, which is roughly an order of magnitude higher than recent estimates of CO2 levels during and shortly after Snowball events. These simulations have neglected the impact of dust aerosols on radiative transfer, which is an assumption of potentially grave importance. In this paper it is argued, using the Dust Entrainment and Deposition (DEAD) box model driven by GCM results, that atmospheric dust aerosol concentrations may have been one to two orders of magnitude higher during a Snowball Earth event than today. It is furthermore asserted on the basis of calculations using NCAR’s Single Column Atmospheric Model (SCAM)—a radiative–convective model with sophisticated aerosol, cloud, and radiative parameterizations—that when the surface albedo is high, such increases in dust aerosol loading can produce several times more surface warming than an increase in the partial pressure of CO2 from 10−4 to 10−1 bar. Therefore the conclusion is reached that including dust aerosols in simulations may reconcile the CO2 levels required for Snowball termination in climate models with observations.
Land–Ocean Asymmetry of Tropical Precipitation Changes in the Mid-Holocene
Authors: Hsu Yang-Hui , Chou Chia , Wei Kuo-Yen 
Published: June 2010

Abstract
A series of model experiments were conducted using an intermediate ocean–atmosphere–land model for a better understanding of a distinct land–sea asymmetry in tropical precipitation differences between the mid-Holocene and preindustrial climates. In austral (boreal) summer, most reduced (enhanced) precipitation occurs over continental convective regions, while most enhanced (reduced) precipitation occurs over oceanic convection zones. This land–sea asymmetry of tropical precipitation is particularly clear in austral summer. During the mid-Holocene, the solar forcing presents both spatial and seasonal asymmetric patterns. While the boreal summer insolation is stronger at high latitudes of the Northern Hemisphere in the mid-Holocene than at present, the austral summer insolation is weaker with a more spatially symmetric distribution about the equator. Because of the slow response time of the ocean to forcing, the direct insolation forcing of the current season is cancelled by the ocean memory of an earlier insolation forcing, which in the case of the mid-Holocene is opposite to the current season insolation forcing. As a result, tropical sea surface temperature variation, as well as the tropical atmospheric temperature and moisture changes, is small, which gives rise to a different precipitation response from under the condition of stronger atmospheric temperature and moisture changes, such as in the case of postindustrial global warming induced by an increased concentration of atmospheric greenhouse gases. Thus, the cancellation between the direct and memory effects of the seasonally asymmetric insolation forcing leaves the net energy into the atmosphere to be responsible for the land–sea asymmetry of tropical precipitation changes.
Eosinophil differentiation in the bone marrow is inhibited by T cell–derived IFN-γ
Authors: de Bruin Alexander M. , Buitenhuis Miranda , van der Sluijs Koenraad F. , van Gisbergen Klaas P. J. M. , Boon Louis , Nolte Martijn A. 
Published: June 2010

AbstractTo explore whether and how T cells can affect myelopoiesis, we investigated myeloid differentiation in a model for T cell-mediated immune activation. We found that CD70-transgenic (CD70TG) mice, which have elevated numbers of interferon-γ (IFN-γ)–producing effector T cells in the periphery and bone marrow, are almost devoid of eosinophilic granulocytes. Induction of allergic airway inflammation in these mice failed to induce eosinophilia as well as airway hyperresponsiveness. CD70TG mice also have strongly reduced numbers of eosinophil lineage-committed progenitors, whereas granulocyte/macrophage progenitors from these mice are unable to generate eosinophils in vitro. We found that granulocyte/macrophage progenitors express IFN-γR1 and that IFN-γ is sufficient to inhibit eosinophil differentiation of both murine and human progenitor cells in vitro. We demonstrate that inhibition of eosinophil development in CD70TG mice is IFN-γ–dependent and that T cell–derived IFN-γ is sufficient to inhibit eosinophil formation in vivo. Finally, we found that IFN-γ produced on anti-CD40 treatment and during viral infection can also suppress eosinophil formation in wild-type mice. These data demonstrate that IFN-γ inhibits the differentiation of myeloid progenitors to eosinophils, indicating that the adaptive immune system plays an important role in orchestrating the formation of the appropriate type of myeloid cells during immune activation.
Highly active antiretroviral treatment against STLV-1 infection combining reverse transcriptase and HDAC inhibitors
Authors: Afonso Philippe V. , Mekaouche Mourad , Mortreux Franck , Toulza Frédéric , Moriceau Antoine , Wattel Eric , Gessain Antoine , Bangham Charles R. M. , Dubreuil Guy , Plumelle Yves , Hermine Olivier , Estaquier Jérome , Mahieux Renaud 
Published: June 2010

Abstract
Approximately 3% of all human T-lymphotropic virus type 1 (HTLV-1)–infected persons will develop a disabling inflammatory disease of the central nervous system known as HTLV-1–associated myelopathy/tropical spastic paraparesis, against which there is currently no efficient treatment. As correlation exists between the proviral load (PVL) and the clinical status of the carrier, it is thought that diminishing the PVL could prevent later occurrence of the disease. We have conducted a study combining valproate, an inhibitor of histone deacetylases, and azidothymidine, an inhibitor of reverse transcriptase, in a series of baboons naturally infected with simian T-lymphotropic virus type 1 (STLV-1), whose PVL was equivalent to that of HTLV-1 asymptomatic carriers. We show that the combination of drugs caused a strong decrease in the PVL and prevented the transient rise in PVL that is seen after treatment with histone deacetylases alone. We then demonstrate that the PVL decline was associated with an increase in the STLV-1–specific cytotoxic T-cell population. We conclude that combined treatment with valproate to induce viral expression and azidothymidine to prevent viral propagation is a safe and effective means to decrease PVL in vivo. Such treatments may be useful to reduce the risk of HAM/TSP in asymptomatic carriers with a high PVL.
Histidine-rich glycoprotein promotes bacterial entrapment in clots and decreases mortality in a mouse model of sepsis
Authors: Shannon Oonagh , Rydengård Victoria , Schmidtchen Artur , Mörgelin Matthias , Alm Per , Sørensen Ole E. , Björck Lars 
Published: June 2010

AbstractStreptococcus pyogenes is a significant bacterial pathogen in humans. In this study, histidine-rich glycoprotein (HRG), an abundant plasma protein, was found to kill S pyogenes. Furthermore, S pyogenes grew more efficiently in HRG-deficient plasma, and clots formed in this plasma were significantly less effective at bacterial entrapment and killing. HRG-deficient mice were strikingly more susceptible to S pyogenes infection. These animals failed to control the infection at the local subcutaneous site, and abscess formation and inflammation were diminished compared with control animals. As a result, bacterial dissemination occurred more rapidly in HRG-deficient mice, and they died earlier and with a significantly higher mortality rate than control animals. HRG-deficient mice supplemented with purified HRG gave the same phenotype as control animals, demonstrating that the lack of HRG was responsible for the increased susceptibility. The results demonstrate a previously unappreciated role for HRG as a regulator of inflammation and in the defense at the local site of bacterial infection.
Insecticidal activity of two proteases against Spodoptera frugiperda larvae infected with recombinant baculoviruses
Authors: Gramkow Aline Welzel , Perecmanis Simone , Sousa Raul Lima Barbosa , Noronha Eliane Ferreira , Felix Carlos Roberto , Nagata Tatsuya , Ribeiro Bergmann Morais 
Published: June 2010

Abstract

Background
Baculovirus comprise the largest group of insect viruses most studied worldwide, mainly because they efficiently kill agricutural insect pests. In this study, two recombinant baculoviruses containing the ScathL gene from Sarcophaga peregrina (vSynScathL), and the Keratinase gene from the fungus Aspergillus fumigatus (vSynKerat), were constructed. and their insecticidal properties analysed against Spodoptera frugiperda larvae.

Results
Bioassays of third-instar and neonate S. frugiperda larvae with vSynScathL and vSynKerat showed a decrease in the time needed to kill the infected insects when compared to the wild type virus. We have also shown that both recombinants were able to increase phenoloxidase activity in the hemolymph of S. frugiperda larvae. The expression of proteases in infected larvae resulted in destruction of internal tissues late in infection, which could be the reason for the increased viral speed of kill.

Conclusions
Baculoviruses and their recombinant forms constitute viable alternatives to chemical insecticides. Recombinant baculoviruses containing protease genes can be added to the list of engineered baculoviruses with great potential to be used in integrated pest management programs.
The role of F1 ATP synthase beta subunit in WSSV infection in the shrimp, Litopenaeus vannamei
Authors: Liang Yan , Cheng Jun-Jun , Yang Bing , Huang Jie 
Published: June 2010

Abstract

Background
Knowledge of the virus-host cell interaction could inform us of the molecular pathways exploited by the virus. Studies on viral attachment proteins (VAPs) and candidate receptor proteins involved in WSSV infection, allow a better understanding of how these proteins interact in the viral life cycle. In this study, our aim was to find some host cellular membrane proteins that could bind with white spot syndrome virus (WSSV).

Results
Two proteins were evident by using a virus overlay protein binding assay (VOPBA) with WSSV. A protein with molecular weight 53 kDa, named BP53, was analyzed in this study, which was homologous with the F1-ATP synthase beta subunit by mass spectrometry analysis. Rapid amplification of cDNA ends (RACE) PCR was performed to identify the full-length cDNA of the bp53 gene. The resulting full-length gene consisted of 1836 bp, encoding 525 amino acids with a calculated molecular mass of 55.98 kDa. The deduced amino acid sequence contained three conserved domains of the F1-ATP synthase beta subunit. BP53 was therefore designated the F1-ATP synthase beta subunit of L. vannamei. The binding of WSSV to BP53 were also confirmed by competitive ELISA binding assay and co-immunoprecipitation on magnetic beads. To investigate the function of BP53 in WSSV infection, it was mixed with WSSV before the mixture was injected intramuscularly into shrimp. The resulting mortality curves showed that recombinant (r) BP53 could attenuate WSSV infection.

Conclusions
The results revealed that BP53 is involved in WSSV infection. Here is the first time showed the role of shrimp F1-ATP synthase beta subunit in WSSV infection.