bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA methyltransferase inhibitor RG108 and histone deacetylase inhibitors cooperate to enhance NB4 cell differentiation and E‐cadherin re‐expression by chromatin remodelling
Authors: Savickiene Jurate , Treigyte Grazina , Jazdauskaite Arune , Borutinskaite Veronika‐Viktorija , Navakauskiene Ruta 
Published: July 2012

AbstractEpigenetic silencing of cancer‐related genes by abnormal methylation and the reversal of this process by DNA methylation inhibitors represents a promising strategy in cancer therapy. As DNA methylation affects gene expression and chromatin structure, we investigated the effects of novel DNMT (DNA methyltransferase) inhibitor, RG108, alone and in its combinations with structurally several HDAC (histone deacetylase) inhibitors [sodium PB (phenyl butyrate) or BML‐210 (N‐(2‐aminophenyl)‐N′phenyloctanol diamine), and all‐trans RA (retinoic acid)] in the human PML (promyelocytic leukaemia) NB4 cells. RG108 at different doses from 20 to 100 μM caused time‐, but not a dose‐dependent inhibition of NB4 cell proliferation without cytotoxicity. Temporal pretreatment with RG108 before RA resulted in a dose‐dependent cell growth inhibition and remarkable acceleration of granulocytic differentiation. Prolonged treatments with RG108 and RA in the presence of HDAC inhibitors significantly increased differentiation. RG108 caused time‐dependent re‐expression of methylation‐silenced E‐cadherin, with increase after temporal or continuous treatments with RG108 and RA, or RA together with PB in parallel, in cell maturation, suggesting the role of E‐cadherin as a possible therapeutic marker. These processes required both PB‐induced hyperacetylation of histone H4 and trimethylation of histone H3 at lysine 4, indicating the cooperative action of histone modifications and DNA methylation/demethylation in derepression of E‐cadherin. This work provides novel experimental evidence of the beneficial role of the DNMT inhibitor RG108 in combinations with RA and HDACIs in the effective differentiation of human PML based on epigenetics.
Virtual melting as a new mechanism of stress relaxation under high strain rate loading
Authors: Levitas Valery I. , Ravelo Ramon 
Published: July 2012

Generation and motion of dislocations and twinning are the main mechanisms of plastic deformation. A new mechanism of plastic deformation and stress relaxation at high strain rates (10
9
–10
12
s
-1
) is proposed, under which virtual melting occurs at temperatures much below the melting temperature. Virtual melting is predicted using a developed, advanced thermodynamic approach and confirmed by large-scale molecular dynamics simulations of shockwave propagation and quasi-isentropic compression in both single and defective crystals. The work and energy of nonhydrostatic stresses at the shock front drastically increase the driving force for melting from the uniaxially compressed solid state, reducing the melting temperature by 80% or 4,000 K. After melting, the relaxation of nonhydrostatic stresses leads to an undercooled and unstable liquid, which recrystallizes in picosecond time scales to a hydrostatically loaded crystal. Characteristic parameters for virtual melting are determined from molecular dynamics simulations of Cu shocked/compressed along the

and

directions and Al shocked/compressed along the

direction.
Excessive wave reflections on admission predict post‐discharge events in patients hospitalized due to acute heart failure
Authors: Sung Shih‐Hsien , Yu Wen‐Chung , Cheng Hao‐Min , Lee Ching‐Wei , Lin Mei‐Mei , Chuang Shao‐Yuan , Chen Chen‐Huan 
Published: July 2012

AimsThe role of wave reflections in the pathogenesis of acute heart failure syndrome (AHFS) remains unclear. The present study investigated the long‐term prognostic values of the carotid augmentation index (cAI), carotid augmented pressure (cAP), amplitude of the reflected pressure wave from a decomposed carotid pressure wave (Pb), and carotid pulse pressure (PP) on admission in patients hospitalized due to AHFS.Methods and resultsA total of 120 patients (72 ± 14 years, 83.3% men) hospitalized due to AHFS (55.8% with systolic heart failure) were enrolled. Measures of cAI, cAP, Pb, carotid PP, and carotid–femoral pulse wave velocity (cf‐PWV) by tonometry and thoracic fluid content (TFC) by impedance cardiography were obtained within 24 h of admission. N‐terminal pro brain natriuretic peptide (NT‐proBNP) levels were determined before discharge. Patients were followed up for a median of 601 days, accruing 66 adverse events including re‐hospitalization for heart failure, non‐fatal myocardial infarction, non‐fatal stroke, and death. In univariate Cox analysis, all measures significantly predicted post‐discharge events (all P < 0.05). In multivariate analysis, cAP [hazard ratio per SD and 95% confidence interval: 1.32 (1.051–1.67), P = 0.017], Pb [1.44 (1.13–1.84), P = 0.004] and carotid PP [1.35 (1.05–1.73), P = 0.019], but not cAI, TFC, or cf‐PWV, significantly independently predicted events with adjustments for age, estimated glomerular filtration rate, haemoglobin, and NT‐proBNP.ConclusionOn‐admission measures of wave reflection magnitude, including cAP, Pb, and carotid PP, may be useful for predicting long‐term outcomes in AHFS patients. The results support a major role for wave reflection in the pathogenesis of AHFS.
Antisense Reduction of NADP-Malic Enzyme in Flaveria bidentis Reduces Flow of CO2 through the C4 Cycle
Authors: Pengelly Jasper J.L. , Tan Jackie , Furbank Robert T. , von Caemmerer Susanne 
Published: July 2012

Abstract
An antisense construct targeting the C4 isoform of NADP-malic enzyme (ME), the primary enzyme decarboxylating malate in bundle sheath cells to supply CO2 to Rubisco, was used to transform the dicot Flaveria bidentis. Transgenic plants (α-NADP-ME) exhibited a 34% to 75% reduction in NADP-ME activity relative to the wild type with no visible growth phenotype. We characterized the effect of reducing NADP-ME on photosynthesis by measuring in vitro photosynthetic enzyme activity, gas exchange, and real-time carbon isotope discrimination (Ɗ). In α-NADP-ME plants with less than 40% of wild-type NADP-ME activity, CO2 assimilation rates at high intercellular CO2 were significantly reduced, whereas the in vitro activities of both phosphoenolpyruvate carboxylase and Rubisco were increased. Ɗ measured concurrently with gas exchange in these plants showed a lower Ɗ and thus a lower calculated leakiness of CO2 (the ratio of CO2 leak rate from the bundle sheath to the rate of CO2 supply). Comparative measurements on antisense Rubisco small subunit F. bidentis plants showed the opposite effect of increased Ɗ and leakiness. We use these measurements to estimate the C4 cycle rate, bundle sheath leak rate, and bundle sheath CO2 concentration. The comparison of α-NADP-ME and antisense Rubisco small subunit demonstrates that the coordination of the C3 and C4 cycles that exist during environmental perturbations by light and CO2 can be disrupted through transgenic manipulations. Furthermore, our results suggest that the efficiency of the C4 pathway could potentially be improved through a reduction in C4 cycle activity or increased C3 cycle activity.
Structural Basis of the Allosteric Inhibitor Interaction on the HIV‐1 Reverse Transcriptase RNase H Domain
Authors: Christen Martin T. , Menon Lakshmi , Myshakina Nataliya S. , Ahn Jinwoo , Parniak Michael A. , Ishima Rieko 
Published: July 2012

HIV‐1 reverse transcriptase (RT) has been an attractive target for the development of antiretroviral agents. Although this enzyme is bi‐functional, having both DNA polymerase and ribonuclease H (RNH) activities, there is no clinically approved inhibitor of the RNH activity. Here, we characterize the structural basis and molecular interaction of an allosteric site inhibitor, BHMP07, with the wild‐type (WT) RNH fragment. Solution NMR experiments for inhibitor titration on WT RNH showed relatively wide chemical shift perturbations, suggesting a long‐range conformational effect on the inhibitor interaction. Comparisons of the inhibitor‐induced NMR chemical shift changes of RNH with those of RNH dimer, in the presence and absence of Mg2+, were performed to determine and verify the interaction site. The NMR results, with assistance of molecular docking, indicate that BHMP07 preferentially binds to a site that is located between the RNH active site and the region encompassing helices B and D (the ‘substrate‐handle region’). The interaction site is consistent with the previous proposed site, identified using a chimeric RNH (p15‐EC) [Gong et al. (2011) Chem Biol Drug Des 77, 39–47], but with slight differences that reflect the characteristics of the amino acid sequences in p15‐EC compared to the WT RNH.
Standardization of Gleason grading among 337 European pathologists
Authors: Egevad Lars , Ahmad Amar S , Algaba Ferran , Berney Daniel M , Boccon‐Gibod Liliane , Compérat Eva , Evans Andrew J , Griffiths David , Grobholz Rainer , Kristiansen Glen , Langner Cord , Lopez‐Beltran Antonio , Montironi Rodolfo , Moss Sue , Oliveira Pedro , Vainer Ben , Varma Murali , Camparo Philippe 
Published: July 2012

Aims:  The 2005 International Society of Urological Pathology (ISUP) modification of Gleason grading recommended that the highest grade should always be included in the Gleason score (GS) in prostate biopsies. We analysed the impact of this recommendation on reporting of GS 6 versus 7.Methods and results:  Fifteen expert uropathologists reached two‐thirds consensus on 15 prostate biopsies with GS 6–7 cancer. Eighty‐five microphotographs were graded by 337 of 617 members of the European Network of Uropathology (ENUP), representing 19 countries. There was agreement between expert and majority member GS in 12 of 15 cases, while members upgraded in three cases. Among members and the expert consensus, a GS >6 was assigned by 64.5% and 60%, respectively. Mean member GS was higher than consensus GS in nine of 15 cases. A Gleason pattern (GP) 5 was reported by 0.3–5.6% in 10 cases. Agreement between consensus and member GS was 58.2–89.3% (mean 71.4%) in GS 6 cases and 46.3–63.8% (mean 56.4%) in GS 7 cases (P = 0.009).Conclusions:  While undergrading of prostate cancer used to be prevalent, some now tend to overgrade. Minimum diagnostic criteria for GP 4 and 5 in biopsies need to be better defined. Image libraries reviewed by experts may be useful for standardization.
Bayesian model of Hamilton Depression Rating Score (HDRS) with memantine augmentation in bipolar depression
Authors: Stevens Jasper , Bies Robert R. , Shekhar Anantha , Anand Amit 
Published: July 2012

AimPresynaptic and post‐synaptic glutamatergic modulation is associated with antidepressant activity that takes several weeks to reach a maximal full effect. Limiting mood elevating effects after single drug administration may be the result of compensatory synaptic processes. Therefore, using augmentation treatment with agents having presynaptic and post‐synaptic effects on the glutamatergic system, this study aims to evaluate the effect of augmentation therapy on the rate of change in mood elevation in patients with bipolar depression.MethodsIn a pilot study, 29 outpatients with bipolar depression on a stable lamotrigine dose regimen received placebo or memantine pills daily (titrated up by 5 mg week–1 to 20 mg) in a randomized, double‐blind, parallel group, 8 week study. Patients were evaluated weekly using the 17‐item Hamilton Depression Rating Score (HDRS) and all data were analyzed simultaneously. Linear, exponential, maximal effect, Gompertz and inverse Bateman functions were evaluated using a Bayesian approach population pharmacodynamic model framework. In these models, differences in parameters were examined across the memantine and placebo augmentation groups.ResultsA Gompertz function with a treatment switch on the parameter describing the speed of HDRS decline (γ, 95% confidence interval [CI]) best described the data (γmemantine = 1.8, 95% CI 0.9, 3.6), γplacebo = 1.2, 95% CI 0.5, 3.5)). Between subject variability was identified on baseline HDRS (2.9, 95% CI 1.5, 4.4) and amplitude of score improvement (4.3, 95% CI 2.7, 6.5).ConclusionsThis pharmacodynamic approach identified an increased speed of response after memantine augmentation, compared with placebo augmentation in bipolar depression patients.
Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects
Authors: Legangneux Eric , Gardin Anne , Johns Donald 
Published: July 2012

AimPrevious studies have shown transient decreases in heart rate (HR) following administration of sphingosine 1‐phosphate (S1P) receptor modulators including BAF312. This study was conducted to determine whether dose titration of BAF312 reduces or eliminates these effects.MethodsFifty‐six healthy subjects were randomized 1:1:1:1 to receive BAF312 in one of two dose titration (DT) regimens (DT1 and DT2: 0.25–10 mg over 9–10 days), no titration (10 mg starting dose) or placebo. Pharmacodynamic and pharmacokinetic parameters were assessed.ResultsNeither DT1 nor DT2 resulted in clinically significant bradycardia or atrioventricular conduction effects. Both titration regimens showed a favourable difference on each of days 1–12 vs. the non‐titration regimen on day 1 for HR effects (P < 0.0001). On day 1, the geometric mean ratio of the fraction from the previous day in minimum daily HR between DT1 and non‐titration was 1.18 (95% confidence interval [CI] 1.13, 1.23) and 1.14 (95% CI 1.09, 1.18) for DT2 (both P < 0.05) with significant differences noted through to day 12. Non‐titration HRs showed considerable separation from placebo throughout the study. There was no statistically significant reduction in HR vs. placebo on day 1 in either titration regimen. On days 3–7 subjects in DT1 and DT2 experienced minor reductions in HR vs. placebo (approximately 5 beats min−1; P ≤ 0.0001). From days 9–12, HRs in both titration regimens were comparable with placebo.ConclusionBoth titration regimens effectively attenuated the initial bradyarrhythmia observed on day 1 of treatment with BAF312 10 mg.
Statins and risk of treated incident diabetes in a primary care population
Authors: Zaharan Nur Lisa , Williams David , Bennett Kathleen 
Published: July 2012

Aims(i) To examine the incidence of new onset treated diabetes in patients treated with different types of statins and (ii) the relationship between the duration and dose of statins and the subsequent development of new onset treated diabetes.MethodsA retrospective cohort study was performed using the Irish Health Services Executive Primary Care Reimbursement Services national pharmacy claims database. Individuals who received any medicines were identified from January 2001 to January 2009 (n = 1 235 671). Patients newly treated with statins from 1 January 2002 to 31 December 2007 were identified (n = 239 628). Cases were identified as individuals newly treated with antidiabetic medication (n = 38 503). Adjusted hazards ratios (HR) with 95% confidence intervals (CI) were calculated to examine the association between statins (any vs. none) and time to new onset treated diabetes using Cox proportional hazard regression. The dose and duration response relationship between statins and new onset treated diabetes was examined using restricted spline functions to assess the linearity of the relationship.ResultsStatin use was associated with an increased risk of new onset treated diabetes (HR = 1.18, 95% CI 1.15, 1.22). Increased risk of new onset treated diabetes was found with rosuvastatin (HR = 1.41, 95% CI 1.31, 1.52), atorvastatin (HR = 1.23, 95% CI 1.19, 1.27) and simvastatin (HR = 1.15, 95% CI 1.05, 1.25). There were statistically significant overall dose and duration effects for all statins, excepting fluvastatin, which only demonstrated a duration effect.ConclusionAn increased risk of new onset treated diabetes was found in those treated with statins showing significant duration and dose effect. Further study is required to confirm this association.
Bead-size directed distribution of Pseudomonas aeruginosa results in distinct inflammatory response in a mouse model of chronic lung infection
Authors: Christophersen L J , Trøstrup H , Malling Damlund D S , Bjarnsholt T , Thomsen K , Jensen P Ø , Hougen H P , Høiby N , Moser C 
Published: July 2012

Summary
Chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients is characterized by biofilms, tolerant to antibiotics and host responses. Instead, immune responses contribute to the tissue damage. However, this may depend on localization of infection in the upper conductive or in the peripheral respiratory zone. To study this we produced two distinct sizes of small alginate beads (SB) and large beads (LB) containing P. aeruginosa. In total, 175 BALB/c mice were infected with either SB or LB. At day 1 the quantitative bacteriology was higher in the SB group compared to the LB group (P &lt; 0·003). For all time-points smaller biofilms were identified by Alcian blue staining in the SB group (P &lt; 0·003). Similarly, the area of the airways in which biofilms were identified were smaller (P &lt; 0·0001). A shift from exclusively endobronchial to both parenchymal and endobronchial localization of inflammation from day 1 to days 2/3 (P &lt; 0·05), as well as a faster resolution of inflammation at days 5/6, was observed in the SB group (P &lt; 0·03). Finally, both the polymorphonuclear neutrophil leucocyte (PMN) mobilizer granulocyte colony-stimulating factor (G-CSF) and chemoattractant macrophage inflammatory protein-2 (MIP-2) were increased at day 1 in the SB group (P &lt; 0·0001). In conclusion, we have established a model enabling studies of host responses in different pulmonary zones. An effective recognition of and a more pronounced host response to infection in the peripheral zones, indicating that increased lung damage was demonstrated. Therefore, treatment of the chronic P. aeruginosa lung infection should be directed primarily at the peripheral lung zone by combined intravenous and inhalation antibiotic treatment.
Growth and production of Pacific ocean perch (Sebastes alutus) in nursery habitats of the Gulf of Alaska
Authors: ROOPER CHRISTOPHER N. , BOLDT JENNIFER L. , BATTEN SONIA , GBURSKI CHRISTOPHER 
Published: July 2012

AbstractNursery areas for juvenile fishes are often important for determining recruitment in marine populations by providing habitats that can maximize growth and thereby minimize mortality. Pacific ocean perch (POP, Sebastes alutus) have an extended juvenile period where they inhabit rocky nursery habitats. We examined POP nursery areas to link growth potential to recruitment. Juvenile POP were captured from nursery areas in 2004 and 2008, and estimated growth rates ranged from −0.19 to 0.60 g day−1 based on differences in size between June and August. Predicted growth rates from a bioenergetics model ranged from 0.05 to 0.49 g day−1 and were not significantly different than observed. Substrate preferences and the distribution of their preferred habitats were utilized to predict the extent of juvenile POP nursery habitat in the Gulf of Alaska. Based on densities of fish observed on underwater video transects and the spatial extent of nursery areas, we predicted 278 and 290 million juvenile POP were produced in 2004 and 2008. Growth potential for juvenile POP was reconstructed using the bioenergetics model, spring zooplankton bloom timing and duration and bottom water temperature for 1982–2008. When a single outlying recruitment year in 1986 was removed, growth potential experienced by juvenile POP in nursery areas was significantly correlated to the recruitment time‐series from the stock assessment, explaining ∼30% of the variability. This research highlights the potential to predict recruitment using habitat‐based methods and provides a potential mechanism for explaining some of the POP recruitment variability observed for this population.
Distribution of the Vasotocin Subtype Four Receptor (VT4R) in the Anterior Pituitary Gland of the Chicken, Gallus gallus, and its Possible Role in the Avian Stress Response
Authors: Selvam R. , Jurkevich A. , Kang S. W. , Mikhailova M. V. , Cornett L. E. , Kuenzel W. J. 
Published: July 2012

The neurohormone arginine vasotocin (AVT) in non mammalian vertebrates is homologous to arginine vasopressin (AVP) in mammals. Its actions are mediated via G protein‐coupled receptors that belong to the vasotocin/mesotocin family. Because of the known regulatory effects of nonapeptide hormones on anterior pituitary functions, receptor subtypes in that family have been proposed to be located in anterior pituitary cells. Recently, an avian vasotocin receptor subtype designated VT4R has been cloned, which shares 69% sequence homology with a human vasopressin receptor, the V1aR. In the present study, a polyclonal antibody to the VT4R was developed and validated to confirm its specificity to the VT4R. The antibody was used to test the hypothesis that the VT4R is present in the avian anterior pituitary and is specifically associated with certain cell types, where its expression is modulated by acute stress. Western blotting of membrane protein extracts from pituitary tissue, the use of HeLa cells transfected with the VT4R and peptide competition assays all confirmed the specificity of the antibody to the VT4R. Dual‐labelling immunofluorescence microscopy was utilised to identify pituitary cell types that contained immunoreactive VT4R. The receptor was found to be widely distributed throughout the cephalic lobe but not in the caudal lobe of the anterior pituitary. Immunoreactive VT4R was associated with corticotrophs. Approximately 89% of immunolabelled corticotrophs were shown to contain the VT4R. The immunoreactive VT4R was not found in gonadotrophs, somatotrophs or lactotrophs. To determine a possible functional role of the VT4R and previously characterised VT2R, gene expression levels in the anterior pituitary were determined after acute immobilisation stress by quantitative reverse transcriptase‐polymerase chain reaction. The results showed a significant increase in plasma corticosterone levels (three‐ to four‐fold), a significant reduction of VT4R mRNA and an increase of VT2R mRNA (P < 0.05) in acutely immobilised chicks compared to controls. The data suggest a role of the VT4R in the avian stress response.
Over‐expression of a conserved RNA‐binding motif (RRM) domain (csRRM2) improves components of Brassica napus yield by regulating cell size
Authors: Qi Weiwei , Zhang Fengqi , Sun Fan , Huang Yongjuan , Guan Rongzhan , Yang Jinshui , Luo Xiaojin 
Published: July 2012

With 4 figures and 1 tableAbstractOilseed rape (Brassica napus L.) is the second most important oilseed crop in the world, and greater production of rape oil is required to satisfy the growing demand for it. We previously found that the cell size and yield of rice (Oryza sativa) and cotton can be increased by over‐expression of the RNA‐binding domains (RRMs) of the flowering control locus A (FCA) protein. We also found that B. napus FCA‐RRM2 shares a high level of sequence similarity with the RRM2 domains of other plants. We isolated B. napus FCA‐RRM2 from variety No.1 ‘Nannongyou’ of Brassica napus. Transformation experiments demonstrated that over‐expression of B. napus FCA‐RRM2 increases plant size, organ size, cell size, plant productivity and oil content in transgenic rape plants by down‐regulating the cell‐cycle‐related gene cyclin‐B2‐1, a known activator of cyclin‐dependent kinase 1 at the G2/M boundary. These results provide a practical approach for the genetic improvement of B. napus and possibly provide a model for investigating cell size regulation.