bluuebunny/crossref_metadata_2025 huggingface dataset:
Isotope fractionation and mixing in methane plumes from the Logatchev hydrothermal field
Authors: Keir Robin S. , Schmale Oliver , Seifert Richard , Sültenfuß Jürgen
Published: May 2009

As methane is consumed in the deep sea, its 13C/12C ratio progressively increases because of kinetic isotope fractionation. Many submarine hydrothermal vents emit methane with carbon isotope ratios that are higher than those of background methane in the surrounding ocean. Since the latter exists at low concentrations, mixing of background methane with vent fluid tends to decrease the 13C/12C ratio as concentration decreases, opposite to the trend produced by consumption. We investigated CH4 concentration and δ13C together with δ3He in plumes from the Logatchev hydrothermal field (LHF) located at 14°45′N, 45°W, which generates relatively heavy methane (δ13C ≈ −13‰) by serpentinization of ultramafic rock. The measured methane and δ3He were well correlated at high concentrations, indicating a CH4/3He ratio of 1 × 108 in the vent fluids. These tracer distributions were also simulated with an advection‐diffusion model in which methane consumption only occurs above a certain threshold concentration. We utilized δ3He to calculate the methane remaining in solution after oxidation, f, and the deviation of δ13C from the value expected from mixing alone, Δδ13C. Both in the model and in the data, the entire set of Δδ13C values are not correlated with log f, which is due to continuous oxidation within the plume while mixing with background seawater. A linear relationship, however, is found in the model for methane at concentrations sufficiently above background, and many of the samples with elevated CH4 north of LHF exhibit a linear trend of Δδ13C versus log f as well. From this trend, the kinetic isotope fractionation factor in the LHF plumes appears to be about 1.015. This value is somewhat higher than found in some other deep‐sea studies, but it is lower than found in laboratory incubation experiments.
Dual acylation is required for trafficking of growth-associated protein-43 (GAP-43) to endosomal recycling compartment via an Arf6-associated endocytic vesicular pathway
Authors: Trenchi Alejandra , Gomez Guillermo A. , Daniotti Jose L.
Published: May 2009

GAP-43 (growth-associated protein-43) is a dually palmitoylated protein, at cysteine residues at positions 3 and 4, that mostly localizes in plasma membrane both in neural and non-neural cells. In the present study, we have examined membrane association, subcellular distribution and intracellular trafficking of GAP-43 in CHO (Chinese hamster ovary)-K1 cells. Using biochemical assays and confocal and video microscopy in living cells we demonstrated that GAP-43, at steady state, localizes at the recycling endosome in addition to the cytoplasmic leaflet of the plasma membrane and TGN (trans-Golgi network). Pharmacological inhibition of newly synthesized GAP-43 acylation or double mutation of Cys3 and Cys4 of GAP-43 completely disrupts TGN, plasma membrane and recycling endosome association. A combination of selective photobleaching techniques and time-lapse fluorescence microscopy reveals a dynamic association of GAP-43 with recycling endosomes in equilibrium with the plasma membrane pool. Newly synthesized GAP-43 is found mainly associated with the TGN, but not with the pericentriolar recycling endosome, and traffics to the plasma membrane by a brefeldin A-insensitive pathway. Impairment of plasma membrane fusion and internalization by treatment with tannic acid does affect the trafficking of GAP-43 from plasma membrane to recycling endosomes which reveals a vesicle-mediated retrograde trafficking of GAP-43. Here, we also show that internalization of GAP-43 is regulated by Arf (ADP-ribosylation factor) 6. Taken together, these results demonstrate that dual acylation is required for sorting of peripheral membrane-associated GAP-43 to recycling endosome via an Arf6-associated endocytic vesicular pathway.
AMPKα1 regulates the antioxidant status of vascular endothelial cells
Authors: Colombo Sergio L. , Moncada Salvador
Published: May 2009

AMPK (AMP-activated protein kinase) is a key regulator of cellular energy because of its capacity to detect changes in the concentration of AMP. Recent evidence, however, indicates the existence of alternative mechanisms of activation of this protein. Mitochondrial ROS (reactive oxygen species), generated as a result of the interaction between nitric oxide and mitochondrial cytochrome c oxidase, activate AMPKα1 in HUVECs (human umbilical-vein endothelial cells) at a low oxygen concentration (i.e. 3%). This activation is independent of changes in AMP. In the present study we show, using HUVECs in which AMPKα1 has been silenced, that this protein is responsible for the expression of genes involved in antioxidant defence, such as manganese superoxide dismutase, catalase, γ-glutamylcysteine synthase and thioredoxin. Furthermore, peroxisome proliferator-activated-coactivator-1, cAMP-response-element-binding protein and Foxo3a (forkhead transcription factor 3a) are involved in this signalling pathway. In addition, we show that silencing AMPKα1 in cells results in a reduced mitochondrial and eNOS (endothelial NO synthase) content, reduced cell proliferation, increased accumulation of ROS and apoptosis. Thus AMPKα1 in HUVECs regulates both their mitochondrial content and their antioxidant defences. Pharmacological activation of AMPKα1 in the vascular endothelium may be beneficial in conditions such as metabolic syndrome, Type 2 diabetes and atherosclerosis, not only because of its bioenergetic effects but also because of its ability to counteract oxidative stress.
The small G-proteins Rac1 and Cdc42 are essential for myoblast fusion in the mouse
Authors: Vasyutina Elena , Martarelli Benedetta , Brakebusch Cord , Wende Hagen , Birchmeier Carmen
Published: May 2009

Rac1 and Cdc42 are small G-proteins that regulate actin dynamics and affect plasma membrane protrusion and vesicle traffic. We used conditional mutagenesis in mice to demonstrate that Rac1 and Cdc42 are essential for myoblast fusion in vivo and in vitro. The deficit in fusion of Rac1 or Cdc42 mutant myoblasts correlates with a deficit in the recruitment of actin fibers and vinculin to myoblast contact sites. Comparison of the changes observed in mutant myogenic cells indicates that Rac1 and Cdc42 function in a nonredundant and not completely overlapping manner during the fusion process. Our genetic analysis demonstrates thus that the function of Rac in myoblast fusion is evolutionarily conserved from insects to mammals and that Cdc42, a molecule hitherto not implicated in myoblast fusion, is essential for the fusion of murine myoblasts.
Neonatal outcomes and four‐year follow‐up after spontaneous or iatrogenic preterm prelabor rupture of membranes before 24 weeks
Authors: CHAULEUR CÉLINE , ROCHIGNEUX STÉPHANIE , SEFFERT PIERRE , CHENE GAUTIER , BILLIEMAZ KAREN , COLLET FRÉDÉRIQUE
Published: May 2009

Objective. To assess the neonatal outcome and four‐year follow‐up of pregnancies complicated by preterm prelabor rupture of membranes (PPROM) before 24 weeks. Design. Retrospective study. Setting. University Hospital of Saint Etienne, tertiary level center, France. Methods. Obstetric and neonatal records of 38 pregnancies and 44 fetuses born between 1999 and 2004 (six years) with PPROM between 14 and 23 + 6 weeks of gestation were studied. We analyzed spontaneous (group A) and iatrogenic PPROM (Group B) cases, including maternal, fetal, placental, and neonatal characteristics. Surviving infants were followed until the age of four. Results. Median gestational age at PPROM was 21 weeks [range 15–23 + 6]. Of the 38 women with PPROM, 22 (A) had spontaneous PPROM and 16 (B) underwent an invasive procedure during pregnancy. Expectant management was applied to 25 women: 12 (13 fetuses) from group A and 13 (16 fetuses) from group B. Median latency from PPROM to delivery was 35 days [range 1–163 days]. The two groups showed significant differences. The overall survival rate was 59% (17 fetuses) and three babies from group A died in the hospital. Survival rate of infants discharged from hospital was 48% (14/29). Of 14 surviving infants, 71% had a normal neurological and developmental outcome at four years. Only two infants from group A survived without obvious sequelae. Conclusion. Pregnancy after iatrogenic PPROM had a better prognosis than after spontaneous PPROM. Intensive management with corticosteroids and antibiotics appeared to be helpful. Neonatal survival in spontaneous PPROM before 24 weeks remained very poor and discussing pregnancy termination in these cases seems legitimate.
Amniotic fluid embolism: Still a diagnostic enigma for obstetrician and pathologist?
Authors: TURILLAZZI EMANUELA , GRECO PANTALEO , NERI MARGHERITA , POMARA CRISTOFORO , RIEZZO IRENE , FINESCHI VITTORIO
Published: May 2009

Eight fatal cases of amniotic fluid embolism (AFE) are described to identify definable and preventable risk factors increasing the incidence of AFE. Maternal age, past medical history, previous pregnancies and outcome, prenatal care, gestational age, neonatal outcome, mode of delivery, time of the onset of clinical symptoms, and maternal autopsy findings were retrospectively analyzed. Risk factors and clinical manifestations present in the patients were investigated. Peripartum clinical information included tachycardia and shock as the most frequent symptoms (62.5%), while bradycardia and coma were present in 37.5% of the victims. The interval between onset of labor and symptoms ranged between 0.4 and 7.5 hours. All the women died within seven hours of the onset of the symptoms. AFE can neither be predicted nor prevented as cases occur sporadically with a broad spectrum of clinical manifestations that are less consistent than that previously reported.
Ultrasound-guided vacuum-assisted biopsy of microcalcifications detected at screening mammography
Authors: Cho Nariya , Moon Woo Kyung , Cha Joo Hee , Kim Sun Mi , Jang Mijung , Chang Jung Min , Chung Se Yeong
Published: May 2009

Background: Microcalcifications detected at screening mammography are frequently diagnosed by means of a stereotactic biopsy. Ultrasound (US)-guided percutaneous breast biopsy has several advantages over stereotactic biopsy, e.g., it offers real-time needle visualization, improves patient comfort, the procedure time is generally considered to be shorter, and it usually does not require ionizing radiation or dedicated equipment.

Purpose: To assess the frequency of calcification retrieval and factors affecting retrieval success for US-guided 11-G vacuum-assisted biopsies of microcalcifications.

Material and Methods: Seventy-five consecutive women (age range: 25–68 years, mean age: 47 years) with 75 lesions of microcalcifications detected at screening mammography underwent US-guided 11-G vacuum-assisted biopsy. Calcification retrieval was defined as being successful when calcifications were detected in radiographs of specimens. Mammographic, ultrasonographic, and histologic findings were analyzed to identify factors that affected calcification retrieval.

Results: Among 75 lesions that had US-guided vacuum-assisted biopsy, calcifications were retrieved in 53 (71%) lesions. Calcification retrieval was more frequent for lesions; associated with masses or dilated ducts at US (85% [41/48] vs. 44% [12/27], P<0.001), located in the anterior or middle part of the breast vs. posterior part of the breast (81% [47/58] vs. 35% [6/17], P=0.001), of maximal diameter more than 10 mm (82% [41/50] vs. 48% [12/25], P=0.002), with a segmental or regional distribution vs. clustered distribution (95% [18/19] vs. 63% [35/56], P=0.008), or lesions of category 4c or 5 vs. category 4a or 4b (100% [8/8] vs. 67% [45/67], P=0.054) at mammography.

Conclusion: US-guided 11-G vacuum-assisted biopsy retrieved calcifications from 71% (53/75) of lesions. Successful calcification retrieval was found to be related to the visibility of associated masses or dilated ducts by US, and to lesion depth, size, and distribution, and level of suspicion at mammography.
Quantitative apparent diffusion coefficients in the characterization of brain tumors and associated peritumoral edema
Authors: Server A. , Kulle B. , Mæhlen J. , Josefsen R. , Schellhorn T. , Kumar T. , Langberg C.W. , Nakstad P.H.
Published: May 2009

Background: Conventional magnetic resonance (MR) imaging has a number of limitations in the diagnosis of the most common intracranial brain tumors, including tumor specification and the detection of tumoral infiltration in regions of peritumoral edema.

Purpose: To prospectively assess if diffusion-weighted MR imaging (DWI) could be used to differentiate between different types of brain tumors and to distinguish between peritumoral infiltration in high-grade gliomas, lymphomas, and pure vasogenic edema in metastases and meningiomas.

Material and Methods: MR imaging and DWI was performed on 93 patients with newly diagnosed brain tumors: 59 patients had histologically verified high-grade gliomas (37 glioblastomas multiforme, 22 anaplastic astrocytomas), 23 patients had metastatic brain tumors, five patients had primary cerebral lymphomas, and six patients had meningiomas. Apparent diffusion coefficient (ADC) values of tumor (enhancing regions or the solid portion of tumor) and peritumoral edema, and ADC ratios (ADC of tumor or peritumoral edema to ADC of contralateral white matter, ADC of tumor to ADC of peritumoral edema) were compared with the histologic diagnosis. ADC values and ratios of high-grade gliomas, primary cerebral lymphomas, metastases, and meningiomas were compared by using ANOVA and multiple comparisons. Optimal thresholds of ADC values and ADC ratios for distinguishing high-grade gliomas from metastases were determined by receiver operating characteristic (ROC) curve analysis.

Results: Statistically significant differences were found for minimum and mean of ADC tumor and ADC tumor ratio values between metastases and high-grade gliomas when including only one factor at a time. Including a combination of in total four parameters (mean ADC tumor, and minimum, maximum and mean ADC tumor ratio) resulted in sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of 72.9, 82.6, 91.5, and 54.3% respectively. In the ROC curve analysis, the area under the curve of the combined four parameters was the largest (0.84), indicating a good test.

Conclusion: Our results suggest that ADC values and ADC ratios (minimum and mean of ADC tumor and ADC tumor ratio) may be helpful in the differentiation of metastases from high-grade gliomas. It cannot distinguish high-grade gliomas from lymphomas, and lymphomas from metastases. ADC values and ADC ratios in peritumoral edema cannot be used to differentiate edema with infiltration of tumor cells from vasogenic edema when measurements for high-grade gliomas, lymphomas, metastases, and meningiomas were compared.
The 35th Sir Frederick Bartlett Lecture: Eye movements and attention in reading, scene perception, and visual search
Authors: Rayner Keith
Published: May 2009

Eye movements are now widely used to investigate cognitive processes during reading, scene perception, and visual search. In this article, research on the following topics is reviewed with respect to reading: (a) the perceptual span (or span of effective vision), (b) preview benefit, (c) eye movement control, and (d) models of eye movements. Related issues with respect to eye movements during scene perception and visual search are also reviewed. It is argued that research on eye movements during reading has been somewhat advanced over research on eye movements in scene perception and visual search and that some of the paradigms developed to study reading should be more widely adopted in the study of scene perception and visual search. Research dealing with “real-world” tasks and research utilizing the visual-world paradigm are also briefly discussed.
Fishery management responses to climate change in the North Pacific
Authors: Stram Diana L. , Evans Diana C. K.
Published: May 2009

Stram, D. L., and Evans, D. C. K. 2009. Fishery management responses to climate change in the North Pacific. – ICES Journal of Marine Science, 66: 1633–1639. In the North Pacific, warming trends, coupled with declining sea ice, raise concerns about the effects of climate change on fish populations and ecosystem dynamics. Scientists are only beginning to understand the potential feedback mechanisms that will affect everything from plankton populations to major commercial fish species distributions, yet fishery managers have a responsibility to prepare for and respond to changing fishing patterns and potential ecosystem effects. There are ways for fishery managers to be proactive, while waiting for better information to unfold. The North Pacific Fishery Management Council (Council) and the National Marine Fisheries Service have jurisdiction over offshore fisheries in Alaska, USA. Recently, the Council has undertaken risk-averse management actions, in light of uncertainty about the effects of warming trends (and loss of sea ice) and resulting changes to fishing activities in the North Pacific. The Council has assessed whether opportunities for unregulated fishing could result from changes in fish distribution, has closed the Arctic Ocean to all commercial fishing pending further research, and has established extensive area closures where fishing with bottom-trawl gear is prohibited to protect vulnerable crab habitat and to control the northern expansion of the trawl fleet into newly ice-free waters. In cases where linkages between climate variables and fish distributions can be identified, the Council is developing adaptive management measures to respond to varying distributions of fish and shellfish. Finally, the Council has also tried to re-examine existing information to gain a better understanding of climate and ecosystem effects on fishery management. The pilot Fishery Ecosystem Plan for the Aleutian Islands maps interactions among climate factors and ecosystem components and suggests indicators for the Council to monitor.
Nitric Oxide as a Partner of Reactive Oxygen Species Participates in Disease Resistance to Necrotrophic Pathogen Botrytis cinerea in Nicotiana benthamiana
Authors: Asai Shuta , Yoshioka Hirofumi
Published: May 2009

Nitric oxide (NO) is an essential regulatory molecule in plant immunity in synergy with reactive oxygen species (ROS). However, little is known about the role of NO in disease resistance to necrotrophic pathogens. NO and oxidative bursts were induced during necrotrophic fungal pathogen Botrytis cinerea and Nicotiana benthamiana compatible interaction. Histochemical analyses showed that both NO and ROS were produced in adjacent cells of invaded areas in N. benthamiana leaves. Activation of salicylic acid–induced protein kinase, which regulates the radical burst, and several defense-related genes were induced after inoculation of B. cinerea. Loss-of-function analyses using inhibitors and virus-induced gene silencing were done to investigate the role of the radical burst in pathogenesis. We showed that NO plays a pivotal role in basal defense against B. cinerea and PR-1 gene expression in N. benthamiana. By contrast, ROS function has a negative role in resistance or has a positive role in expansion of disease lesions during B. cinerea–N. benthamiana interaction.
Identification of Bacterial Proteins Mediating the Interactions Between Pseudomonas putida UW4 and Brassica napus (Canola)
Authors: Cheng Zhenyu , Duan Jin , Hao Youai , McConkey Brendan J. , Glick Bernard R.
Published: May 2009

The influence of canola root exudates on the proteome of Pseudomonas putida UW4 and the mutant strain P. putida UW4/AcdS–, which lacks a functional 1-aminocyclopropane-1-carboxylate deaminase gene, was examined using two-dimensional difference in-gel electrophoresis. Seventy-two proteins with significantly altered expression levels in the presence of canola root exudates were identified by mass spectrometry. Many of these proteins are involved in nutrient transport and utilization, cell envelope synthesis, and transcriptional or translational regulation and, hence, may play important roles in plant–bacterial interactions. Four proteins showing large changes in expression in response to canola root exudates in both the wild-type and mutant strains of P. putida UW4 (i.e., outer membrane protein F, peptide deformylase, transcription regulator Fis family protein, and a previously uncharacterized protein) were both overexpressed and disrupted in P. putida UW4 in an effort to better understand their functions. Functional studies of these modified strains revealed significantly enhanced or inhibited plant-growth-promoting abilities compared with the wild-type P. putida UW4, in agreement with the suggested involvement of three of these four proteins in plant–bacterial interactions. The work reported here suggests strategies to both identify potential antibacterial agents and develop bacterial strains that might be useful adjuncts to agriculture. This approach may be an effective means of identifying key proteins mediating the interactions of bacteria with their rhizosphere environment.
Adhesion and Fitness in the Bean Phyllosphere and Transmission to Seed of Xanthomonas fuscans subsp. fuscans
Authors: Darsonval A. , Darrasse A. , Durand K. , Bureau C. , Cesbron S. , Jacques M.-A.
Published: May 2009

Deciphering the mechanisms enabling plant-pathogenic bacteria to disperse, colonize, and survive on their hosts provides the necessary basis to set up new control methods. We evaluated the role of bacterial attachment and biofilm formation in host colonization processes for Xanthomonas fuscans subsp. fuscans on its host. This bacterium is responsible for the common bacterial blight of bean (Phaseolus vulgaris), a seedborne disease. The five adhesin genes (pilA, fhab, xadA1, xadA2, and yapH) identified in X. fuscans subsp. fuscans CFBP4834-R strain were mutated. All mutants were altered in their abilities to adhere to polypropylene or seed. PilA was involved in adhesion and transmission to seed, and mutation of pilA led to lower pathogenicity on bean. YapH was required for adhesion to seed, leaves, and abiotic surfaces but not for in planta transmission to seed or aggressiveness on leaves. Transmission to seed through floral structures did not require any of the known adhesins. Conversely, all mutants tested, except in yapH, were altered in their vascular transmission to seed. In conclusion, we showed that adhesins are implicated in the various processes leading to host phyllosphere colonization and transmission to seed by plant-pathogenic bacteria.
Sexual conflict as a partitioning of selection
Authors: Westneat David F. , Sih Andrew
Published: May 2009

Sexual conflict appears to be a powerful force in evolution. We suggest that selection theory can readily be adapted for cases of sexual conflict and illustrate how it can provide a new perspective on what traits cause conflict and might respond to its presence. Use of selection theory resolves some terminological confusion, provides operational measures of conflict and generates a conceptual tool for parsing the causes and consequences of conflict in complex systems of male–female interactions.
Climate change effects on migration phenology may mismatch brood parasitic cuckoos and their hosts
Authors: Saino Nicola , Rubolini Diego , Lehikoinen Esa , Sokolov Leonid V. , Bonisoli-Alquati Andrea , Ambrosini Roberto , Boncoraglio Giuseppe , Møller Anders P.
Published: May 2009

Phenological responses to climate change vary among taxa and across trophic levels. This can lead to a mismatch between the life cycles of ecologically interrelated populations (e.g. predators and prey), with negative consequences for population dynamics of some of the interacting species. Here we provide, to our knowledge, the first evidence that climate change might disrupt the association between the life cycles of the common cuckoo (
Cuculus canorus
), a migratory brood parasitic bird, and its hosts. We investigated changes in timing of spring arrival of the cuckoo and its hosts throughout Europe over six decades, and found that short-distance, but not long-distance, migratory hosts have advanced their arrival more than the cuckoo. Hence, cuckoos may keep track of phenological changes of long-distance, but not short-distance migrant hosts, with potential consequences for breeding of both cuckoo and hosts. The mismatch to some of the important hosts may contribute to the decline of cuckoo populations and explain some of the observed local changes in parasitism rates of migratory hosts.
Three subclasses of a Drosophila insulator show distinct and cell type-specific genomic distributions
Authors: Bushey Ashley M. , Ramos Edward , Corces Victor G.
Published: May 2009

Insulators are protein-bound DNA elements that are thought to play a role in chromatin organization and the regulation of gene expression by mediating intra- and interchromosomal interactions. Suppressor of Hair-wing [Su(Hw)] and Drosophila CTCF (dCTCF) insulators are found at distinct loci throughout the Drosophila melanogaster genome and function by recruiting an additional protein, Centrosomal Protein 190 (CP190). We performed chromatin immunoprecipitation (ChIP) and microarray analysis (ChIP–chip) experiments with whole-genome tiling arrays to compare Su(Hw), dCTCF, boundary element-associated factor (BEAF), and CP190 localization on DNA in two different cell lines and found evidence that BEAF is a third subclass of CP190-containing insulators. The DNA-binding proteins Su(Hw), dCTCF, and BEAF show unique distribution patterns with respect to the location and expression level of genes, suggesting diverse roles for these three subclasses of insulators in genome organization. Notably, cell line-specific localization sites for all three DNA-binding proteins as well as CP190 indicate multiple levels at which insulators can be regulated to affect gene expression. These findings suggest a model in which insulator subclasses may have distinct functions that together organize the genome in a cell type-specific manner, resulting in differential regulation of gene expression.
Assessment of selection mapping near the myostatin gene (GDF‐8) in cattle
Authors: Wiener P. , Gutiérrez‐Gil B.
Published: May 2009

Domestic species provide a unique opportunity to examine the effects of selection on the genome. The myostatin gene (GDF‐8) has been under strong selection in a number of cattle breeds because of its influence on muscle conformation and association with the ‘double‐muscling’ phenotype. This study examined genetic diversity near this gene in a set of breeds including some nearly fixed for the allele associated with double‐muscling (MH), some where the allele is segregating at intermediate frequency and some where the allele is absent. A set of microsatellites and SNPs were used to examine patterns of diversity at the centromeric end of bovine chromosome 2, the region where GDF‐8 is located, using various statistical methods. The putative position of a selected gene was moved across the genomic region to determine, by regression, a best position of reduced heterozygosity. Additional analyses examined extended homozygous regions and linkage disequilibrium patterns. While the SNP data was not found to be very informative for selection mapping in this dataset, analyses of the microsatellite data provided evidence of selection on GDF‐8 in several breeds. These results suggested that, of the breeds examined, the allele was most recently introduced into the South Devon. Limitations to the selection‐mapping approach were highlighted from the analysis of the SNP data and the situation where the MH allele was at intermediate frequency.
Seven novel KIT mutations in horses with white coat colour phenotypes
Authors: Haase B. , Brooks S. A. , Tozaki T. , Burger D. , Poncet P.‐A. , Rieder S. , Hasegawa T. , Penedo C. , Leeb T.
Published: May 2009

White coat colour in horses is inherited as a monogenic autosomal dominant trait showing a variable expression of coat depigmentation. Mutations in the KIT gene have previously been shown to cause white coat colour phenotypes in pigs, mice and humans. We recently also demonstrated that four independent mutations in the equine KIT gene are responsible for the dominant white coat colour phenotype in various horse breeds. We have now analysed additional horse families segregating for white coat colour phenotypes and report seven new KIT mutations in independent Thoroughbred, Icelandic Horse, German Holstein, Quarter Horse and South German Draft Horse families. In four of the seven families, only one single white horse, presumably representing the founder for each of the four respective mutations, was available for genotyping. The newly reported mutations comprise two frameshift mutations (c.1126_1129delGAAC; c.2193delG), two missense mutations (c.856G>A; c.1789G>A) and three splice site mutations (c.338‐1G>C; c.2222‐1G>A; c.2684+1G>A). White phenotypes in horses show a remarkable allelic heterogeneity. In fact, a higher number of alleles are molecularly characterized at the equine KIT gene than for any other known gene in livestock species.
A missense mutation (p.Leu2153His) of thefactor VIIIgene causes cattle haemophilia A
Authors: Khalaj M. , Abbasi A. R. , Shimojo K. , Moritomo Y. , Yoneda K. , Kunieda T.
Published: May 2009

Two cases of hereditary bleeding disorder diagnosed as haemophilia A were recently observed in Japanese Brown cattle. We sequenced the entire coding region of thefactor VIIIgene of the affected animals to find a causative mutation. A nucleotide substitution of T to A resulting in an amino acid substitution of leucine to histidine (p.Leu2153His) was identified in a highly conserved residue in the C1 domain of factor VIII. Genotyping of 254 normal animals including the pedigree of the affected animals and randomly sampled animals of different breeds confirmed that the substitution is the causative mutation of cattle haemophilia A.
Maraviroc modelling strategy: use of early phase 1 data to support a semi‐mechanistic population pharmacokinetic model
Authors: Weatherley Barry , McFadyen Lynn
Published: May 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The non‐compartmental pharmacokinetics of maraviroc have been published for a number of phase 1 studies (including mass balance) but there has been no previous attempt to integrate the results into a model that is of utility beyond phase 1.

WHAT THIS STUDY ADDS

• This study provides a novel approach for pooling phase 1 non‐compartmental data (normalized AUC) and assessing the influence of key covariates for drugs with non‐linear/complex absorption patterns. We show a detailed example of how data may be integrated from a number of studies/sources in early drug development to construct semi‐mechanistic pharmacokinetic models (partitioning absorption and extraction components) for later phase applications (population pharmacokinetics and pharmacokinetics/pharmacodynamics).

AIMS

To model the basic pharmacokinetic (PK) characteristics of maraviroc to construct an integrated semi‐mechanistic PK model for use in later population PK analyses.

METHODS

Three analyses were performed utilizing intravenous, oral and radiolabel data. Firstly, a PK disposition model was developed from data from 20 healthy males who received 3, 10 or 30 mg of intravenous maraviroc. Secondly, a sigmoid Emaxvs dose model of dose‐normalized non‐compartmental AUC from oral dosing in 134 healthy young males and females across five phase 1 studies was constructed. This described absorption dose non‐linearities and tested for the influence of food, formulation and dose frequency on model parameters. The third analysis developed a mass balance model for both absorption and disposition of maraviroc with 300 mg solution and predicted the mass balance after administration of 100 mg tablet formulation.

RESULTS

A four‐compartment PK model best described the intravenous data and no influence of dose was found on clearance. Total clearance was 48 l h−1 (2.2% SE). The main covariate effect in the non‐compartmental analysis reproduced the dose‐dependency of food through a five‐fold increase in the ED50 of the sigmoid Emax model. The mass balance models calculated that 33.3% and 22.9% of 300 mg solution and 100 mg tablet doses, respectively, are systemically available, and first‐pass metabolism extracts 62% of an absorbed dose, estimating a hepatic blood flow of 101 l h−1.

CONCLUSIONS

The analysis demonstrates a novel integration approach to build a maraviroc semi‐mechanistic population PK model for further use in volunteers and patients.
Fractured reservoirs with fracture corridors
Authors: Questiaux Jean‐Marie , Couples Gary D. , Ruby Nicolas
Published: May 2009

Outcrop studies reveal a common occurrence of tabular zones of significantly‐increased fracture intensity affecting otherwise well‐lithified rocks. These zones, called fracture corridors, can have a profound effect on multi‐phase fluid flow in the subsurface. Using standard geo‐modelling tools, it is possible to generate 3D realizations of reservoirs that contain distributions of such fracture corridors that are consistent with observations, including the vertical frequency in pseudo‐wells inserted into the model at random locations. These models can generate the inputs to flow simulation. The approach adopted here is to run the flow simulations in a single‐porosity representation where the flow effects of fractures are upscaled into equivalent cell‐based properties, preserving a clear spatial relationship between the input geology and the resulting cellular model. The simulated reservoir performance outcomes are very similar to those seen in real oilfields: extreme variability between wells, early water breakthrough, disappointing recoveries and patchy saturation distributions. Thus, a model based on fracture corridors can provide an explanation for the observed flow performance of a suitable field. However, the use of seismics to identify fracture corridors is not an easy task. New work is needed to predict the seismic responses of fracture corridor systems to be able to judge whether it is likely that we can robustly detect and characterize these flow‐significant features adequately.
MyD88 and interferon‐α/β are differentially required for dendritic cell maturation but dispensable for development of protective memory against Listeria
Authors: Tam Miguel A. , Wick Mary Jo
Published: May 2009

Signalling pathways mediated by MyD88 are important for sensing Toll‐like receptor (TLR) ligands and directing an immune response. However, the influence of MyD88‐derived cytokines and interferon (IFN)‐α/β, the latter being made by both MyD88‐dependent and ‐independent pathways, in phenotypic and functional dendritic cell (DC) maturation during infection is poorly understood. Here we investigate the contribution of MyD88‐dependent and ‐independent pathways to DC maturation, CD8 T‐cell activation and the generation of protective memory against Listeria monocytogenes. We show that neither MyD88 deficiency alone nor MyD88/IFN‐αβR double deficiency alters Listeria‐induced costimulatory molecule up‐regulation on DCs in vivo. In contrast, DCs from infected IFN‐αβR−/− mice had higher CD80 and CD86 expression than wild‐type DCs. We then examined the function of DCs matured in infected knockout mice. We found that DCs from Listeria‐infected MyD88−/− and MyD88−/− IFN‐αβR−/− mice induced little or no IFN‐γ by CD8 T cells, respectively. In contrast, DCs from infected IFN‐αβR−/− mice had a greater capacity to induce IFN‐γ compared with DCs from infected wild‐type mice. When the CD8 T‐cell memory response was analysed, infected MyD88−/− and MyD88−/− IFN‐αβR−/− mice were found to have fewer bacteria‐specific memory CD8 T cells than wild‐type mice. However, the fraction of bacteria‐specific CD8 T cells making IFN‐γ was similar in all mouse strains, and MyD88−/− and MyD88−/− IFN‐αβR−/− mice survived lethal challenge. Together the data suggest an inhibitory effect of IFN‐α/β on functional DC maturation during Listeria infection and reveal overlapping roles of MyD88‐induced cytokines and IFN‐α/β in DC maturation and protective anti‐Listeria immunity.
Cloning, expression and functional analysis of a general odorant‐binding protein 2 gene of the rice striped stem borer, Chilo suppressalis (Walker) (Lepidoptera: Pyralidae)
Authors: Gong Z.‐J. , Zhou W.‐W. , Yu H.‐Z. , Mao C.‐G. , Zhang C.‐X. , Cheng J.A. , Zhu Z.‐R.
Published: May 2009

A full‐length cDNA encoding a general odorant binding protein 2 (GOBP2) was cloned from the antennae of the rice striped stem borer, Chilo suppressalis (Lepidoptera: Pyralidae), by the combination of reverse transcription PCR (RT‐PCR) and rapid amplification of cDNA ends PCR (RACE‐PCR). The cDNA contains a 489 bp open reading frame, which encodes a 162 amino acid protein, termed as Ch. suppressalis GOBP2 (CsupGOBP2). CsupGOBP2 is similar in the number of amino acids and protein sequence to GOBP2s in other species of Lepidoptera. RT‐PCR results showed that CsupGOBP2 mRNA was highly expressed in the adult antennae of both females and males, as was CsupGOBP2 protein as revealed by Western blot analysis. CsupGOBP2 expressed in Escherichia coli was purified by affinity chromatography, refolding and gel filtration from the inclusion body. Fluorescence emission spectra and competitive binding assays by using N‐phenyl‐1‐naphthylamine as first binding ligand and odorants as potential competitors revealed that the CsupGOBP2 protein has significant affinity to cis‐11‐hexadecenal (Z11–16:Ald), the main component of Ch. suppressalis pheromone and to laurinaldehyd and benzaldehyde, two general plant volatile aldehydes.
The Campoletis sonorensis ichnovirus vankyrin protein P‐vank‐1 inhibits apoptosis in insect Sf9 cells
Authors: Fath‐Goodin A. , Kroemer J. A. , Webb B. A.
Published: May 2009

The Campoletis sonorensis ichnovirus (CsIV) vankyrin genes encode proteins containing truncated ankyrin repeat domains with sequence homology to the inhibitory domains of NF‐κB transcription factor inhibitors, IκBs. The CsIV vankyrin proteins are thought to be involved in the suppression of NF‐κB activity during immune response and/or developmental events in the parasitized host. Here we report that when P‐vank‐1 was expressed stably from Sf9 cells, prolonged survival of these cells was observed after baculovirus infection, UV irradiation, and treatment with the apoptosis‐inducing chemical camptothecin compared to untransformed Sf9 cells. Furthermore, P‐vank‐1 inhibited nuclear and internucleosomal degradation and caspase activity after induction of apoptosis in Sf9 cells stably expressing P‐vank‐1. This is the first report of a polydnavirus protein with anti‐apoptotic function.
Effect of starch gelatinisation on nutrient digestibility and plasma metabolites in pigeons
Authors: Abd El‐Khalek E. , Kalmar I. , Van Weyenberg S. , Werquin G. , Janssens G. P. J.
Published: May 2009

Feed manufacturing exerts physical and chemical changes in ingredients, including the gelatinisation of starch. Studies on the effect of the degree of starch gelatinisation on nutrient digestibility, metabolism and subsequent performance show inconsistent results, and no data are available in pigeons. In a cross‐over trial, fourteen adult pigeons were randomly divided into two groups, in which two extruded pellet diets were tested. Both the diets were similar in ingredient composition and nutrient content, but differed in extrusion conditions, resulting in a different degree of starch gelatinisation: pellets with high gelatinisation degree (HG; 73.6% gelatinisation) and low gelatinisation degree (LG; 53.1% gelatinisation). After a 14‐day adaptation period, all excreta were gathered per bird during a 5‐day collection period. Coefficients of apparent digestibility of dry matter (DM), crude protein (CP), ether extract (EE), crude fibre (CF), crude ash (CA) and nitrogen free extract (NFE) as well as apparent nitrogen retention were calculated from proximate analyses of feed and excreta. Further, excreta consistency was subjectively scored. Blood samples were taken at the end of each period and plasma samples were analysed for glucose, fructosamine and triglycerides. Feed intake and body weight changes were recorded weekly. The apparent digestibility coefficients (ADCs) of DM, OM, CP, EE, CA and NFE were significantly higher in the LG group (p ≤ 0.05). The ADC of crude fibre was numerically higher in the LG group but not significant, and no significant differences were found in starch digestibility. Excreta consistency score tended to be higher in the LG diet group. Neither plasma glucose nor plasma fructosamine values were significantly different between the two test diets. The results of this study show that lower degree of starch gelatinisation in extruded diets can enhance digestibility in pigeons.
Prediction of digestible protein content of dry extruded dog foods: comparison of methods
Authors: Hervera M. , Baucells M. D. , González G. , Pérez E. , Castrillo C.
Published: May 2009

The aim of this study was to check the accuracy of laboratory methods to predict the apparent protein digestibility (CPd, %) and digestible protein content (DP, g/kgDM) of dog foods, avoiding the use of experimental animals in digestion trials. Twenty‐eight commercial dry extruded dog foods were tested by three different methodologies: an adaptation of the in vitro incubation method described by Hervera et al. (J Anim Physiol Anim Nutr 2007, 91: 205) for estimation of digestible energy of commercial dog foods, a modification of the pH drop methodology proposed by Hsu et al. (J Food Sci 1977, 42: 1269) for protein evaluation of human foods and the Near Infra Red Spectroscopy (NIRS) technology. All the methods assessed revealed very good, similar accuracy in the prediction of DP content either using the in vitro method (r = 0.99; RSD = 6.76; CV = 2.31%), the pH drop method (r = 0.99; RSD = 6.94; CV = 3.02%) or the NIRS (R2 = 0.96; SECV = 10.50) method, although the in vitro digestion method showed the highest accuracy approach of in vivo crude protein apparent digestibility: CPd in vitro (r = 0.81; RSD = 2.01; CV = 2.41%); CPd pH‐drop (r = 0.78; RSD = 2.48; CV = 2.98%) and NIRS (r2cv = 0.53; SECV = 2.37).
Dietary incorporation of feedstuffs naturally high in organic selenium for racing pigeons (Columba livia): effects on plasma antioxidant markers after a standardised simulation of a flying effort
Authors: Schoonheere N. , Dotreppe O. , Pincemail J. , Istasse L. , Hornick J. L.
Published: May 2009

Selenium is a trace element of importance for animal health. It is essential for adequate functioning of many enzymes such as, the antioxidant enzyme, glutathione peroxidase, which protects the cell against free radicals. A muscular effort induces a rise in reactive oxygen species production which, in turn, can generate an oxidative stress. Two groups of eight racing pigeons were fed respectively with a diet containing 30.3 (control group) and 195.3 (selenium group) μg selenium/kg diet. The pigeons were submitted to a standardised simulation of a flying effort during 2 h. Blood was taken before and after the effort to measure antioxidant markers and blood parameters related to muscle metabolism. Plasma selenium concentration and glutathione peroxidase activity were significantly higher in the selenium group. There were no significant differences for the other measured parameters. As a consequence of the effort, the pigeons of the selenium group showed a higher increase of glutathione peroxidase activity and a smaller increase of plasma lactate concentration. Variations because of the effort in the other markers were not significantly different between the two groups. It is concluded that the selenium status was improved with the feeding of feedstuffs high in Selenium.
Two cases of discontinuation syndrome following cessation of memantine
Authors: Kwak Yong Tae , Han Il‐Woo , Suk Seung‐Han , Koo Min‐Seong
Published: May 2009

Although memantine is widely used and generally considered safe, an abrupt cessation of memantine may result in discontinuation syndrome that can be distressing and result in decline of natural course. We report two patients who developed significant behavior disturbance after abrupt cessation of memantine. Although re‐trial of memantine improves these symptoms, more additional drugs may be required to achieve previous status. Therefore, abrupt cessation of memantine should be prudent and require cautious follow up.
The Value of Vocalizing: Five‐Month‐Old Infants Associate Their Own Noncry Vocalizations With Responses From Caregivers
Authors: Goldstein Michael H. , Schwade Jennifer A. , Bornstein Marc H.
Published: May 2009

The early noncry vocalizations of infants are salient social signals. Caregivers spontaneously respond to 30%–50% of these sounds, and their responsiveness to infants’ prelinguistic noncry vocalizations facilitates the development of phonology and speech. Have infants learned that their vocalizations influence the behavior of social partners? If they have, infants should show an extinction burst in vocalizing when adults temporarily stop responding to infant vocalizations. Thirty‐eight 5‐month‐olds were tested in the still‐face paradigm with an unfamiliar adult. When the adult assumed a still face, infants showed an extinction burst. Thus, 5‐month‐olds have learned the social efficacy of their vocalizations on caregivers’ behavior. Furthermore, the magnitude of 5‐month infants’ extinction bursts predicted their language comprehension at 13 months.
The Etiology of Science Performance: Decreasing Heritability and Increasing Importance of the Shared Environment From 9 to 12 Years of Age
Authors: Haworth Claire M. A. , Dale Philip S. , Plomin Robert
Published: May 2009

During childhood and adolescence, increases in heritability and decreases in shared environmental influences have typically been found for cognitive abilities. A sample of more than 2,500 pairs of twins from the Twins Early Development Study was used to investigate whether a similar pattern would be found for science performance from 9 to 12 years. Science performance was based on teacher‐assessed U.K. National Curriculum standards. Science at 9 years showed high heritability (64%) and modest shared environmental (16%) estimates. In contrast to the expected developmental pattern, heritability was significantly lower at 12 years (47%) and shared environmental influences were significantly higher (32%). Understanding what these increasingly important shared environmental influences are could lead to interventions that encourage engagement in science throughout the lifespan.
Differential Effects of Maternal Sensitivity to Infant Distress and Nondistress on Social‐Emotional Functioning
Authors: Leerkes Esther M. , Blankson A. Nayena , O’Brien Marion
Published: May 2009

Associations between maternal sensitivity to infant distress and nondistress and infant social‐emotional adjustment were examined in a subset of dyads from the NICHD Study of Early Child Care (N = 376). Mothers reported on infant temperament at 1 and 6 months postpartum, and maternal sensitivity to distress and nondistress were observed at 6 months. Child behavior problems, social competence, and affect dysregulation were measured at 24 and 36 months. Maternal sensitivity to distress but not to nondistress was related to fewer behavioral problems and higher social competence. In addition, for temperamentally reactive infants, maternal sensitivity to distress was associated with less affect dysregulation. Sensitivity to nondistress only prevented affect dysregulation if sensitivity to distress was also high.