bluuebunny/crossref_metadata_2025 huggingface dataset:
Fungal Endophytes in Mediterranean Oak Forests: A Lesson fromDiscula quercina
Authors: Moricca S. , Ragazzi A.
Published: March 2008

Fungal endophytes that colonize forest trees are widespread, but they are less well known than endophytes infecting grasses. The few studies on endophytes in trees mainly concern the tropical areas and the northernmost latitudes, while similar investigations in the Mediterranean region have so far been scarce and incidental. Endophytes are studied mostly in economically important forests suffering from diseases, such as oak forests. One common endophyte that has received some study on oak is the mitosporic Discula quercina. This paper, after first addressing some basic problems on tree endophytes, examines the ecology of D. quercina in Mediterranean oak stands. D. quercina is usually viewed as a symptomless colonizer of healthy Quercus cerris, infecting new leaves early in the growing season, in an unstable equilibrium between transient mutualism/neutralism and latent pathogenesis. It is postulated here that climatic factors can change the endophytic nature of D. quercina, turning it into a weak pathogen or an opportunistic invader of senescing and indeed healthy trees. It is argued more generally that stochastic events can cause the lifestyle of an endophyte to switch from beneficial/neutral to pathogenic, transforming the tree–endophyte interaction, an interaction that depends in part on the matching genomes of the tree and endophyte, and on the environmental context.
Genotyping of Benzimidazole-Resistant and Dicarboximide-Resistant Mutations in Botrytis cinerea Using Real-Time Polymerase Chain Reaction Assays
Authors: Banno Shinpei , Fukumori Fumiyasu , Ichiishi Akihiko , Okada Kiyotsugu , Uekusa Hidetoshi , Kimura Makoto , Fujimura Makoto
Published: March 2008

Botrytis cinerea, an economically important gray mold pathogen, frequently exhibits multiple fungicide resistance. A fluorescence resonance energy transfer-based real-time polymerase chain reaction assay has been developed to detect benzimidazole- and dicarboximide-resistant mutations. Three benzimidazole-resistant mutations—198Glu to Ala (E198A), F200Y, and E198K—in β-tubulin BenA were detected using a single set of fluorescence-labeled sensor and anchor probes by melting curve analysis. Similarly, three dicarboximide-resistant mutations—I365S, V368F plus Q369H, and Q369P—in the histidine kinase BcOS1 were successfully distinguished. Unassigned melting profiles in BenA genotyping assay resulted in the identification of a new benzimidazole-resistant BenA E198V mutation. This mutation conferred resistance to carbendazim as do E198A and E198K mutations. The isolates with BenA E198V mutation showed a negative cross-resistance to diethofencarb, but to a lesser extent than the E198A mutants. A survey of 210 B. cinerea field isolates revealed that most of benzimidazole-resistant isolates possessed the E198V or E198A mutation in the BenA gene, and the I365S mutation in the BcOS1 gene was also frequently observed in Japanese isolates. However, benzimidazole-resistant isolates with BenA F200Y or E198K mutations, which confer the diethofencarb-insensitive phenotype, were rare. Our BenA and BcOS1 genotyping is a rapid and reliable method that is suitable for monitoring the fungicide-resistant field population.
Using the TxtAB Operon to Quantify Pathogenic Streptomyces in Potato Tubers and Soil
Authors: Qu Xinshun , Wanner Leslie A. , Christ Barbara J.
Published: March 2008

The phytotoxin thaxtomin, produced by plant pathogenic Streptomyces species, is the only known pathogenicity determinant for common scab diseases of potato and other root and tuber crops. Genes encoding thaxtomin synthetase (txtAB) are found on a pathogenicity island characteristic of genetically diverse plant pathogenic Streptomyces species. In this study, an SYBR Green quantitative real-time polymerase chain reaction (PCR) assay using primers designed to anneal to the txtAB operon of Streptomyces was developed to quantify pathogenic bacterial populations in potatoes and soil. The real-time PCR assay was specific for pathogenic Streptomyces strains. The detection limit of the assay was 10 fg of the target DNA, or one genome equivalent. Cycle threshold (Ct) values were linearly correlated with the concentration of the target DNA (correlation coefficient R2 = 0.99) and were not affected by the presence of plant DNA extracts, indicating the usefulness of the assay for quantitative analyses of the pathogenic bacteria in plant tissues. The amount of pathogenic Streptomyces DNA in total DNA extracts from 1 g asymptomatic and symptomatic tubers was quantified using the assay and ranged from 101 to 106 pg. A standard curve was established to quantify pathogenic Streptomyces in soil. Using the standard curve, numbers of pathogenic Streptomyces colony forming units were extrapolated to range from 103 to 106 per gram of soil from potato fields where common scab was found. This real-time PCR assay using primers designed from the txtAB operon allows rapid, accurate, and cost effective quantification of pathogenic Streptomyces strains in potato tubers and in soil.
Influence of Host Resistance on the Genetic Structure of the White Pine Blister Rust Fungus in the Western United States
Authors: Richardson B. A. , Klopfenstein N. B. , Zambino P. J. , McDonald G. I. , Geils B. W. , Carris L. M.
Published: March 2008

Cronartium ribicola, the causal agent of white pine blister rust, has been devastating to five-needled white pines in North America since its introduction nearly a century ago. However, dynamic and complex interactions occur among C. ribicola, five-needled white pines, and the environment. To examine potential evolutionary influences on genetic structure and diversity of C. ribicola in western United States, population genetic analyses of C. ribicola were conducted using amplified fragment length polymorphism (AFLP) molecular markers. The fungus was sampled at six sites. Collections for two of the six sites were from separate plantings of resistant-selected western white pine and sugar pine. Heterozygosity based on polymorphic loci among populations ranged from 0.28 to 0.40, with resistant-selected plantations at the extremes. Genetic differentiation was also highest between these two populations. Principal coordinates analysis and Bayesian assignment placed most isolates that are putative carriers of virulence to major-gene resistance into a discernable cluster, while other isolates showed no clustering by site or host species. These results indicate that C. ribicola in western North America is not genetically uniform, despite its presumed single site of introduction and relatively brief residence. Moreover, major-gene resistance appears to have imposed strong selection on the rust, resulting in reduced genetic diversity. In contrast, no evidence of selection was observed in C. ribicola from hosts that exhibit only multigenic resistance.
Alternaria brassicae Produces a Host-Specific Protein Toxin from Germinating Spores on Host Leaves
Authors: Parada R. Y. , Sakuno E. , Mori N. , Oka K. , Egusa M. , Kodama M. , Otani H.
Published: March 2008

Spore suspensions of Alternaria brassicae, the causal agent of gray leaf spot in Brassica plants, were incubated on the leaves of cabbage (B. oleracea) and spore germination fluid (SGF) was collected after 48 h. A high molecular weight (HMW) fraction (>10 kDa) was separated from the SGF by ultrafiltration. In a detached leaf assay, the HMW fraction induced visible symptoms only on host leaves and the toxicity was lost by treatment with proteinase K or heat at 60°C for 15 min, indicating the presence of host-specific protein toxin(s). A protein toxin in the HMW fraction was purified by several chromatography steps. The toxin induced water-soaked symptoms followed by chlorosis at concentrations of 0.5 to 1 μg/ml on host leaves, but not on nonhost leaves even at 50 μg/ml. The toxin also had infection-inducing activity when added to spore suspension of a nonpathogenic isolate of A. alternata, causing symptoms similar to the infection of A. brassicae only on host leaves. These results indicate that a new host-specific protein toxin named ABR-toxin is released from germinating spores of A. brassicae on host leaves. ABR-toxin migrated as a protein of 27.5 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The isoelectric point of ABR-toxin was estimated to be approximately 7.0 and 21 N-terminal amino acid residues were sequenced.
Further Evidence of Mirafiori lettuce big-vein virus but Not of Lettuce big-vein associated virus with Big-Vein Disease in Lettuce
Authors: Sasaya Takahide , Fujii Hiroya , Ishikawa Koichi , Koganezawa Hiroki
Published: March 2008

Mirafiori lettuce big-vein virus (MLBVV) and Lettuce big-vein associated virus (LBVaV) are found in association with big-vein disease of lettuce. Discrimination between the two viruses is critical for elucidating the etiology of big-vein disease. Using specific antibodies to MLBVV and LBVaV for western blotting and exploiting differences between MLBVV and LBVaV in host reaction of cucumber and temperature dependence in lettuce, we separated the two viruses by transfering each virus from doubly infected lettuce plants to cucumber or lettuce plants. A virus-free fungal isolate was allowed to acquire the two viruses individually or together. To confirm the separation, zoospores from MLBVV-, LBVaV-, and dually infected lettuce plants were used for serial inoculations of lettuce seedlings 12 successive times. Lettuce seedlings were infected at each transfer either with MLBVV alone, LBVaV alone, or both viruses together, depending on the virus carried by the vector. Lettuce seedlings infected with MLBVV alone developed the big-vein symptoms, while those infected with LBVaV alone developed no symptoms. In field surveys, MLBVV was consistently detected in lettuce plants from big-vein-affected fields, whereas LBVaV was detected in lettuce plants not only from big-vein-affected fields but also from big-vein-free fields. LBVaV occurred widely at high rates in winter-spring lettuce-growing regions irrespective of the presence of MLBVV and, hence, of the presence of the big-vein disease.
Developmental growth patterns of the filter-feeder pterosaur,Pterodaustro guiñazui
Authors: Chinsamy A , Codorniú L , Chiappe L
Published: March 2008

Life-history parameters of pterosaurs such as growth and ontogenetic development represent an enigma. This aspect of pterosaur biology has remained perplexing because few pterosaur taxa are represented by complete ontogenetic series. Of these,Pterodaustrois unique in that besides being represented by hundreds of individuals with wing spans ranging from 0.3 to 2.5 m, it includes an embryo within an egg. Here we present a comprehensive osteohistological assessment of multiple skeletal elements of a range of ontogenetic sizes ofPterodaustro, and we provide unparalleled insight into its growth dynamics. We show that, upon hatching,Pterodaustrojuveniles grew rapidly for approximately 2 years until they reached approximately 53% of their mature body size, whereupon they attained sexual maturity. Thereafter, growth continued for at least another 3–4 years at comparatively slower rates until larger adult body sizes were attained. Our analysis further provides definitive evidence thatPterodaustrohad a determinate growth strategy.
Visual signals of status and rival assessment in
Polistes dominulus
paper wasps
Authors: Tibbetts Elizabeth A , Lindsay Rebecca
Published: March 2008

Aggressive competition is an important aspect of social interactions, but conflict can be costly. Some animals are thought to minimize the costs of conflict by using conventional signals of agonistic ability (i.e. badges of status) to assess rivals. Although putative badges have been found in a range of taxa, little research has tested whether individuals use badges to assess potential rivals before they engage in aggressive contests. Here, choice trials were used to test how the variable black facial patterns in
Polistes dominulus
wasps are used during rival assessment. Focal wasps were given access to two patches of food, each guarded by a wasp whose facial pattern had been experimentally altered. Wasps chose food patches based on the facial pattern of the guard, preferring to challenge guards with facial patterns indicating a low level of quality, while avoiding guards with facial patterns indicating a high level of quality. Therefore, status badges play an important role during rival assessment; paper wasps use facial patterns alone to quickly assess the agonistic abilities of strangers.
Automatic identification of bird targets with radar via patterns produced by wing flapping
Authors: Zaugg Serge , Saporta Gilbert , van Loon Emiel , Schmaljohann Heiko , Liechti Felix
Published: March 2008

Bird identification with radar is important for bird migration research, environmental impact assessments (e.g. wind farms), aircraft security and radar meteorology. In a study on bird migration, radar signals from birds, insects and ground clutter were recorded. Signals from birds show a typical pattern due to wing flapping. The data were labelled by experts into the four classes BIRD, INSECT, CLUTTER and UFO (unidentifiable signals). We present a classification algorithm aimed at automatic recognition of bird targets. Variables related to signal intensity and wing flapping pattern were extracted (via continuous wavelet transform). We used support vector classifiers to build predictive models. We estimated classification performance via cross validation on four datasets. When data from the same dataset were used for training and testing the classifier, the classification performance was extremely to moderately high. When data from one dataset were used for training and the three remaining datasets were used as test sets, the performance was lower but still extremely to moderately high. This shows that the method generalizes well across different locations or times. Our method provides a substantial gain of time when birds must be identified in large collections of radar signals and it represents the first substantial step in developing a real time bird identification radar system. We provide some guidelines and ideas for future research.
Constructing the effect of alternative intervention strategies on historic epidemics
Authors: Cook A.R , Gibson G.J , Gottwald T.R , Gilligan C.A
Published: March 2008

Data from historical epidemics provide a vital and sometimes under-used resource from which to devise strategies for future control of disease. Previous methods for retrospective analysis of epidemics, in which alternative interventions are compared, do not make full use of the information; by using only partial information on the historical trajectory, augmentation of control may lead to predictions of a paradoxical increase in disease. Here we introduce a novel statistical approach that takes full account of the available information in constructing the effect of alternative intervention strategies in historic epidemics. The key to the method lies in identifying a suitable mapping between the historic and notional outbreaks, under alternative control strategies. We do this by using the Sellke construction as a latent process linking epidemics. We illustrate the application of the method with two examples. First, using temporal data for the common human cold, we show the improvement under the new method in the precision of predictions for different control strategies. Second, we show the generality of the method for retrospective analysis of epidemics by applying it to a spatially extended arboreal epidemic in which we demonstrate the relative effectiveness of host culling strategies that differ in frequency and spatial extent. Some of the inferential and philosophical issues that arise are discussed along with the scope of potential application of the new method.
Human mobility models and opportunistic communications system design
Authors: Hui Pan , Crowcroft Jon
Published: March 2008

In this paper, we seek to improve understanding of the structure of human mobility, with a view to using this for designing algorithms for the dissemination of data among mobile users. We analyse community structures and node centrality from the human mobility traces and use these two metrics to design efficient forwarding algorithms in terms of delivery ratio and delivery cost for mobile networks. This is the first empirical study of community and centrality using real human mobility datasets.
Short messages
Authors: Wischik D.J
Published: March 2008

This paper has three purposes. The first one is to explain to a general audience what is involved in retrieving a web page or performing some other complex network transaction, and what can make it slow, and why the problem of slowness is likely to get worse as networked applications become more complex. The second is to describe, to those who program networked applications, certain facts that we have learnt from modelling communication networks, notably the fact of heavy-tailed distributions in traffic, which may allow more efficient applications to be written. The third is to describe to network modellers an interesting class of problems relating to algorithm design for communication networks.
Flow-level performance and user mobility in wireless data networks
Authors: Borst Sem
Published: March 2008

Channel conditions in wireless networks exhibit huge variations across space and time, giving rise to vast fluctuations in the transmission rates. Channel-aware scheduling strategies provide an effective mechanism for improving throughput performance by exploiting such rate variations, and these have been extensively examined at the packet level for a static user configuration. In this paper, we discuss the performance implications at the flow level for a dynamic user population, taking into account variations on a slower time scale and wide-range user mobility as well. First of all, we present simple necessary conditions for flow-level stability and prove that these are in fact (near) sufficient for a wide family of utility-based scheduling strategies. It is further shown how the flow-level performance of the proportional fair scheduling strategy may be evaluated by means of a processor-sharing model with a state-dependent service rate. In addition, we examine the impact of variations on a slower time scale, and establish that the so-called fluid and quasi-stationary regimes yield explicit, insensitive performance bounds. Finally, we turn our attention to a network of several base stations (BSs) with handoffs of active sessions governed by wide-range user mobility. It is demonstrated that mobility increases the capacity, not only in the case of globally optimal scheduling but also when each of the BSs adheres to a local fair-sharing discipline.
De novo bacterial genome sequencing: Millions of very short reads assembled on a desktop computer
Authors: Hernandez David , François Patrice , Farinelli Laurent , Østerås Magne , Schrenzel Jacques
Published: March 2008

Novel high-throughput DNA sequencing technologies allow researchers to characterize a bacterial genome during a single experiment and at a moderate cost. However, the increase in sequencing throughput that is allowed by using such platforms is obtained at the expense of individual sequence read length, which must be assembled into longer contigs to be exploitable. This study focuses on the Illumina sequencing platform that produces millions of very short sequences that are 35 bases in length. We propose a de novo assembler software that is dedicated to process such data. Based on a classical overlap graph representation and on the detection of potentially spurious reads, our software generates a set of accurate contigs of several kilobases that cover most of the bacterial genome. The assembly results were validated by comparing data sets that were obtained experimentally for Staphylococcus aureus strain MW2 and Helicobacter acinonychis strain Sheeba with that of their published genomes acquired by conventional sequencing of 1.5- to 3.0-kb fragments. We also provide indications that the broad coverage achieved by high-throughput sequencing might allow for the detection of clonal polymorphisms in the set of DNA molecules being sequenced.
Phylogenetic analysis of the endemic New Caledonian cockroach Lauraesilpha. Testing competing hypotheses of diversification
Authors: Murienne J. , Pellens R. , Budinoff R. B. , Wheeler W. C. , Grandcolas P.
Published: March 2008

New Caledonia is a tropical hotspot of biodiversity with high rates of regional and local endemism. Despite offering an ideal setting to study the evolution of endemism, New Caledonia has received little attention compared with the other nearby hotspots, particularly New Zealand. Most studies of the Neocaledonian endemism have been carried out at the regional level, comparing the various groups and species present in New Caledonia but absent in neighboring territories. In addition, remarkably high short‐range endemism has been documented among plants, lizard and invertebrates, although these have usually been done, lacking a phylogenetic perspective. Most studies of Neocaledonian endemism have referred to the geological Gondwanan antiquity of the island and its metalliferous soils derived from ultramafic rocks. Very old clades are thought to have been maintained in refugia and diversified on the metalliferous soils. The present study documents the pattern of diversification and establishment of short‐range endemism in a phylogenetic context using the Neocaledonian cockroach genus Lauraesilpha. Mitochondrial and nuclear genes were sequenced to reconstruct phylogenetic relationships among the species of this genus. These relationships, in the light of the species distribution, do not support the hypothesis that species diversified via an adaptive radiation on metalliferous soils and are not consistent with areas of highest rainfall. Species of Lauraesilpha have similar altitudinal ranges and ecological habits and are short‐range endemics on mountains. What our analysis did reveal was that closely related species are found on nearby or contiguous mountains, and thus these formations probably played the key role establishing short‐range endemism (in association with recent climatic changes).

© The Willi Hennig Society 2008.
Unanticipated difficult airway management in anaesthetised patients: a prospective study of the effect of mannequin training on management strategies and skill retention
Authors: Kuduvalli P. M. , Jervis A. , Tighe S. Q. M. , Robin N. M.
Published: March 2008

This prospective study on a medium‐fidelity simulator (SimMan®, Laerdal Medical Corporation, Wappingers Falls, NY, USA) examined the management of unanticipated difficult airway by 21 anaesthetists and the effect of training in this context. There were two scenarios investigated: ‘cannot intubate, can ventilate’(CI) and ‘cannot intubate, cannot ventilate’(CICV). Following initial evaluation, volunteers underwent training in the ‘Difficult Airway Society’ (DAS) algorithms and associated technical skills. At 6–8 weeks and 6–8 months, performance was compared with the initial evaluation. There was a more structured approach following training (p < 0.05), which was sustained at 6–8 months, but only for the CICV scenario (p < 0.01). In CI, use of standard and intubating laryngeal mask airway increased following training (p = 0.021). This was sustained over time (p = 0.01). In both scenarios there was a reduced incidence of equipment misuse (p < 0.0005), which was sustained over time (p < 0.0001). We conclude that simulation‐based training significantly improves performance for at least 6–8 weeks. Training should be repeated at intervals of 6 months or less.
Effects of methylene blue on propofol requirement during anaesthesia induction and surgery
Authors: Licker M. , Diaper J. , Robert J. , Ellenberger C.
Published: March 2008

Delayed emergence from anaesthesia and neurological disturbances have been reported in patients undergoing parathyroidectomy who received methylene blue (MB) pre‐operatively. We hypothesised that MB would decrease propofol requirements. The Bispectral index (BIS) and a target‐controlled infusion of propofol were used in two groups of 11 matched patients. Patients in one group were pretreated with MB. During induction, clinical sedation scores and BIS values were significantly lower at the predicted effect‐site propofol concentration of 2 μg.ml−1 in the MB compared with the control group. Intra‐operatively, although similar BIS values were achieved in the two groups, patients pretreated with MB required a mean 50% lower dose of propofol compared with controls. In view of these findings, care should be taken to ensure an adequate depth of anaesthesia by titrating the administration of anaesthetic agents whenever MB is infused peri‐operatively.
The effect of bolus administration of remifentanil on QTc interval during induction of sevoflurane anaesthesia
Authors: Kweon T. D. , Nam S. B. , Chang C. H. , Kim M. S. , Lee J. S. , Shin C. S. , June D. B. , Han D. W.
Published: March 2008

Stimulation of the sympathetic nervous system associated with tracheal intubation causes corrected QT (QTc) interval prolongation. We postulated that the use of remifentanil during induction of anaesthesia might prevent this. Sixty unpremedicated, ASA grade 1 patients were selected and randomly allocated to receive either saline (group S), remifentanil 0.5 μg.kg−1 (group R 0.5) or remifentanil 1.0 μg.kg−1 (group R1.0) 1 min before laryngoscopy. The QTc interval was significantly prolonged immediately following intubation in group S and group R0.5, but it remained stable in group R1.0, compared with the QTc interval just before laryngoscopy. It is concluded that the administration of remifentanil 1.0 μg.kg−1 before intubation can prevent the prolongation of the QTc interval associated with tracheal intubation during induction of anaesthesia with sevoflurane.
In vivo visualization of donepezil binding in the brain of patients with Alzheimer's disease
Authors: Okamura Nobuyuki , Funaki Yoshihito , Tashiro Manabu , Kato Motohisa , Ishikawa Yoichi , Maruyama Masahiro , Ishikawa Hiroyasu , Meguro Kenichi , Iwata Ren , Yanai Kazuhiko
Published: March 2008

What is already known about this subject

• Deficit in central cholinergic neurotransmission is a consistent change associated with Alzheimer's disease (AD).

• Donepezil hydrochloride exhibits selective inhibition of acetylcholinesterase (AChE) and is widely used for the treatment of AD.

• The biodistribution of donepezil in the brain after administration is not precisely understood in vivo.

• There is no method to measure the amount of binding of orally administered donepezil to AChE.

What this study adds

• This study clearly visualizes the distribution of donepezil in human brain using [11C]‐donepezil and positron emission tomography.

• This study demonstrates prominent reduction of the donepezil binding site in the AD brain.

• This study provides methodology to measure the AChE binding occupancy of orally administered donepezil and provides a new surrogate marker for evaluation and prediction of response to donepezil treatment.

Aims

The aims of this study were to visualize in vivo binding of donepezil to acetylcholinesterase (AChE) in the brain and to establish a method for measuring the amount of binding of orally administered donepezil.

Methods

[5‐11C‐methoxy]‐donepezil ([11C]‐donepezil) was radiolabelled as a positron emission tomography (PET) tracer. The biodistribution of [11C]‐donepezil was measured by PET in 10 AD patients and six elderly normal subjects. Two AD patients underwent additional PET measurements after oral administration of donepezil for 6 months.

Results

[11C]‐donepezil‐PET images demonstrated high densities of tracer distribution in AChE‐rich brain regions such as the striatum, thalamus, and cerebellum. Compared with elderly normal subjects, patients with mild AD exhibited about 18–20% reduction of donepezil binding in the neocortex and hippocampus, while patients with moderate AD exhibited about 24–30% reduction of donepezil binding throughout the brain. Orally administered donepezil (5 mg day−1) induced 61.6–63.3% reduction of donepezil binding in AD brains. The distribution volume of [11C]‐donepezil in the hippocampus was significantly correlated with MMSE scores in AD patients.

Conclusions

[11C]‐donepezil‐PET enables quantitative measurement of donepezil binding in the brain. AD patients exhibited reduction of donepezil binding in the brain, even in the early stage of disease. Longitudinal evaluation by this technique enables determination of AChE binding occupancy of orally administered donepezil.
Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers
Authors: Abel Samantha , Van Der Ryst Elna , Rosario Maria C. , Ridgway Caroline E. , Medhurst Christine G. , Taylor‐Worth Richard J. , Muirhead Gary J.
Published: March 2008

AIMS

To evaluate the pharmacokinetics, safety and tolerability of single and multiple oral doses of maraviroc in healthy volunteers.

METHODS

Three double‐blind, placebo‐controlled, dose‐escalation studies with either single or multiple doses of maraviroc were conducted in healthy volunteers. Plasma and urine samples were collected to investigate the pharmacokinetics of maraviroc and evaluate any changes with respect to dose and duration/frequency of dosing. Safety and toleration of maraviroc were also assessed.

RESULTS

Maraviroc is rapidly absorbed following oral administration, and plasma Tmax is achieved within 0.5–4.0 h postdose. Steady‐state plasma concentrations are achieved after 7 consecutive days of dosing. Although the pharmacokinetics of maraviroc is nonproportional over the dose range studied (3–1200 mg), the degree of nonproportionality is small at clinically relevant doses. Renal clearance is approximately 10–12 l h−1 and appears unaffected by increasing maraviroc doses. Maraviroc does not significantly modulate the activity of CYP2D6 or CYP3A4 at clinically relevant doses. There were no serious adverse events in any of these studies, and doses up to 900 mg were generally well tolerated, with postural hypotension being the dose‐limiting event. There was no pattern or dose relationship observed with maraviroc with regard to laboratory abnormalities, including hepatic transaminases. No clinically significant increases in QTc were noted at clinically relevant doses.

CONCLUSIONS

Maraviroc is absorbed into the systemic circulation and reaches steady state by day 7 of multiple dosing. It does not significantly influence the activity of major drug‐metabolizing enzymes and is well tolerated at clinically relevant doses, with most adverse events being mild or moderate.
The effects of cotrimoxazole or tenofovir co‐administration on the pharmacokinetics of maraviroc in healthy volunteers
Authors: Abel Samantha , Russell Deborah , Whitlock Lyndsey A. , Ridgway Caroline E. , Muirhead Gary J.
Published: March 2008

AIMS

To assess the potential of cotrimoxazole and tenofovir, drugs which are inhibitors and/or substrates of renal transporters, to alter the pharmacokinetic profile of maraviroc.

METHODS

Two randomized, placebo‐controlled, two‐way crossover studies were conducted in healthy male and female subjects. In study 1, 16 subjects, aged 18–45 years, received maraviroc (300 mg b.i.d.) with and without cotrimoxazole (960 mg b.i.d.; 160 mg trimethoprim and 800 mg sulfamethoxazole). In study 2, 12 subjects, aged 21–45 years, received maraviroc (300 mg b.i.d.) with and without tenofovir (300 mg q.d.). For study 1, blood was collected predose and on days 1–7. In study 2, blood was collected predose, on day 1 and days 3–7. In both studies, blood was collected at intervals up to 12 h postdose on day 7. Urine was collected on day 7, 0–12 h post morning dose. Blood and urine were analysed for maraviroc using liquid chromatography/tandem mass spectrometry.

RESULTS

The geometric mean ratios for Cmax and AUC12 were 119% and 111%, respectively, for maraviroc plus cotrimoxazole and 104% and 103%, respectively, for maraviroc plus tenofovir, compared with maraviroc plus placebo. Renal clearance of maraviroc plus placebo was 8.3 l h−1 and 8.5 l h−1 and was 7.8 l h−1 for maraviroc plus cotrimoxazole and maraviroc plus tenofovir. There were no serious or severe adverse events or any clinically significant changes in laboratory tests, blood pressure, or electrocardiograms.

CONCLUSIONS

Neither cotrimoxazole nor tenofovir caused a clinically significant effect on the pharmacokinetics of maraviroc. Maraviroc 300 mg b.i.d. was well tolerated when co‐administered with either cotrimoxazole or tenofovir.
Population pharmacokinetic/ pharmacodynamic analysis of CCR5 receptor occupancy by maraviroc in healthy subjects and HIV‐positive patients
Authors: Rosario Maria C. , Jacqmin Philippe , Dorr Pat , James Ian , Jenkins Timothy M. , Abel Samantha , Van Der Ryst Elna
Published: March 2008

BACKGROUND

Maraviroc, a noncompetitive antagonist of the CCR5 coreceptor, was recently approved in the USA as a treatment of HIV infection. For antiretroviral agents that target the virus, antiviral effect can be related to some extent to plasma drug concentrations. For CCR5 antagonists that target the host cells, receptor occupancy in vivo might be a better predictor of efficacy.

AIMS

To develop a population pharmacokinetic (PK)–pharmacodynamic (PD) model that describes CCR5 receptor occupancy by maraviroc after oral administration at different doses in healthy volunteers and HIV‐positive patients and to assess the relevance of receptor occupancy in predicting the decrease in viral load (HIV‐1 RNA copies ml−1) in HIV‐positive patients.

METHODS

Receptor occupancy data from 88 individuals enrolled in two multiple dose trials were included in the population PK–receptor binding model. Out of the 88 individuals, 25 were HIV‐1‐infected patients and had viral load measurements, whereas the remaining 63 were healthy volunteers. Doses ranged from 3 mg b.i.d. to 600 mg q.d. A previously published PK–PD disease model describing the effect of maraviroc on the viral load was updated by replacing its PD module by the receptor occupancy model. Simulated viral load–time profiles with the updated model were compared with the profiles observed in patients.

RESULTS

The majority of measured plasma concentrations were associated with receptor occupancy ≥50% even at the lowest dose of 3 mg b.i.d. A simple direct Emax model appeared to describe satisfactorily the PK–receptor occupancy relationship. The estimated KD was around 0.0894 ng ml−1, far below the operational in vivo antiviral IC50 of 8 ng ml−1. Accordingly, simulations led to marked overprediction of the decrease in viral load–time profiles.

CONCLUSIONS

Maraviroc receptor occupancy close to the maximum is required to induce a significant decrease in viral load, indicating that in vivo CCR5 receptor occupancy by maraviroc is not a direct measure of drug inhibitory activity. Considering the imprecision of the measurement in the upper flat part of the maraviroc concentration vs. percent CCR5 occupancy curve, it can reasonably be concluded that routine monitoring of receptor occupancy as a biomarker for maraviroc efficacy will not be helpful. Based on this analysis, it was decided not to use receptor occupancy as a biomarker of viral load inhibition during the development of CCR5 antagonist compounds.
A receptor theory‐based semimechanistic PD model for the CCR5 noncompetitive antagonist maraviroc
Authors: Jacqmin Philippe , McFadyen Lynn , Wade Janet R.
Published: March 2008

AIM

To develop a novel combined viral dynamics/operational model of (ant‐)agonism that describes the pharmacodynamic effects of maraviroc, a noncompetitive CCR5 inhibitor, on viral load.

METHODS

A common theoretical framework based on receptor theory and the operational model of (ant‐)agonism has been developed to describe the binding of maraviroc to the CCR5 receptor and the subsequent decrease in viral load. The anchor point of the operational model in the differential equations of the viral dynamic model is the infection rate constant; this is assumed to be dependent on the number of free activated receptors on each target cell.

RESULTS

The new model provides one explanation for the apparent discrepancy between thein vivobinding of maraviroc to the CCR5 receptor (KD = 0.089 ng ml−1) and the estimatedin vivoinhibition (IC50 = 8 ng ml−1) of the infection rate. The estimatedKEvalue of the operational model indicates that only 1.2% of free activated receptors are utilized to elicit 50% of the maximum infection rate.

CONCLUSIONS

The developed model suggests that the target cells, when activated, express more receptors (spare receptors) than needed. In the presence of maraviroc these spare receptors first require blocking before any decrease in the infection rate, and consequently in the viral load at equilibrium, can be detected. The model allows the simultaneous simulation of the binding of maraviroc to the CCR5 receptor and the change in viral load after both short‐ and long‐term treatment.
Stromal cell‐derived factor‐1 promotes bone marrow‐derived cells differentiation to cardiomyocyte phenotypes in vitro
Authors: Chen M. , Xie H.‐Q. , Deng L. , Li X.‐Q. , Wang Y. , Zhi W. , Yang Z.‐M.
Published: March 2008

Abstract.  Objective: Recent studies have demonstrated the potential of bone marrow‐derived cells (BMDC) to differentiate into cardiomyocytes. Up‐regulation of stromal cell‐derived factor‐1 (SDF‐1), a member of the chemokine CXC subfamily, mediating recruitment of BMDC has been documented in infarcted myocardium; however, it remains unknown whether SDF‐1 plays a role in cardiomyogenesis of BMDC. Materials and methods: Adherent BMDCs were cultured with SDF‐1, or specific inhibitor for PI3K, CXCR4 or Akt with SDF‐1, respectively. After 2 weeks, mRNAs and proteins from BMDCs were examined. Results: Two weeks after supplementation with SDF‐1, either murine or human adherent BMDC cultured in vitro expressed cardiac specific mRNAs (NKX2.5, atrial natriuretic factor and heavy chain β‐myosin) and proteins (troponin I and heavy chain cardiac myosin), and expression levels were partly decreased by combined treatment of CXCR4, PI3K or Akt inhibitor, with SDF‐1. Conclusions: The novel findings suggest that beyond its role in mobilization and homing of BMDC, SDF‐1 can promote BMDC to give rise to cardiomyocyte phenotypes in vitro, and the SDF‐1/CXCR4/PI3K/Akt pathway may be one of the molecular mechanisms regulating cardiomyogenesis.
Associations with multiple pituitary hormone deficiency in patients with an ectopic posterior pituitary gland
Authors: Murray P. G. , Hague C. , Fafoula O. , Patel L. , Raabe A. L. , Cusick C. , Hall C. M. , Wright N. B. , Amin R. , Clayton P. E.
Published: March 2008

Introduction  The presence of an ectopic posterior pituitary gland (EPP) on magnetic resonance imaging (MRI) is associated with hypopituitarism with one or more hormone deficiencies. We aimed to identify risk factors for having multiple pituitary hormone deficiency (MPHD) compared to isolated growth hormone deficiency (IGHD) in patients with an EPP.

Methods  In 67 patients (45 male) with an EPP on MRI, the site (hypothalamic vs. stalk) and surface area (SA) [ × (maximum diameter/2) × (maximum height/2), mm2] of the EPP were recorded and compared in patients with IGHD and MPHD in relation to clinical characteristics.

Results  In MPHD (n = 32) compared to IGHD (n = 35) patients: age of presentation was younger (1·4 [0·1–10·7]vs. 4·0 [0·1–11·3] years, P = 0·005), major incidents during pregnancy were increased (47%vs. 20%, P = 0·02) as were admissions to a neonatal intensive care unit (NICU) (60%vs. 26%, P = 0·04), whilst EPP SA was lower (12·3 [2·4–34·6]vs. 25·7 [6·9–48·2] mm2, P < 0·001). In patients with a hypothalamic (n = 56) compared to a stalk sited EPP (n = 11): prevalence of MPHD was greater (55%vs. 9%,P = 0·05) and EPP surface area was smaller (17·3 [2·4–48·2]vs. 25·3 [11·8–38·5] mm2, P < 0·001). In regression analysis, after adjusting for age, presence of MPHD was associated with: major incidents during pregnancy (RR 6·8 [95%CI 1·2–37·7]), hypothalamic EPP site (RR 10·9 [1·0–123·9]) and small EPP SA (RR 2·5 [1·0–5·0] for tertiles of SA).

Conclusion  In patients with an EPP, adverse antenatal events, size (small) and position (hypothalamic) of the posterior pituitary gland on MRI were associated with MPHD. These findings suggest that adverse factors during pregnancy may be important for the development of an EPP.
A cyanobacterial bloom prevents fish trophic cascades
Authors: RONDEL CAROLINE , ARFI ROBERT , CORBIN DANIEL , LE BIHAN FRÉDÉRIC , NDOUR EL HADJI , LAZZARO XAVIER
Published: March 2008

1. We experimentally compared the impacts of visually feeding zooplanktivorous fish and filter‐feeding omnivorous fish in shallow tropical Dakar Bango reservoir, Senegal. We provoked a cyanobacterial Anabaena bloom under mesotrophic to eutrophic N‐limited conditions in 18 enclosures assigned to six Nile tilapia life‐stage treatments, at typical biomasses: fishless control (C), zooplanktivorous fry (Z), omnivorous juveniles (O), herbivorous fingerlings (H) and two combinations (OZ, OH).

2. All fish grew well, but as prevalent inedible phytoplankton dampened fish effects, community‐level trophic cascades did not occur. Planktivore types acted independently and affected differentially the biomasses of total zooplankton, cyclopoids, nauplii, cladocerans, invertebrate carnivores, large herbivores, colonial cyanobacteria and Chlorophyta. They neither influenced the total biomass of phytoplankton, nor most water chemistry characteristics. Responses were apparently not fish‐biomass related. The bloom collapsed synchronously in all enclosures, coinciding with enrichment ending, with a return to clear water within 12 days.

3. Our results support the hypothesis that excess nutrients and prevalent inedible cyanobacteria inhibit the cascading effects of natural biomass levels of both visually feeding zooplanktivores and filter‐feeding omnivores. In N‐limited meso‐eutrophic shallow tropical lakes with predominantly small herbivorous zooplankton, neither the type nor the biomass of planktivorous fish present seems likely to prevent the transient outburst of cyanobacterial blooms. Such fragile ecosystems may thus not sustain a trophic state suitable for drinking water production, unless human impacts are restricted. The generality of restoration approaches based on ecological engineering should be further explored.
Warming and depth interact to affect carbon dioxide concentration in aquatic mesocosms
Authors: FLANAGAN KYLA M. , MCCAULEY EDWARD
Published: March 2008

1. Climate change may significantly influence lake carbon dynamics and consequently the exchange of CO2 with the atmosphere. Warming will accelerate multiple processes that either absorb or release CO2, making predicting the net effect of warming on CO2 exchange with the atmosphere difficult. Here we experimentally test how the CO2 flux of deep and shallow systems responds to warming. To do this, we conducted a greenhouse experiment using mesocosms of two depths, experiencing either ambient or warmed temperatures.

2. Deeper mesocosms were found to have a lower average CO2 concentration than shallower mesocosms under ambient temperature conditions. In addition, warming interacts with mesocosm depth to affect the average CO2 concentration; there was no effect of warming on the average CO2 concentration of deep mesocosms, but shallow mesocosms had significantly lower average CO2 concentrations when warmed.

3. The difference in CO2 concentration resulting from the depth manipulation was due to varying loss rates of particulate carbon to the sediments. There was a strong negative correlation between CO2 and sedimentation rates in the deep mesocosms suggesting that high particulate carbon loss to the sediments lowered the CO2 concentration in the water column. There was no correlation between CO2 and sedimentation rates observed for shallow mesocosms suggesting enhanced carbon regeneration from the sediments was maintaining higher CO2 concentrations in the water column.

4. Relationships between CO2 and algal concentrations indicate that the reduction in CO2 concentrations resulting from warming is due to increased per capita algal turnover rates depleting CO2 in the water column. Our results suggest that the carbon dynamics and CO2 flux of shallow systems will be affected more by climate warming than deep systems and the net effect of warming is to increase CO2 uptake.
Methane emission from Siberian arctic polygonal tundra: eddy covariance measurements and modeling
Authors: WILLE CHRISTIAN , KUTZBACH LARS , SACHS TORSTEN , WAGNER DIRK , PFEIFFER EVA‐MARIA
Published: March 2008

Eddy covariance measurements of methane flux were carried out in an arctic tundra landscape in the central Lena River Delta at 72°N. The measurements covered the seasonal course of mid‐summer to early winter in 2003 and early spring to mid‐summer in 2004, including the periods of spring thaw and autumnal freeze back. The study site is characterized by very cold and deep permafrost and a continental climate with a mean annual air temperature of −14.7 °C. The surface is characterized by wet polygonal tundra, with a micro‐relief consisting of raised moderately dry sites, depressed wet sites, polygonal ponds, and lakes. We found relatively low fluxes of typically 30 mg CH4 m−2 day−1 during mid‐summer and identified soil temperature and near‐surface atmospheric turbulence as the factors controlling methane emission. The influence of atmospheric turbulence was attributed to the high coverage of open water surfaces in the tundra. The soil thaw depth and water table position were found to have no clear effect on methane fluxes. The excess emission during spring thaw was estimated to be about 3% of the total flux measured during June–October. Winter emissions were modeled based on the functional relationships found in the measured data. The annual methane emission was estimated to be 3.15 g m−2. This is low compared with values reported for similar ecosystems. Reason for this were thought to be the very low permafrost temperature in the study region, the sandy soil texture and low bio‐availability of nutrients in the soils, and the high surface coverage of moist to dry micro‐sites. The methane emission accounted for about 14% of the annual ecosystem carbon balance. Considering the global warming potential of methane, the methane emission turned the tundra into an effective greenhouse gas source.
Storage, patterns and controls of soil organic carbon in the Tibetan grasslands
Authors: YANG YUANHE , FANG JINGYUN , TANG YANHONG , JI CHENGJUN , ZHENG CHENGYANG , HE JINSHENG , ZHU BIAO
Published: March 2008

The soils of the Qinghai‐Tibetan Plateau store a large amount of organic carbon, but the magnitude, spatial patterns and environmental controls of the storage are little investigated. In this study, using data of soil organic carbon (SOC) in 405 profiles collected from 135 sites across the plateau and a satellite‐based dataset of enhanced vegetation index (EVI) during 2001–2004, we estimated storage and spatial patterns of SOC in the alpine grasslands. We also explored the relationships between SOC density (soil carbon storage per area) and climatic variables and soil texture. Our results indicated that SOC storage in the top 1 m in the alpine grasslands was estimated at 7.4 Pg C (1 Pg=1015 g), with an average density of 6.5 kg m−2. The density of SOC decreased from the southeastern to the northwestern areas, corresponding to the precipitation gradient. The SOC density increased significantly with soil moisture, clay and silt content, but weakly with mean annual temperature. These variables could together explain about 72% of total variation in SOC density, of which 54% was attributed to soil moisture, suggesting a key role of soil moisture in shaping spatial patterns of SOC density in the alpine grasslands.