bluuebunny/crossref_metadata_2025 huggingface dataset:
Reliable prediction of regulator targets using 12 Drosophila genomes
Authors: Kheradpour Pouya , Stark Alexander , Roy Sushmita , Kellis Manolis
Published: November 2007

Gene expression is regulated pre- and post-transcriptionally via cis-regulatory DNA and RNA motifs. Identification of individual functional instances of such motifs in genome sequences is a major goal for inferring regulatory networks yet has been hampered due to the motifs’ short lengths that lead to many chance matches and poor signal-to-noise ratios. In this paper, we develop a general methodology for the comparative identification of functional motif instances across many related species, using a phylogenetic framework that accounts for the evolutionary relationships between species, allows for motif movements, and is robust against missing data due to artifacts in sequencing, assembly, or alignment. We also provide a robust statistical framework for evaluating motif confidence, which enables us to translate evolutionary conservation into a confidence measure for each motif instance, correcting for varying motif length, composition, and background conservation of the target regions. We predict targets of fly transcription factors and miRNAs in alignments of 12 recently sequenced Drosophila species. When compared to extensive genome-wide experimental data, predicted targets are of high quality, matching and surpassing ChIP-chip microarrays and recovering miRNA targets with high sensitivity. The resulting regulatory network suggests significant redundancy between pre- and post-transcriptional regulation of gene expression.
Accurate gene-tree reconstruction by learning gene- and species-specific substitution rates across multiple complete genomes
Authors: Rasmussen Matthew D. , Kellis Manolis
Published: November 2007

Comparative genomics provides a general methodology for discovering functional DNA elements and understanding their evolution. The availability of many related genomes enables more powerful analyses, but requires rigorous phylogenetic methods to resolve orthologous genes and regions. Here, we use 12 recently sequenced Drosophila genomes and nine fungal genomes to address the problem of accurate gene-tree reconstruction across many complete genomes. We show that existing phylogenetic methods that treat each gene tree in isolation show large-scale inaccuracies, largely due to insufficient phylogenetic information in individual genes. However, we find that gene trees exhibit common properties that can be exploited for evolutionary studies and accurate phylogenetic reconstruction. Evolutionary rates can be decoupled into gene-specific and species-specific components, which can be learned across complete genomes. We develop a phylogenetic reconstruction methodology that exploits these properties and achieves significantly higher accuracy, addressing the species-level heterotachy and enabling studies of gene evolution in the context of species evolution.
Targeted discovery of novel human exons by comparative genomics
Authors: Siepel Adam , Diekhans Mark , Brejová Broňa , Langton Laura , Stevens Michael , Comstock Charles L.G. , Davis Colleen , Ewing Brent , Oommen Shelly , Lau Christopher , Yu Hung-Chun , Li Jianfeng , Roe Bruce A. , Green Phil , Gerhard Daniela S. , Temple Gary , Haussler David , Brent Michael R.
Published: November 2007

A complete and accurate set of human protein-coding gene annotations is perhaps the single most important resource for genomic research after the human-genome sequence itself, yet the major gene catalogs remain incomplete and imperfect. Here we describe a genome-wide effort, carried out as part of the Mammalian Gene Collection (MGC) project, to identify human genes not yet in the gene catalogs. Our approach was to produce gene predictions by algorithms that rely on comparative sequence data but do not require direct cDNA evidence, then to test predicted novel genes by RT–PCR. We have identified 734 novel gene fragments (NGFs) containing 2188 exons with, at most, weak prior cDNA support. These NGFs correspond to an estimated 563 distinct genes, of which >160 are completely absent from the major gene catalogs, while hundreds of others represent significant extensions of known genes. The NGFs appear to be predominantly protein-coding genes rather than noncoding RNAs, unlike novel transcribed sequences identified by technologies such as tiling arrays and CAGE. They tend to be expressed at low levels and in a tissue-specific manner, and they are enriched for roles in motor activity, cell adhesion, connective tissue, and central nervous system development. Our results demonstrate that many important genes and gene fragments have been missed by traditional approaches to gene discovery but can be identified by their evolutionary signatures using comparative sequence data. However, they suggest that hundreds—not thousands—of protein-coding genes are completely missing from the current gene catalogs.
A second-generation combined linkage–physical map of the human genome: Table 1.
Authors: Matise Tara C. , Chen Fang , Chen Wenwei , De La Vega Francisco M. , Hansen Mark , He Chunsheng , Hyland Fiona C.L. , Kennedy Giulia C. , Kong Xiangyang , Murray Sarah S. , Ziegle Janet S. , Stewart William C.L. , Buyske Steven
Published: November 2007

We have completed a second-generation linkage map that incorporates sequence-based positional information. This new map, the Rutgers Map v.2, includes 28,121 polymorphic markers with physical positions corroborated by recombination-based data. Sex-averaged and sex-specific linkage map distances, along with confidence intervals, have been estimated for all map intervals. In addition, a regression-based smoothed map is provided that facilitates interpolation of positions of unmapped markers on this map. With nearly twice as many markers as our first-generation map, the Rutgers Map continues to be a unique and comprehensive resource for obtaining genetic map information for large sets of polymorphic markers.
The effective elastic thickness of the lithosphere and the evolution of foreland basins
Authors: Watts A. B.
Published: November 2007

The elastic thickness of the continental lithosphere is strongly ‘bi‐modal’. Foreland basins reflect this bi‐modality with narrow, deep basins (e.g. Apennines) and wide, shallow ones (e.g. Ganges). The bi‐modal distribution cannot be explained by thermal models which describe the relationship between elastic thickness and plate age in the oceans, suggesting the involvement of factors other than secular cooling. The high values (80–90 km) are consistent with present‐day temperature gradients of the cratons and the scatter within cratons may be explained by changes in the radiogenic heat production. The low values (10–20 km), however, are more difficult to explain. Foreland basins develop by flexure in front of thrust/fold loads as they advance over former passive margins and onto the cratons. Recent studies suggest that passive margins are underlain by highly attenuated crust and lithosphere which has a low elastic thickness that remains low for long periods (> 108 yr) of time. Foreland basins may inherit these low values as they migrate over a passive margin. Stratigraphic modelling suggests that the low elastic thicknesses would have a profound effect on the development of foreland basins predicting as they do the asymmetry, the pattern of onlap and, the transition from the ‘underfilled’ to ‘overfilled’ phase. Why stretched crust and lithosphere is so weak on long time‐scales is enigmatic. Rifting, however, seems to proceed in such a way that the strong uppermost part of the crust is effectively ‘de‐coupled’ from any support that it might otherwise receive from the strong underlying mantle.
Geomorphic controls on sediment accumulation at margins of foreland basins
Authors: Fraser GORDON S. , DeCelles PETER G.
Published: November 2007

The occurrence of cyclic patterns of sedimentation on a large scale, or abrupt changes in lithology or facies patterns in foreland basins, are most commonly attributed to tectonism. Climatic controls are invoked much less often, and geomorphic controls are rarely considered except for small‐scale features. Tectonism is the first‐order control on sedimentation at mountain fronts by providing accommodation space for sediment accumulation, and the requisite energy for the system to operate. However, geomorphic controls on sediment yield from source areas, transformation of sediment yield in transfer systems, and feedback mechanisms between source areas and depositional basins may be the secondary controls on sediment dispersal and accumulation near mountain fronts.

Drainage basins pass through a series of stages during their evolution. Sediment flux is large during initial stages of basin evolution, allowing fans to prograde rapidly. But as drainage nets in the source area expand, and valleys increase their capacity to store sediment eroded from interfluves, the quantity and caliber of the sediment load at the outlet diminishes, and fan sequences begin to fine upward. Eventually the source area drainage network will expand to its maximum size. Relief is greatest in the source area at this time, and the quantity and calibre of the sediment eroded from valley walls reaches a maximum. Dynamic equilibrium between fan and source area is attained and a period during which spontaneous incision of source area valleys, fanhead entrenchment, and depositional lobe progradation occurs The amount and size of sediment supplied to the fan reaches a maximum at this time, and fan deposits coarsen upward through this period. However, feedback relationships between fan and depositional basin limit the ability of fans to prograde basinward. Fans begin to retrograde as relief in the source area declines and storage capacity increases. Fining‐upward sequences arc deposited and basinal facies encroach on the fan during this final phase.

Ancient alluvial fans commonly consist of coarsening‐ then fining‐upward stratigraphic sequences consistent with this evolutionary model, and cross‐sections of alluvial fan deposits normally show that fan facies stack vertically near their upland sources. A typical first‐order fan deposit ranges in thickness between 100 m and 250 m, but those in foreland basins near thrust margins are considerably thicker, possibly in response to increased accommodation space provided by basin subsidence, extended periods of downcutting caused by continued movement on the thrust, and to basinward translation of the source area.
Timing and record of foreland sedimentation during the initiation of the Sevier orogenic belt in central Utah
Authors: Yingling VIRGINIA L. , Heller PAUL L.
Published: November 2007

The stratigraphic record in the San Rafael Swell region of central Utah suggests that thrust loading and attendant foreland sedimentation began in adjacent parts of the Sevier orogenic belt during Albian time. Regional stratigraphy, isopachs, gravel composition and grain‐size trends suggest that the Morrison Formation of Late Jurassic age and Buckhorn Conglomerate Member of the Cedar Mountain Formation of Early Cretaceous age were not derived from the adjacent thrust belt as they neither thicken nor coarsen significantly towards the west. In contrast, the upper member of the Cedar Mountain Formation of Albian age and Dakota Sandstone of early Cenomanian age rapidly coarsen and thicken westward towards the thrust belt, suggesting that these units were deposited during a time of rapid flexural subsidence early in the history of thrust loading by the Sevier belt. Hence, in the case of the foreland basin in central Utah, basin subsidence rates and asymmetry provides the strongest evidence of the initiation of thrust‐belt loading by the adjacent Sevier orogenic belt.
Non‐marine sedimentation in the overfilled part of the Jurassic‐Cretaceous Cordilleran foreland basin: Morrison and Cloverly Formations, central Wyoming, USA
Authors: DeCelles PETER G. , Burden ELLIOTT T.
Published: November 2007

Lithostratigraphic, chronostratigraphic, sedimentological and penological data from the Upper Jurassic‐Lower Cretaceous Morrison and Cloverly Formations in central Wyoming allow detailed characterization of the early history of the central part of the Cordilleran foreland basin. The Morrison is divisible into three informal members: (1) a lower sandstone, deposited by a complex coastal dune‐foreshore–fluvial system during retreat of the Sundance sea; (2) a middle mudstone, deposited by muddy fluvial and ephemeral lacustrine systems during a period of regional, seasonal aridity; and (3) an upper sandstone, deposited by a sandy fluvial system of variable sinuosity. The overlying Cloverly Formation is divisible into two informal members: (1) a lower mudstone (previously considered as part of the Morrison Formation), deposited by muddy fluvial and lacustrine systems; and (2) an upper chert‐pebble conglomerate and sandstone, deposited primarily by gravel‐dominant braided rivers. Palynological data and a single fission‐track date indicate that the lower part of the middle Morrison mudstone is early to middle Oxfordian and the upper part of the lower Cloverly mudstone is Valanginian.

Morrison sandstones are subarkosic, with average %QFL = 91,6, 3 and %QmFLt = 83, 6, 11. Cloverly sandstones are cherty litharenites and sublitharenites, with average %QFL = 99.6, 0,0.4 and %QmFLt = 82,0,18 (Gazzi‐Dickinson point‐counting method). Palaeocurrent data and sandstone compositions indicate a complex provenance including exirrabasinal sources in lower Mesozoic and upper Palaeozoic sedimentary and volcanic rocks of the Cordillera and intrabasinal sources of Proterozoic clasts in south‐central Wyoming. Cloverly sandstone compositions in the eastern part of the study area were influenced by short‐term fluvial reworking within the basin.

The thickness of the composite Morrison‐Cloverly succession is practically constant over a distance of several hundred km east of the Idaho‐Wyoming thrust belt, and its internal chronostratigraphic zones are subparallel. On the other hand, equivalent strata in the Gannett Group of the thrust belt are at least three times thicker. This indicates that the Morrison and Cloverly in central Wyoming were deposited within the overfilled part of the foreland basin. Preliminary regional correlation indicates that coarse‐grained lithofacies in these rocks are significantly time‐transgressive, generally becoming younger toward the E and NE. Overfilling of the early Cordilleran foreland basin in central Wyoming was accomplished by progradation from the W and S. In spite of their three‐dimensional (3D) complexity, the Morrison and Cloverly Formations generally confirm theoretical model predictions for overfilled foreland basins.
Temporal and spatial controls on the alluvial architecture of an axial drainage system: late Eocene Escanilla Formation, southern Pyrenean foreland basin, Spain
Authors: Bentham PETER A. , Burbank DOUGLAS W. , Puigdefabregas CAI
Published: November 2007

In young or currently active foreland basins of the world, along‐orogen variations in structural deformation and/or depositional environments are common elements of the later phases of basin development. The late Eocene Escanilla Formation of the South‐Central Pyrenean foreland basin represents an ancient drainage system in which such variability can be studied in detail using high‐resolution magnetostratigraphy combined with a more traditional field‐based approach. Downstream changes in the nature of the alluvial system were strongly influenced by the on‐going Eocene structural partitioning of the foreland basin as it began to become incorporated into the southward‐advancing South Pyrenean thrust system. Lower subsidence rates within these allochthonous ‘piggy‐back’ sub‐basins served to increase channel‐body interconnectedness of sheet‐like alluvial conglomerates, to inhibit the preservation of significant volumes of fine‐grained overbank material, and to promote the extensive development of pedogenic calcretes.

During the phase of coastal progradation along the subsiding basin axis, a number of N‐S‐trending anticlines impeded the westward progradation of the alluvial system, producing a strong diachrony in the age of a Lutetian‐Priabonian‐aged deltaic system along the orogen. Fold growth across the western oblique ramp of the South‐Central Unit thrust system dramatically influenced middle to late Eocene drainage patterns and lithofacies distributions. Within the portions of the drainage system upstream of these active folds, the alluvial deposits were periodically ponded, allowing the deposition of micritic lacustrine limestones. Fluctuations in regional base‐level exerted control on the drainage system upstream into the alluvial drainage basin. Base‐level rises caused short reversals in the longer‐term westward regression of marine environments across the foreland basin, whereas base‐level falls produced widespread sheet conglomerate deposition.
The planform of epeirogeny: vertical motions of Australia during the Cretaceous
Authors: Russell MARK , Gurnis MICHAEL
Published: November 2007

Estimates of dynamic motion of Australia since the end of the Jurassic have been made by modeling marine flooding and comparing it with palaeogeographical reconstructions of marine inundation. First, sediment isopachs were back stripped from present‐day topography. Dynamic motion was determined by the displacement needed to approximate observed flooding when allowance is made for changes in eustatic sea‐level. The reconstructed inundation patterns suggest that during the Cretaceous, Australia remained a relatively stable platform, and flooding in the eastern interior during the Early Cretaceous was primarily the result of the regional tectonic motion. Vertical motion during the Cretaceous was much smaller than the movement since the end of the Cretaceous. Subsidence and marine flooding in the Eromanga and Surat Basins, and the subsequent 500 m of uplift of the eastern portion of the basin, may have been driven by changes in plate dynamics during the Mesozoic. Convergence along the north‐east edge of Australia between 200 and 100 Ma coincides with platform sedimentation and subsidence within the Eromanga and Surat Basins. A major shift in the position of subduction at 140 Ma was coeval with the marine incursion into the Eromanga. When subduction ended at 95 Ma, marine inundation of the Eromanga also ended. Subsidence and uplift of the eastern interior is consistent with dynamic models of subduction in which subsidence is generated when the dip angle of the slab decreases and uplift is generated when subduction terminates (i.e. the dynamic load vanishes). Since the end of the Cretaceous, Australia has uniformly subsided by about 250 m with little apparent tilting. This vertical subsidence may have resulted from the northward migration of the continent from a dynamic topography high and geoid low toward lower dynamic topography and a higher geoid.
Constraints on the vertical motion of eastern Australia during the Mesozoic
Authors: Gallagher KERRY , Dumitru TREVOR A. , Gleadow ANDREW J. W.
Published: November 2007

Backstripping and apatite fission track analysis are used to constrain the Mesozoic vertical motion of the eastern Australian basins (Eromanga, Surat and Clarence‐Moreton). The backstripping results show that subsidence was linear during the Jurassic, and the rate of subsidence shows an overall increase (by a factor of about 2) towards the eastern margin. The Cretaceous section is well preserved only in the Eromanga Basin, and the backstripping results show that the apparent subsidence rate increased by a factor of 5–10 during the Early Cretaceous. The sediments show a lithological cyclicity which is the result of a variable influx of volcanogenic detritus from the convergent eastern margin. The rapid Cretaceous subsidence corresponds to a large influx of this volcanogenic material, resulting in progressively non‐marine deposition at a time when global sea‐level was rising.

The apatite fission track data suggest that the Cretaceous section was probably deposited over the Surat and Clarence‐Moreton Basins but has since been eroded off. The exhumation‐induced cooling may have commenced earlier in the eastern region (Late Cretaceous to Early Tertiary) and slightly later to the west (Early to Middle Tertiary). Furthermore, the inferred total amount of removed section is greater (˜2.5 km) in the east than in the west (<1 km). The present‐day thermal regime in the Eromanga Basin is considered to be a relatively recent (<10Ma) phenomenon, as non‐zero fission track ages are maintained in sediments currently at temperatures of ˜120°C.

Overall, the regional backstripping and apatite fission track results support a model of platform tilting, This is related to the inferred subduction along a convergent margin on eastern Australia during the Jurassic to Early Cretaceous. The cessation of subduction, and subsequent opening of the Tasman Sea in the Late Cretaceous, was accompanied by uplift on the eastern margin and the termination of widespread deposition on the platform.
Spatial variations in tectonic subsidence during Tippecanoe I in the Michigan Basin
Authors: Coakley BERNARD J. , Nadon GREGORY C. , Wang HERBERT F.
Published: November 2007

Episodic tectonic subsidence can be seen from all backstripped wells from the Michigan Basin. These episodes are observed as periods of relatively rapid subsidence, contrasting with the relatively linear subsidence. Steady tectonic subsidence curves have been explained as being due to a decaying thermal anomaly in the underlying uplifted asthenosphere. Rapid episodes of subsidence require another explanation and prompt us to examine the tectonic history of surrounding areas for correlative events.

The Taconic orogeny has been inferred to have influenced the development of the Michigian Basin. To analyse the extent of coupling between the Appalachian foredeep and the Michigan Basin we have used Ordovician formation tops correlated among 172 wells distributed over the whole of Michigan's Lower Peninsula. The spatial variation of tectonic subsidence over this interval supports this suggestion.

Contour maps of decompacted sediment thickness and subsidence rate show substantial changes in form and magnitude during the development of the Tippecanoe I sequence. Early basin‐centred subsidence, during deposition of the Shakopee, St. Peter and Glenwood formations, was followed by tilting toward the Appalachian orogen concurrent with the early stages of the Taconic orogeny. This tilting continued, declining gradually, during deposition of the Black River, Trenton and Utica formations. Deposition during Tippecanoe I in the Michigan Basin may indicate modulation of continuing thermally driven subsidence by flexure of the lithosphere due to Taconic thrust loading, but the distinctive spatial distribution of subsidence over each interval may indicate that the important mechanisms making space available in the basin operated independently, not concurrently, invalidating the flexural model for the coupling and suggesting other regional, tectonic possibilities for models of basin initiation, evolution and filling.
Neocratonic magmatic‐sedimentary basins of post‐Variscan Europe and post‐Kanimblan eastern Australia generated by right‐lateral transtension of Permo‐Carboniferous Pangaea
Authors: Veevers J. J. , Clare A. , Wopfner H.
Published: November 2007

The stress from the initial coalescence of Pangaea during the mid‐Carboniferous (320 Ma) collision of Gondwanaland and Laurussia in the Variscan (Sudetic) magmatic fold belt was transmitted through Pangaea to generate the nappes and thrusts that dismembered the intracratonic Centralian Superbasin during the Alice Springs Orogeny and the megakinks that terminally deformed the Lachlan fold belt along the subducted Andean‐type margin of eastern Australia. Definitive collision was followed by a lacuna on the Pangaean platform that reflects uplift. The first release of heat at ≅ 300 Ma from the self‐induced Pangaean heat anomaly weakened the hypersensitive neocratonic crust of the inactive but still hot European and eastern Australian magmatic fold belts to become stress guides for right‐lateral transtension during anticlockwise rotation of Pangaea. Deep transtensional fractures provided a way into and through the neocratonic crust for magma ranging from S‐type granite to rhyodacitic ignimbrite to basalt, with alkaline undersaturated rocks in some rifts. Lagging behind the magma, the platform subsided at ≅290 Ma in basins by differential weakening of the crust during the release of Pangaean heat. The Gondwana facies accumulated in the Gondwanaland province and the Stephanian‐Rotliegend succession in Europe. The basins of Europe and eastern Australia continued to grow by transtension followed by mid‐Permian (270–265 Ma) thermal sagging and rifting. Their histories then diverged. Europe maintained its post‐orogenic course except in the Alpine region, where rifting and sagging continued to accommodate the western Tethys. The eastern fringe of Australia entered a new, Innamincka, orogenic cycle that developed in embryo at 265 Ma to a fully developed magmatic arc and yoked foreland basin at 258 Ma.
Target concentration intervention is needed for tobramycin dosing in paediatric patients with cystic fibrosis – a population pharmacokinetic study
Authors: Hennig Stefanie , Norris Ross , Kirkpatrick Carl M. J.
Published: November 2007

What is already known about this subject

• Two recent papers have been published which have attempted to build a full population pharmacokinetic model for tobramycin in children with cystic fibrosis.

• However, neither study was able to provide any information about between‐subject variability (BSV) and between‐occasion variability (BOV), which is necessary to justify and draw conclusions about the use of target concentration intervention (TCI).

• In the publications no simulations were provided to show any new directions or evaluate current therapy.

What this study adds

• This study provides sound evidence that TCI must be undertaken in this patient group, as the BOV is significantly less than the BSV.

• The simulations from this model clearly show that current dosing and monitoring methods will not achieve the necessary targets to maximize the pharmacokinetic–pharmacodynamic relationships of aminoglycosides in this patient group.

• The model presented is able to be easily incorporated into Bayesian dose individualization software, e.g. Abbottbase or TCIworks, to achieve dosing targets more accurately.

Aim

The primary aim was to estimate the population pharmacokinetic parameters of once‐daily intravenous (i.v.) tobramycin in paediatric cystic fibrosis (CF) patients and to investigate the influence of covariates. The second aim was to assess the need for target concentration intervention (TCI) for tobramycin in this patient group.

Methods

Retrospective demographic, dosing and concentration data were collected from 35 CF patients (21 female, 14 male) aged 0.5–17.8 years, from whom 318 tobramycin plasma concentrations were available. NONMEM was used to estimate the population pharmacokinetics of tobramycin. Simulations were performed using weight‐based dosing with a weight from a covariate distribution model to evaluated current dosing schedules and monitoring practices.

Results

A two‐compartment model best described the data with population parameter estimates for clearance of central compartment (CL) of 6.37 l h−1 per 70 kg; volume of central compartment (Vc) of 18.7 l per 70 kg; intercompartmental clearance (Q) of 0.393 l h−1; and volume of peripheral compartment (Vper) of 1.32 l. The inclusion of total body weight as covariate reduced the random component of between‐subject variability in CL from 50.1% to 11.7% and in Vc from 62.2% to 11.6%. The between‐occasion variability on CL was estimated in the final model as 6.5%. Simulations show that one dose does not fit all and TCI and dose adjustment are required.

Conclusions

This study provides the first pharmacokinetic model of once‐daily i.v. tobramycin for the use of target concentration intervention in paediatric CF patients.
Population pharmacokinetics and dose simulation of carvedilol in paediatric patients with congestive heart failure
Authors: Albers Stefanie , Meibohm Bernd , Mir Thomas S. , Läer Stephanie
Published: November 2007

What is already known about this subject

• Applying in silico tools such as population pharmacokinetic analysis and simulation will help to find adequate dosing strategies and increase the probability of success for a randomized controlled trial.

• Up to now, for carvedilol in paediatric patients with congestive heart failure (CHF) the dose has been linearly extrapolated from adults, but the results with this dosing strategy are ambiguous.

• Further trials are necessary to establish carvedilol for paediatric patients with CHF.

What this study adds

• Carvedilol pharmacokinetics in paediatric patients with CHF depends on the weight and age of the patient.

• Therefore, the drug exposure differs substantially between patients of different ages receiving the same dose with respect to body weight.

• Simulations revealed that an age‐adjusted carvedilol dosing strategy with higher doses for younger patients with respect to body weight is preferable to a uniform one.

Aims

To investigate the ontogeny of carvedilol pharmacokinetics and to develop an age‐appropriate carvedilol dosing strategy for paediatric patients.

Methods

Data were derived from a prospective, nonplacebo‐controlled study of carvedilol for the treatment of paediatric patients with congestive heart failure and analysed using a nonlinear mixed‐effects modelling approach (NONMEM, Version V 1.1). The population pharmacokinetic model was further utilized for simulations of different carvedilol dosing strategies.

Results

Four hundred and eighty carvedilol plasma concentrations of 41 patients (0.1–19.3 years; median 3.5) were included in the analysis. A two‐compartment model with first‐order absorption and absorption lag served as structural model. Weight and age were the most important covariates for carvedilol pharmacokinetics. The weight‐adjusted clearance was highest for the younger patients with 2.7 l h−1 kg−1 for a 1‐year‐old patient compared with 0.7 l h−1 kg−1 for a 19.3‐year‐old patient. Dose simulations revealed that the area under the plasma concentration–time curve (AUC) as a measure of drug exposure increased with age despite constant doses with respect to body weight. For infants (28 days to 23 months), children (2–11 years) and adolescents (12–15 years) daily doses of 3, 2 and 1 mg kg−1, administered in two or three discrete doses, were necessary to reach an exposure comparable to adults receiving 0.7 mg kg−1 day−1.

Conclusion

The ontogeny of carvedilol pharmacokinetics in paediatric patients depends on age and weight. Dose simulations revealed that younger patients have to be treated with higher doses with respect to body weight to reach the same exposure as adults.
Influence of APOE genotypes and VKORC1 haplotypes on warfarin dose requirements in Asian patients
Authors: Lal Suman , Sandanaraj Edwin , Jada Srinivasa Rao , Kong Ming‐Chai , Lee Lai‐Heng , Goh Boon‐Cher , Lee Soo‐Chin , Chowbay Balram
Published: November 2007

What is already known about this subject

• Recent studies on pharmacogenetics of warfarin have implicated apolipoproteinE (APOE) polymorphisms to influence the vitamin K dependent coagulation cascade and hence the efficacy of warfarin.

• Studies among Caucasian and African Americans showed a significant but conflicting role of apolipoproteinE (APOE) isoforms in warfarin pharmacogenetics.

• The contribution of APOE isoforms in influencing variations in warfarin requirements in Asian subjects remains to be investigated.

What this study adds

• This is the first report of a population study in Asians exploring the role of isoforms encoded by three APOE alleles (ε2, ε3, ε4) in influencing warfarin dose requirements.

• The present study showed that the APOE ε3/ε3 isoform is the predominant genotype in the Asian population.

• The study also showed that APOE isoforms may not be important in affecting warfarin pharmacodynamics in Asian patients. It also suggested that the impact of different APOE isoforms depended on the frequency of APOE genotypes in the population, in particular the ε4 allele containing genotypes.

Aims

To investigate the influence of APOE genotypes and VKORC1 haplotypes on warfarin dose requirements in Asian patients.

Methods

A total of 174 Asian patients (Chinese, n = 96; Malays, n = 50; Indians, n = 28) who had stable daily warfarin doses for at least 1 month were recruited. Following genomic DNA extraction from venous blood, pharmacogenetic analysis of APOE and VKORC1 genes was done by DNA sequencing.

Results

The majority of the Asian patients (78%) harboured the APOE ε3/ε3 genotype. Different APOE genotypes were found not to have any significant influence on mean daily warfarin dose requirements. Warfarin dose requirements in the pooled Asian patients homozygous for the VKORC1 H1 haplotype were significantly lower compared with patients homozygous for the H7 haplotype (H1‐H1 vs. H7‐H7: 2.79 ± 1.06 mg day−1vs. 5.45 ± 2.3 mg day−1, P < 0.001).

Conclusions

The present study suggests that APOE variants have minimal impact on warfarin dose requirements in Asian patients, probably due to the low frequency of ε4 allele containing genotypes.
KSHV/HHV8‐associated lymphomas
Authors: Carbone Antonino , Gloghini Annunziata
Published: November 2007

This review looks at the current state of knowledge on primary effusion lymphoma (PEL) and other Kaposi sarcoma herpesvirus (KSHV)/human herpesvirus 8 (HHV8)‐associated lymphomas. In 1995, KSHV DNA sequences were identified within a distinct subgroup of acquired immunodeficiency syndrome‐related non‐Hodgkin lymphomas localized in body cavities and presenting as pleural, peritoneal and pericardial lymphomatous effusions. Subsequently, the spectrum of KSHV/HHV8‐associated lymphomas has been expanded by the identification of cases of extracavitary solid lymphomas without serous effusions. Despite the diversification in the clinical presentation of KSHV/HHV8‐associated lymphomas, the majority of the cases reported demonstrated similar morphology, immunophenotype and KSHV/HHV8 viral status. KSHV/HHV8 infection is also in multicentric Castleman disease‐associated plasmablastic lymphoma. The exact oncogenic mechanisms of KSHV/HHV8 are not clearly defined. The prognosis for KSHV/HHV8‐associated lymphomas is poor. Novel approaches for therapy, outside traditional chemotherapy with CHOP (cyclophosphamide, doxorubicin, prednisone, vincristine), have been suggested. These include the addition of antiviral therapy as well as inhibition of specific cellular targets.
High CD21 expression inhibits internalization of anti‐CD19 antibodies and cytotoxicity of an anti‐CD19‐drug conjugate
Authors: Ingle Gladys S , Chan Pamela , Elliott J Michael , Chang Wesley S , Koeppen Hartmut , Stephan Jean‐Philippe , Scales Suzie J
Published: November 2007

CD19 and CD21 (CR2) are co‐receptors found on B‐cells and various B‐cell lymphomas, including non‐Hodgkin lymphoma. To evaluate their suitability as targets for therapy of such lymphomas using internalization‐dependent antibody‐drug conjugates [such as antibody‐4‐(N‐maleimidomethyl)cyclohexane‐1‐carboxylate, (N2′‐deacetyl‐N2′‐(3‐mercapto‐1‐oxopropyl)‐maytansine) (MCC‐DM1) conjugates, which require lysosomal degradation of the antibody moiety for efficacy], we examined uptake of antibodies to CD19 and CD21 in a panel of B‐cell lines. Anti‐CD21 antibodies were not sufficiently internalized even in the highest CD21‐expressing Raji cells, resulting in lack of efficacy with anti‐CD21‐MCC‐DM1 conjugates. Anti‐CD19 antibody uptake was variable, and was unexpectedly negatively correlated with CD21 expression. Thus, high CD21‐expressing Raji, ARH77 and primary B‐cells only very slowly internalized anti‐CD19 antibodies, while CD21‐negative or low expressing cells, including Ramos and Daudi, rapidly internalized these antibodies in clathrin‐coated vesicles followed by lysosomal delivery. Anti‐CD19‐MCC‐DM1 caused greater cytotoxicity in the faster anti‐CD19‐internalizing cell lines, implying that the rate of lysosomal delivery and subsequent drug release is important. Furthermore, transfection of Ramos cells with CD21 impeded anti‐CD19 uptake and decreased anti‐CD19‐MCC‐DM1 efficacy, suggesting that CD21‐negative tumours should respond better to such anti‐CD19 conjugates. This may have possible clinical implications, as anti‐CD21 immunohistochemistry revealed only approximately 30% of 54 diffuse large B‐cell lymphoma patients lack CD21 expression.
Process‐specific analysis of nitrite dynamics in a permanent grassland soil by using a Monte Carlo sampling technique
Authors: Rütting T. , Müller C.
Published: November 2007

The aim of the present study was to separate and quantify process‐specific gross nitrite (NO2−) production in a permanent grassland soil and separate the observed NO2− concentration into process‐specific sub‐pools. We re‐analysed data from a laboratory experiment where either the nitrate and/or ammonium ions were labelled with 15N. The simultaneously occurring N transformations were quantified with a 15N tracing tool in combination with a Monte Carlo sampling technique which has been extended by a NO2− sub‐model. Three pathways of NO2− production were identified, that is autotrophic nitrification, denitrification and the oxidation of organic N. The full model contained nine pools and 14 N transformations. This is the first report where such a complex 15N tracing model has been used and where all parameters have been optimized simultaneously. Our analysis shows that on average 52.4% of the total soil NO2− concentration was directly derived from oxidation of organic N. Nitrification and denitrification contributed on average 18.1 and 29.5%, respectively, to the total NO2− pool. However, more than 99% of the gross NO2− production was related to the NH4+ oxidation, which was rapidly further oxidized to NO3−. Our re‐analysis using a Monte Carlo sampling technique resulted in parameter profiles that differed from the original analysis. As the new technique is able to optimize all parameters in one optimization run we regard this technique as superior to the previous one. A process‐based understanding of NO2− dynamics in soils has important implications for the understanding of the production of the greenhouse gas nitrous oxide (N2O), which is tightly linked to NO2− turnover.
Adsorption of the insecticidal protein of Bacillus thuringiensis subsp. kurstaki by minerals: effects of inorganic salts
Authors: Fu Qingling , Wang Wanqin , Hu Hongqing , Chen Shouwen
Published: November 2007

The persistence of the insecticidal protein of Bacillus thuringiensis (Bt) is enhanced by the reactivity with soil particles and may constitute a hazard to the soil ecosystem; however, studies on the fate of the Bt toxin in soil, especially in the presence of inorganic salts, are limited. The effects of different concentrations of KNO3, KH2PO4 and NH4H2PO4 on the adsorption of Bacillus thuringiensis toxin by kaolinite, montmorillonite, goethite and silicon dioxide were investigated. Results showed that small salt concentrations tended to enhance toxin adsorption, whereas large concentrations (> 10 mmol litre−1) inhibited sorption. Similar results were observed regardless of the order in which toxin and inorganic salt were added. The degree to which individual salts affected adsorption decreased in the sequence for minerals, goethite > kaolinite ≥ montmorillonite > silicon dioxide, and for ions, H2PO4− > NO3−, NH4+ > K+. Our results indicate that inorganic salts can markedly influence the adsorption of Bt toxin by soil minerals. This investigation will help in evaluating the behaviour and fate of Bt toxins in the soil environment.
Bayesian Maximum Entropy prediction of soil categories using a traditional soil map as soft information
Authors: Brus D. J. , Bogaert P. , Heuvelink G. B. M.
Published: November 2007

Bayesian Maximum Entropy was used to estimate the probabilities of occurrence of soil categories in the Netherlands, and to simulate realizations from the associated multi‐point pdf. Besides the hard observations (H) of the categories at 8369 locations, the soil map of the Netherlands 1:50 000 was used as soft information (S). The category with the maximum estimated probability was used as the predicted category. The quality of the resulting BME(HS)‐map was compared with that of the BME(H)‐map obtained by using only the hard data in BME‐estimation, and with the existing soil map. Validation with a probability sample showed that the use of the soft information in BME‐estimation leads to a considerable and significant increase of map purity by 15%. This increase of map purity was due to the high purity of the existing soil map (71.3%). The purity of the BME(HS) was only slightly larger than that of the existing soil map. This was due to the small correlation length of the soil categories. The theoretical purity of the BME‐maps overestimated the actual map purity, which can be partly explained by the biased estimates of the one‐point bivariate probabilities of hard and soft categories of the same label. Part of the hard data is collected to describe characteristic soil profiles of the map units which explains the bias. Therefore, care must be taken when using the purposively selected data in soil information systems for calibrating the probability model. It is concluded that BME is a valuable method for spatial prediction and simulation of soil categories when the number of categories is rather small (say < 10). For larger numbers of categories, the computational burden becomes prohibitive, and large samples are needed for calibration of the probability model.
Phylogenetic analysis and seasonal cold acclimation‐associated expression of early light‐induced protein genes of Rhododendron catawbiense
Authors: Peng Yanhui , Lin Wuling , Wei Hui , Krebs Stephen L. , Arora Rajeev
Published: November 2007

The early light‐induced proteins (ELIPs) are nuclear‐encoded, light stress‐induced proteins located in thylakoid membranes and related to light‐harvesting Chl a/b‐binding proteins. Recent evidence from physiological and genetic (mutant) studies supports a photoprotective function for ELIPs, particularly when green tissues are exposed to high light intensities at suboptimal temperatures. Broad‐leaved evergreens belonging to genus Rhododendron are often exposed to a combination of low temperatures and high light in their natural habitat as the understory plants in deciduous forests and, therefore, are expected to employ photoprotective strategies during overwintering phase. Here we report analysis and characterization of previously identified ELIP expressed sequence tags (ESTs) from winter‐collected Rhododendron catawbiense leaves. 5′ or 3′ rapid amplification of complementary DNA ends (RACEs) coupled with bioinformatic analyses were used to identify seven unique ELIPs from the 40 ESTs and were designated as RcELIP1–RcELIP7. Phylogenetic analysis revealed separate clustering of ELIP homologs from lower plants, monocots and eudicots (including RcELIPs) and further indicated an evolutionary divergence of ELIPs among angiosperms and gymnosperms. To gain insights into the cold acclimation (CA) physiology of rhododendrons, relative and absolute quantitative expression of RcELIPs was examined during seasonal CA of R. catawbiense leaves using real time reverse transcriptase–polymerase chain reaction. All seven RcELIPs were distinctly upregulated during the CA. It is postulated that RcELIPs expression constitutes an adaptive response to cold and high light in winter‐adapted rhododendron leaves and perhaps plays a key role in the protection of photosynthetic apparatus from these stresses.
Characterization and differential expression analysis of artichoke phenylalanine ammonia‐lyase‐coding sequences
Authors: De Paolis Angelo , Pignone Domenico , Morgese Anita , Sonnante Gabriella
Published: November 2007

Sequences encoding phenylalanine ammonia‐lyase were isolated from artichoke, by using a sequence homology strategy, by screening a genomic library and by 3′‐rapid amplification of cDNA end (RACE) technology. These analyses and Southern blots suggested that, in artichoke, phenylalanine ammonia‐lyase (PAL) is encoded by a small gene family. The sequences isolated from genomic DNA possess two exons and one intron at the conserved position as in most plant pal characterized to date. The 3′‐RACE analysis also indicated that each member of the artichoke pal gene family was present as a pool of transcripts, different in the length of 3′‐untranslated region. The deduced amino acid sequences were highly similar to those of PAL from lettuce and sunflower. One of the artichoke pal genes was completely sequenced, and its 5′ upstream region contained TATA, CAAT box and cis regulatory elements identified in other phenylpropanoid pathway genes as playing a role in UV and elicitor induction. The expression of three of the identified artichoke pal sequences was evaluated in different plant parts, in developmental stages and after wounding, using gene‐specific primers/probe combinations in real‐time polymerase chain reaction assays. The three putative genes were differentially expressed in the plant parts analysed and were developmentally regulated. Moreover, after leaf mechanical injury, all of them were differentially regulated. The possible involvement of the single pal genes in different physiological processes is discussed.
Arcyptera fusca and Arcyptera tornosi repetitive DNA families: whole‐comparative genomic hybridization (W‐CGH) as a novel approach to the study of satellite DNA libraries
Authors: PITA M. , ZABAL‐AGUIRRE M. , ARROYO F. , GOSÁLVEZ J. , LÓPEZ‐FERNÁNDEZ C. , DE LA TORRE J.
Published: November 2007

Whole‐comparative genomic hybridization (W‐CGH) has been used to exemplify a simple methodology which allows identifying and mapping whole genome differences for highly repetitive DNA sequences between two related species of unknown genomic background. The use of this technique to the species binomy Arcyptera fusca/Arcyptera tornosi has allowed the identification of different DNA families mainly concentrated within the para‐/peri‐centromeric and distal heterochromatic regions of different chromosomes, which are differentially expanded in both genomes. Additionally, W‐CGH allowed chromosome mapping of particular euchromatic regions immersed in the chromosome arms which have been affected by processes of DNA amplification and losses. A molecular approach was also conducted to analyse satellite DNA families in these species. We have found three different families showing an unequal representation in both species. Two of these families showed a centromeric location (EcoRV‐390CEN and Sau3A‐419CEN), whereas the last one was located at distal heterochromatic regions (Sau3A‐197TEL). As A. fusca is a widely distributed species represented in most European high mountains, whereas A. tornosi is an endemic species represented in the Iberian Peninsula, the differences and resemblances reported here offer a good basis to support a close evolutionary relationship between both of the actually isolated species. Finally, W‐CGH allowed identification of an asynchronic pattern of heterochromatin condensation through early prophase (characteristic in both species) which is uncommon or probably has been poorly analysed within classical early condensing chromosome domains through meiosis. The congruence of the obtained cytological and molecular results is analysed in light of the ancestral genome relationship between both species.