bluuebunny/crossref_metadata_2025 huggingface dataset:
Stable isotopes reveal age-dependent trophic level and spatial segregation during adult marine feeding in populations of salmon
Authors: MacKenzie Kirsteen M. , Trueman Clive N. , Palmer Martin R. , Moore Andy , Ibbotson Anton T. , Beaumont William R. C. , Davidson Ian C.
Published: May 2012

MacKenzie, K. M., Trueman, C. N., Palmer, M. R., Moore, A., Ibbotson, A. T., Beaumont, W. R. C., and Davidson, I. C. 2012. Stable isotopes reveal age-dependent trophic level and spatial segregation during adult marine feeding in populations of salmon from the UK. – ICES Journal of Marine Science, 69: 1637–1645. Locating and differentiating the marine feeding areas used by adult salmon (Salmo salar) is essential to stock-based management and conservation, but traditional tagging studies are limited and influenced by the uneven distribution of the fisheries or research vessel surveys. Here, a novel approach is used, based on the observation that the isotopic composition of animal tissues is intrinsically linked to the environmental conditions during tissue growth, which allows for the distinction of pelagic fish feeding in different locations. This isotopic approach is applied using archived collections of salmon scales and shows that (i) salmon act as size-structured pelagic predators, (ii) adult salmon from different natal origins within the UK (and hence components of the southern European stock complex) feed in different oceanic regions before their return, (iii) one-sea-winter (1SW) and multi-sea-winter salmon returning to some rivers in the UK are separated in their marine feeding areas, whereas those from others are not, and (iv) salmon from the rivers sampled are not feeding in regions of the Northwest Atlantic used by 1SW salmon returning to rivers in Newfoundland. Therefore, the stable isotope approach allows for retrospective investigations of marine diet, location, and migration at stock- and cohort-specific levels.
How Homophily Affects the Speed of Learning and Best-Response Dynamics
Authors: Golub Benjamin , Jackson Matthew O.
Published: May 2012

We examine how the speed of learning and best-response processes depends on homophily: the tendency of agents to associate disproportionately with those having similar traits. When agents' beliefs or behaviors are developed by averaging what they see among their neighbors, then convergence to a consensus is slowed by the presence of homophily but is not influenced by network density (in contrast to other network processes that depend on shortest paths). In deriving these results, we propose a new, general measure of homophily based on the relative frequencies of interactions among different groups. An application to communication in a society before a vote shows how the time it takes for the vote to correctly aggregate information depends on the homophily and the initial information distribution.
Detection of Viruses in Sweetpotato from Honduras and Guatemala Augmented by Deep-Sequencing of Small-RNAs
Authors: Kashif M. , Pietilä S. , Artola K. , Jones R. A. C. , Tugume A. K. , Mäkinen V. , Valkonen J. P. T.
Published: May 2012

Sweetpotato (Ipomoea batatas) plants become infected with over 30 RNA or DNA viruses in different parts of the world but little is known about viruses infecting sweetpotato crops in Central America, the center of sweetpotato domestication. Small-RNA deep-sequencing (SRDS) analysis was used to detect viruses in sweetpotato in Honduras and Guatemala, which detected Sweet potato feathery mottle virus strain RC and Sweet potato virus C (Potyvirus spp.), Sweet potato chlorotic stunt virus strain WA (SPCSV-WA; Crinivirus sp.), Sweet potato leaf curl Georgia virus (Begomovirus sp.), and Sweet potato pakakuy virus strain B (synonym: Sweet potato badnavirus B). Results were confirmed by polymerase chain reaction and sequencing of the amplicons. Four viruses were detected in a sweetpotato sample from the Galapagos Islands. Serological assays available to two of the five viruses gave results consistent with those obtained by SRDS, and were negative for six additional sweetpotato viruses tested. Plants coinfected with SPCSV-WA and one to two other viruses displayed severe foliar symptoms of epinasty and leaf malformation, purpling, vein banding, or chlorosis. The results suggest that SRDS is suitable for use as a universal, robust, and reliable method for detection of plant viruses, and especially useful for determining virus infections in crops infected with a wide range of unrelated viruses.
The Genetic Structure of Pseudoperonospora cubensis Populations
Authors: Quesada-Ocampo L. M. , Granke L. L. , Olsen J. , Gutting H. C. , Runge F. , Thines M. , Lebeda A. , Hausbeck M. K.
Published: May 2012

Pseudoperonospora cubensis is a destructive foliar pathogen of economically important cucurbitaceous crops in the United States and worldwide. In this study, we investigated the genetic structure of 465 P. cubensis isolates from three continents, 13 countries, 19 states of the United States, and five host species using five nuclear and two mitochondrial loci. Bayesian clustering resolved six genetic clusters and suggested some population structure by geographic origin and host, because some clusters occurred more or less frequently in particular categories. All of the genetic clusters were present in the sampling from North America and Europe. Differences in cluster occurrence were observed by country and state. Isolates from cucumber had different cluster composition and lower genetic diversity than isolates from other cucurbits. Because genetic structuring was detected, isolates that represent the genetic variation in P. cubensis should be used when developing diagnostic tools, fungicides, and resistant host varieties. Although this study provides an initial map of global population structure of P. cubensis, future genotyping of isolates could reveal population structure within specific geographic regions, across a wider range of hosts, or during different time points during the growing season.
Transmission dynamics of methicillin-resistant
Staphylococcus aureus
in a medical intensive care unit
Authors: Hall Ian M. , Barrass Iain , Leach Steve , Pittet Didier , Hugonnet Stéphane
Published: May 2012

Intensive care units (ICUs) play an important role in the epidemiology of methicillin-resistant
Staphyloccocus aureus
(MRSA). Although successful interventions are multi-modal, the relative efficacy of single measures remains unknown. We developed a discrete time, individual-based, stochastic mathematical model calibrated on cross-transmission observed through prospective surveillance to explore the transmission dynamics of MRSA in a medical ICU. Most input parameters were derived from locally acquired data. After fitting the model to the 46 observed cross-transmission events and performing sensitivity analysis, several screening and isolation policies were evaluated by simulating the number of cross-transmissions and isolation-days. The number of all cross-transmission events increased from 54 to 72 if only patients with a past history of MRSA colonization are screened and isolated at admission, to 75 if isolation is put in place only after the results of the admission screening become available, to 82 in the absence of admission screening and with a similar reactive isolation policy, and to 95 when no isolation policy is in place. The method used (culture or polymerase chain reaction) for admission screening had no impact on the number of cross-transmissions. Systematic regular screening during ICU stay provides no added-value, but aggressive admission screening and isolation effectively reduce the number of cross-transmissions. Critically, colonized healthcare workers may play an important role in MRSA transmission and their screening should be reinforced.
The human foot and heel–sole–toe walking strategy: a mechanism enabling an inverted pendular gait with low isometric muscle force?
Authors: Usherwood J. R. , Channon A. J. , Myatt J. P. , Rankin J. W. , Hubel T. Y.
Published: May 2012

Mechanically, the most economical gait for slow bipedal locomotion requires walking as an ‘inverted pendulum’, with: I, an impulsive, energy-dissipating leg compression at the beginning of stance; II, a stiff-limbed vault; and III, an impulsive, powering push-off at the end of stance. The characteristic ‘M’-shaped vertical ground reaction forces of walking in humans reflect this impulse–vault–impulse strategy. Humans achieve this gait by dissipating energy during the heel-to-sole transition in early stance, approximately stiff-limbed, flat-footed vaulting over midstance and ankle plantarflexion (powering the toes down) in late stance. Here, we show that the ‘M’-shaped walking ground reaction force profile does not require the plantigrade human foot or heel–sole–toe stance; it is maintained in tip–toe and high-heel walking as well as in ostriches. However, the unusual, stiff, human foot structure—with ground-contacting heel behind ankle and toes in front—enables bothmechanically economicalinverted pendular walking andphysiologically economicalmuscle loading, by producing extreme changes in mechanical advantage between muscles and ground reaction forces. With a human foot, and heel–sole–toe strategy during stance, the shin muscles that dissipate energy, or calf muscles that power the push-off, need not be loaded at all—largely avoiding the ‘cost of muscle force’—during the passive vaulting phase.
Structure and optical function of amorphous photonic nanostructures from avian feather barbs: a comparative small angle X-ray scattering (SAXS) analysis of 230 bird species
Authors: Saranathan Vinodkumar , Forster Jason D. , Noh Heeso , Liew Seng-Fatt , Mochrie Simon G. J. , Cao Hui , Dufresne Eric R. , Prum Richard O.
Published: May 2012

Non-iridescent structural colours of feathers are a diverse and an important part of the phenotype of many birds. These colours are generally produced by three-dimensional, amorphous (or quasi-ordered) spongy β-keratin and air nanostructures found in the medullary cells of feather barbs. Two main classes of three-dimensional barb nanostructures are known, characterized by a tortuous network of air channels or a close packing of spheroidal air cavities. Using synchrotron small angle X-ray scattering (SAXS) and optical spectrophotometry, we characterized the nanostructure and optical function of 297 distinctly coloured feathers from 230 species belonging to 163 genera in 51 avian families. The SAXS data provided quantitative diagnoses of the channel- and sphere-type nanostructures, and confirmed the presence of a predominant, isotropic length scale of variation in refractive index that produces strong reinforcement of a narrow band of scattered wavelengths. The SAXS structural data identified a new class of rudimentary or weakly nanostructured feathers responsible for slate-grey, and blue-grey structural colours.SAXS structural data provided good predictions of the single-scattering peak of the optical reflectance of the feathers. The SAXS structural measurements of channel- and sphere-type nanostructures are also similar to experimental scattering data from synthetic soft matter systems that self-assemble by phase separation. These results further support the hypothesis that colour-producing protein and air nanostructures in feather barbs are probably self-assembled by arrested phase separation of polymerizing β-keratin from the cytoplasm of medullary cells. Such avian amorphous photonic nanostructures with isotropic optical properties may provide biomimetic inspiration for photonic technology.
The response of rigid plates to blast in deep water: fluid–structure interaction experiments
Authors: Schiffer Andreas , Tagarielli Vito L.
Published: May 2012

Laboratory-scale dynamic experiments are performed in order to explore the one-dimensional response of unsupported rigid plates to loading by exponentially decaying planar shock waves in deep water. Experiments are conducted in a transparent shock tube allowing measurements of plate motion and imparted impulse, as well as observation of cavitation in water, including motion of breaking fronts and closing fronts. Loading of both air-backed and water-backed rigid plates is examined, and the sensitivity of plate motion and imparted impulse to the structural mass and to the initial hydrostatic pressure in the water is measured. Experiments also serve to validate recently developed theoretical models, whose predictions are found to be in agreement with measurements.
Extreme insular dwarfism evolved in a mammoth
Authors: Herridge Victoria L. , Lister Adrian M.
Published: May 2012

The insular dwarfism seen in Pleistocene elephants has come to epitomize the island rule; yet our understanding of this phenomenon is hampered by poor taxonomy. For Mediterranean dwarf elephants, where the most extreme cases of insular dwarfism are observed, a key systematic question remains unresolved: are all taxa phyletic dwarfs of a single mainland speciesPalaeoloxodon antiquus(straight-tusked elephant), or are some referable toMammuthus(mammoths)? Ancient DNA and geochronological evidence have been used to support aMammuthusorigin for the Cretan‘Palaeoloxodon’ creticus, but these studies have been shown to be flawed. On the basis of existing collections and recent field discoveries, we present new, morphological evidence for the taxonomic status of‘P’. creticus, and show that it is indeed a mammoth, most probably derived from Early PleistoceneMammuthus meridionalisor possibly Late PlioceneMammuthus rumanus. We also show thatMammuthus creticusis smaller than other known insular dwarf mammoths, and is similar in size to the smallest dwarfPalaeoloxodonspecies from Sicily and Malta, making it the smallest mammoth species known to have existed. These findings indicate that extreme insular dwarfism has evolved to a similar degree independently in two elephant lineages.
Physiological consequences of the salmon louse (Lepeophtheirus salmonis) on juvenile pink salmon (Oncorhynchus gorbuscha): implications for wild salmon ecology and management, and for salmon aquaculture
Authors: Brauner C. J. , Sackville M. , Gallagher Z. , Tang S. , Nendick L. , Farrell A. P.
Published: May 2012

Pink salmon,Oncorhynchus gorbuscha, are the most abundant wild salmon species and are thought of as an indicator of ecosystem health. The salmon louse,Lepeophtheirus salmonis, is endemic to pink salmon habitat but these ectoparasites have been implicated in reducing local pink salmon populations in the Broughton Archipelago, British Columbia. This allegation arose largely because juvenile pink salmon migrate past commercial open net salmon farms, which are known to incubate the salmon louse. Juvenile pink salmon are thought to be especially sensitive to this ectoparasite because they enter the sea at such a small size (approx. 0.2 g). Here, we describe how ‘no effect’ thresholds for salmon louse sublethal impacts on juvenile pink salmon were determined using physiological principles. These data were accepted by environmental managers and are being used to minimize the impact of salmon aquaculture on wild pink salmon populations.
Ecophysiology of avian migration in the face of current global hazards
Authors: Klaassen Marcel , Hoye Bethany J. , Nolet Bart A. , Buttemer William A.
Published: May 2012

Long-distance migratory birds are often considered extreme athletes, possessing a range of traits that approach the physiological limits of vertebrate design. In addition, their movements must be carefully timed to ensure that they obtain resources of sufficient quantity and quality to satisfy their high-energy needs. Migratory birds may therefore be particularly vulnerable to global change processes that are projected to alter the quality and quantity of resource availability. Because long-distance flight requires high and sustained aerobic capacity, even minor decreases in vitality can have large negative consequences for migrants. In the light of this, we assess how current global change processes may affect the ability of birds to meet the physiological demands of migration, and suggest areas where avian physiologists may help to identify potential hazards. Predicting the consequences of global change scenarios on migrant species requires (i) reconciliation of empirical and theoretical studies of avian flight physiology; (ii) an understanding of the effects of food quality, toxicants and disease on migrant performance; and (iii) mechanistic models that integrate abiotic and biotic factors to predict migratory behaviour. Critically, a multi-dimensional concept of vitality would greatly facilitate evaluation of the impact of various global change processes on the population dynamics of migratory birds.
Ecophysiology meets conservation: understanding the role of disease in amphibian population declines
Authors: Blaustein Andrew R. , Gervasi Stephanie S. , Johnson Pieter T. J. , Hoverman Jason T. , Belden Lisa K. , Bradley Paul W. , Xie Gisselle Y.
Published: May 2012

Infectious diseases are intimately associated with the dynamics of biodiversity. However, the role that infectious disease plays within ecological communities is complex. The complex effects of infectious disease at the scale of communities and ecosystems are driven by the interaction between host and pathogen. Whether or not a given host–pathogen interaction results in progression from infection to disease is largely dependent on the physiological characteristics of the host within the context of the external environment. Here, we highlight the importance of understanding the outcome of infection and disease in the context of host ecophysiology using amphibians as a model system. Amphibians are ideal for such a discussion because many of their populations are experiencing declines and extinctions, with disease as an important factor implicated in many declines and extinctions. Exposure to pathogens and the host's responses to infection can be influenced by many factors related to physiology such as host life history, immunology, endocrinology, resource acquisition, behaviour and changing climates. In our review, we discuss the relationship between disease and biodiversity. We highlight the dynamics of three amphibian host–pathogen systems that induce different effects on hosts and life stages and illustrate the complexity of amphibian–host–parasite systems. We then review links between environmental stress, endocrine–immune interactions, disease and climate change.
Hormonally mediated maternal effects, individual strategy and global change
Authors: Meylan Sandrine , Miles Donald B. , Clobert Jean
Published: May 2012

A challenge to ecologists and evolutionary biologists is predicting organismal responses to the anticipated changes to global ecosystems through climate change. Most evidence suggests that short-term global change may involve increasing occurrences of extreme events, therefore the immediate response of individuals will be determined by physiological capacities and life-history adaptations to cope with extreme environmental conditions. Here, we consider the role of hormones and maternal effects in determining the persistence of species in altered environments. Hormones, specifically steroids, are critical for patterning the behaviour and morphology of parents and their offspring. Hence, steroids have a pervasive influence on multiple aspects of the offspring phenotype over its lifespan. Stress hormones, e.g. glucocorticoids, modulate and perturb phenotypes both early in development and later into adulthood. Females exposed to abiotic stressors during reproduction may alter the phenotypes by manipulation of hormones to the embryos. Thus, hormone-mediated maternal effects, which generate phenotypic plasticity, may be one avenue for coping with global change. Variation in exposure to hormones during development influences both the propensity to disperse, which alters metapopulation dynamics, and population dynamics, by affecting either recruitment to the population or subsequent life-history characteristics of the offspring. We suggest that hormones may be an informative index to the potential for populations to adapt to changing environments.
Dissecting Arabidopsis Gβ Signal Transduction on the Protein Surface
Authors: Jiang Kun , Frick-Cheng Arwen , Trusov Yuri , Delgado-Cerezo Magdalena , Rosenthal David M. , Lorek Justine , Panstruga Ralph , Booker Fitzgerald L. , Botella José Ramón , Molina Antonio , Ort Donald R. , Jones Alan M.
Published: May 2012

The heterotrimeric G-protein complex provides signal amplification and target specificity. The Arabidopsis (Arabidopsis thaliana) Gβ-subunit of this complex (AGB1) interacts with and modulates the activity of target cytoplasmic proteins. This specificity resides in the structure of the interface between AGB1 and its targets. Important surface residues of AGB1, which were deduced from a comparative evolutionary approach, were mutated to dissect AGB1-dependent physiological functions. Analysis of the capacity of these mutants to complement well-established phenotypes of Gβ-null mutants revealed AGB1 residues critical for specific AGB1-mediated biological processes, including growth architecture, pathogen resistance, stomata-mediated leaf-air gas exchange, and possibly photosynthesis. These findings provide promising new avenues to direct the finely tuned engineering of crop yield and traits.
Methanol[1-(methoxymethanimidoyl)-2-(pyridin-2-ylmethyl)guanidine]bis(perchlorato)copper(II)
Authors: Meenongwa Atittaya , Chaveerach Unchulee , Blake Alexander J.
Published: May 2012

The title complex, [Cu(ClO4)2(C9H13N5O)(CH3OH)], was synthesized from a methanolysis reaction ofN-(methylpyridin-2-yl)cyanoguanidine (L3) and copper(II) perchlorate hexahydrate in a 1:1 molar ratio. The CuIIion is six-coordinated by an N3O3donor set which confers a highly distorted and asymmetric octahedral geometry. Three N-donor atoms from the chelating 1-(methoxymethanimidoyl)-2-(pyridin-2-ylmethyl)guanidine (L3m) ligand and one O atom from the methanol molecule define the equatorial plane, with two perchlorate O atoms in the apical sites, one of which has a long Cu—O bond of 2.9074 (19) Å. The dihedral angle between the five- and six-membered chelate rings is 8.21 (8)°. Two molecules are associated into a dimeric unit by intermolecular N—H...O(perchlorate) hydrogen bonds. Additionally, the weakly coordinated perchlorate anions also link adjacent [Cu(ClO4)2(L3m)(CH3OH)] dimers by hydrogen-bonding interactions, resulting in a two-dimensional layer in the (100) plane. Further C—H...O hydrogen bonds link the two-dimensional layers along [100] to generate a three-dimensional network.
1-[5-(4,5-Dimethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl]ethanone and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde
Authors: Urdaneta Neudo , Nuñez Jesús , González Teresa , Briceño Alexander
Published: May 2012

In both title compounds, C10H13BO3S, (I), and C13H17BO3, (II), the molecules adopt nearly planar conformations. The crystal packing of (I) consists of a supramolecular two-dimensional network with a herringbone-like topology formed by self assembly of centrosymmetric pairs of molecules linkedviadipole–dipole interactions. The crystal structure of (II) consists of a supramolecular two-dimensional network built up from centrosymmetric pairs of moleculesviaπ–π interactions. These pairs of molecules are self-organized in an offset fashion related by a symmetry centre, generating supramolecular ribbons running along the [101] direction. Neighbouring ribbons are stackedviacomplementary van der Waals and hydrophobic methyl–methyl interactions.
3,5-Bis{4-[(benzimidazol-1-yl)methyl]phenyl}-4H-1,2,4-triazol-4-amine and its one-dimensional polymeric complex with HgCl2
Authors: Li Yan-an , Liu Qi-Kui , Ma Jian-Ping , Dong Yu-Bin
Published: May 2012

The molecule of 3,5-bis{4-[(benzimidazol-1-yl)methyl]phenyl}-4H-1,2,4-triazol-4-amine (L), C30H24N8, has an antiperiplanar conformation of the two terminal benzimidazole groups and forms two-dimensional networks along the crystallographicbaxisviatwo types of intermolecular hydrogen bonds. However, incatena-poly[[[dichloridomercury(II)]-μ-3,5-bis{4-[(benzimidazol-1-yl)methyl]phenyl}-4H-1,2,4-triazol-4-amine] dichloromethane hemisolvate], {[HgCl2(C30H24N8)]·0.5CH2Cl2}n, synthesized by the combination ofLwith HgCl2, theLligand adopts a synperiplanar conformation. The HgIIcation lies in a distorted tetrahedral environment, which is defined by two N atoms and two Cl atoms to form a one-dimensional zigzag chain. These zigzag chains stackviahydrogen bonds which expand the dimensionality of the structure from one to two.
meso-Bis{η5-1-[1-(dimethylamino)ethenyl]-3-(trimethylsilyl)cyclopentadienyl}iron(II) and the cobalt(II) analogue
Authors: Duan Xin-E , Tong Hong-Bo , Bai Sheng-Di , Wei Xue-Hong , Liu Dian-Sheng
Published: May 2012

The two title crystalline compounds,viz.meso-bis{η5-1-[1-(dimethylamino)ethenyl]-3-(trimethylsilyl)cyclopentadienyl}iron(II), [Fe(C12H20NSi)2], (II), andmeso-bis{η5-1-[1-(dimethylamino)ethenyl]-3-(trimethylsilyl)cyclopentadienyl}cobalt(II), [Co(C12H20NSi)2], (III), were obtained by the reaction of lithium 1-[1-(dimethylamino)ethenyl]-3-(trimethylsilyl)cyclopentadienide with FeCl2and CoCl2, respectively. For (II), the trimethylsilyl- and dimethylaminoethenyl-substituted cyclopentadienyl (Cp) rings present a nearly eclipsed conformation, and the two pairs of trimethylsilyl and dimethylaminoethenyl substituents on the Cp rings are arranged in an interlocked fashion. In the case of (III), the same substituted Cp rings are perfectly staggered leading to a crystallographically centrosymmetric molecular structure, and the two trimethylsilyl and two dimethylaminoethenyl substituents are oriented in opposite directions, respectively, with the trimethylsilyl group of one Cp ring and the dimethylaminoethenyl group of the other Cp ring arranged more closely than in (II).
Echinoderm microtubule‐associated protein‐like 4–anaplastic lymphoma kinase‐targeted therapy for advanced non‐small cell lung cancer: Molecular and clinical aspects
Authors: Okamoto Isamu , Nakagawa Kazuhiko
Published: May 2012

The identification of oncogenic genomic alterations is expected to facilitate the development of new molecularly targeted therapies for cancer. EML4 (echinoderm microtubule‐associated protein‐like 4)‐ALK (anaplastic lymphoma kinase) was recently identified as a transforming fusion gene in non‐small cell lung cancer (NSCLC). A small‐molecule tyrosine kinase inhibitor of ALK, crizotinib, shows pronounced clinical activity in the treatment of patients with NSCLC positive for EML4‐ALK, and it has rapidly entered into daily clinical practice. This review focuses on the biology and clinical features of, as well as diagnostic testing for, EML4‐ALK‐positive NSCLC. Current data on the efficacy and toxicity of crizotinib are also examined, and future directions for the treatment of NSCLC positive for ALK rearrangement are addressed. (Cancer Sci, doi: 10.1111/j.1349‐7006.2012.02327.x, 2012)
Pharmacokinetic and pharmacodynamic profiling of a P2X7 receptor allosteric modulator GSK1482160 in healthy human subjects
Authors: Ali Zahid , Laurijssens Bart , Ostenfeld Thor , McHugh Simon , Stylianou Anastasia , Scott‐Stevens Paul , Hosking Louise , Dewit Odile , Richardson Jill C. , Chen Chao
Published: May 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• P2X7 receptors are involved in the production of pro‐inflammatory cytokines, such as Il‐1β, by central and peripheral immune cells. Il‐1β has been implicated as an important mediator of inflammation. Therefore, the P2X7 receptor is an attractive therapeutic target for inflammatory diseases.

WHAT THIS STUDY ADDS

• Findings in pharmacokinetics, pharmacodynamics, safety and tolerability of a P2X7 receptor modulator, GSK1482160, from the first human study for the molecule are described. A pharmacokinetic/pharmacodynamic model for LPS‐stimulated ATP‐induced Il‐1β production in blood allowed the integration of all relevant data and provided in vivo evidence of the nature of the drug–receptor interaction. The model has the potential to be used to simulate future trials.

AIMS This paper describes findings from the first‐in‐human study for GSK1482160, an orally available allosteric P2X7 receptor modulator. The study aimed to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of the compound in healthy subjects.

METHODS Escalating single doses of up to 1 g were administered to healthy subjects in a single‐blind and placebo‐controlled fashion. Safety, tolerability, blood drug concentrations and ex vivo Il‐1β production in blood were evaluated.

RESULTS Drug concentration peaked within 3.5 h of dosing under fasting conditions and declined thereafter with a relatively short half‐life of less than 4.5 h. Exposure was proportional to dose with between subject variability of less than 60%. A PK/PD model quantified Il‐1β as a function of drug exposure. The model allowed simulation of in vivo pharmacology for various untested dose levels and regimens. Furthermore, the mechanistic model supported the hypothesis that the compound reduces the efficacy of ATP at the P2X7 receptor without affecting its affinity. No major safety or tolerability concerns were identified in this small study (n= 29), except for one case of asymptomatic accelerated idioventricular rhythm at the top dose.

CONCLUSION The model‐based approach maximized analysis power by integrating all biomarker data and revealed mechanistic insight into the pharmacology of P2X7 modulation by GSK1482160. Simulations by this model ultimately led to the discontinuation of the development of this compound. The therapeutic relevance of the P2X7 receptor remains to be tested in patients. The mechanistic‐model‐based approach can be applied widely to drug development.
ID1 expression associates with other molecular markers and is not an independent prognostic factor in cytogenetically normal acute myeloid leukaemia
Authors: Damm Frederik , Wagner Katharina , Görlich Kerstin , Morgan Michael , Thol Felicitas , Yun Haiyang , Delwel Ruud , Valk Peter J. M. , Löwenberg Bob , Heuser Michael , Ganser Arnold , Krauter Jürgen
Published: May 2012

In acute myeloid leukaemia with normal karyotype (CN‐AML), gene mutations (e.g. NPM1, FLT3, CEBPA) as well as deregulated gene expression affect outcome. High expression of ID1 was described as a negative prognostic factor. We have shown that CEBPA regulates ID1 expression. Therefore, we analysed the prognostic impact of ID1 expression in 269 patients (aged 16–60 years) with CN‐AML in the context of other molecular markers, particularly CEBPA mutations. ID1high status was an independent negative prognostic factor for overall survival (OS) in multivariate analysis when analysed together with age, extramedullary disease, platelets, expression of BAALC and WT1, FLT3‐internal tandem duplication, NPM1, WT1 single nucleotide polymorphism rs16754 and IDH1. ID1 expression was higher in CEBPA wildtype patients than in patients with monoallelic CEBPA mutations and these patients showed higher ID1 expression compared to patients with biallelic CEBPA mutations. Thus, when CEBPA mutations were considered, ID1 expression lost its prognostic impact. Likewise, the negative impact of ID1high status on relapse‐free survival (RFS) was lost when CEBPA mutations were included in the analysis. In CEBPA wildtype patients, ID1 expression had no impact on complete remission‐rate, OS or RFS. In conclusion, CEBPA mutations seem to deregulate ID1 expression. Therefore, ID1 expression is not an independent prognostic factor in CN‐AML.
An alternative allergen:adjuvant formulation potentiates the immunogenicity and reduces allergenicity of a novel subcutaneous immunotherapy product for treatment of grass‐pollen allergy
Authors: Rask C. , Lund L. , Lund G. , Heydenreich B. , Wurtzen P. , Bellinghausen I. , Saloga J. , Lund K.
Published: May 2012

Background

Subcutaneous specific immunotherapy (SCIT) has proven sustained clinical efficacy against allergy. The recommended regimen for SCIT is a gradual updosing over a period of weeks. Commonly, in commercial products for SCIT, the specific allergen is formulated with an adjuvant, most often in the form of aluminium hydroxide (AlOH). It has been shown that allergen‐specific IgG antibodies are induced as a result of successful SIT.

Objective

To investigate the possibility of optimizing the formulation of AlOH‐based grass‐pollen allergy vaccines for SCIT in a way that allows for shorter updosing regimens while maintaining the immunogenicity of the vaccine.

Methods

Mice were immunized with various concentrations of Phleum pratense (Phl p) allergen extract and AlOH or a fixed dilution of the maintenance doses of one conventional and one alternatively formulated vaccine. The kinetics of Phl p‐specific IgG antibody responses in serum and spleen T cell responses were determined. Allergenicity, measured as the ability of the formulations to activate human basophils, was also determined. In addition, human T cell responses and the expression of dendritic cell surface markers after vaccine challenge in vitro were analysed.

Results

Specific IgG antibody responses were shown to depend on the AlOH concentration, but not on the allergen concentrations. The immunogenicity of the conventional formulation and the alternative formulation was shown to be similar with regard to the in vivo‐induced IgG and T cell responses. In contrast, the allergenicity of the alternative formulation was significantly reduced compared with the conventional formulation.

Conclusion

The optimization of the formulation allows for administration of a lower dose of allergen while maintaining the immunogenicity of the product and at the same time reducing allergenicity.

Clinical Relevance

This study indicates that the optimization of the allergen and the adjuvant formulation could benefit the safety/efficacy profile and allow for shorter updosing.
HIF‐1α up‐regulation is associated with adverse clinicopathological and biological factors in neuroblastomas
Authors: Dungwa Josiah V , Hunt Linda P , Ramani Pramila
Published: May 2012

Dungwa J V, Hunt L P & Ramani P (2012) Histopathology 61, 417–427

HIF‐1α up‐regulation is associated with adverse clinicopathological and biological factors in neuroblastomas

Aims:  To study the expression of hypoxia‐inducible factor 1α (HIF‐1α) in clinical neuroblastoma (NB) samples and its association with the clinicopathological features, biological features and survival of NB patients.

Methods and results:  Immunohistochemistry indicated that elevated HIF‐1α expression was present in 30 of 90 (33%) NBs. This expression was correlated significantly and positively with higher clinical stage (P = 0.002), ≥18 months of age at presentation (P = 0.020), high‐risk group (P = 0.005), unfavourable pathology (P = 0.002), MYCN amplification (P < 0.001), 1p deletion (P = 0.004) and 17q gain (P = 0.002). Enzyme‐linked immunosorbent assays showed that total HIF‐1α protein was significantly higher in NBs of patients with all examined adverse prognostic factors except for age. Univariate survival analysis revealed that higher‐than‐median HIF‐1α total protein levels were associated significantly with a decrease in event‐free survival (EFS) (P = 0.017), but not in overall survival (OS) (P = 0.12). HIF‐1α immunoexpression by ≥10% of tumour cells was associated significantly with decreased OS and EFS (P = 0.002 and P = 0.004, respectively), but not in multivariate analysis after adjusting for the high‐risk group (P = 0.16 and P = 0.19, respectively).

Conclusions:  HIF‐1α was increased significantly in patients with NB associated with unfavourable characteristics. HIF‐1α is a prognostic indicator of poor OS and EFS and defines subgroups of NBs with aggressive clinical behaviour.
Size‐related variation in protein abundance in the brain and abdominal tissue of bumble bee workers
Authors: Wolschin F. , Shpigler H. , Amdam G. V. , Bloch G.
Published: May 2012

Female bumble bee workers of the same species often show a profound body size variation that is linked to a division of labour. Large individuals are more likely to forage whereas small individuals are more likely to perform in‐nest activities. A higher sensory sensitivity, stronger circadian rhythms as well as better learning and memory performances appear to better equip large individuals for outdoor activities compared to their smaller siblings. The molecular mechanisms underlying worker functional polymorphism remain unclear. Proteins are major determinants of an individual's morphology and behaviour. We hypothesized that the abundance of proteins such as metabolic enzymes as well as proteins involved in neuronal functions would differ with body size and provide insights into the mechanisms underlying size‐dependent physiological specialization in bumble bee workers. We conducted protein quantification measurements based on liquid chromatography coupled with tandem mass spectrometry on tissue samples derived from small and large Bombus impatiens and Bombus terrestris workers. Proteins found to differ significantly in abundance between small and large workers belong to the categories of structure, energy metabolism and stress response. These findings provide the first proteomic insight into mechanisms associated with size‐based division of labour in social insects.
Interactions among fire, grazing, harvest and abiotic conditions shape palm demographic responses to disturbance
Authors: Mandle Lisa , Ticktin Tamara
Published: May 2012

1. Determining the drivers of plant demography is integral to understanding the processes that shape plant species abundances and distributions. Despite recognition that interactions among drivers have important effects on demographic processes, few demographic studies test for interactions among multiple drivers in plants.

2. We used a factorial‐design experiment to study the interactive effects among three common forms of disturbance in the tropics (fire history, grazing and leaf harvest by humans) on the vital rates of Phoenix loureiri (mountain date palm) in South India. In addition, we tested for interactive effects among these disturbances, abiotic conditions and plant size. We also tested for non‐consumptive effects of grazing and harvest, such as trampling, by measuring the intensities of grazing and harvest in plots open to these disturbances.

3. Intensities of leaf harvest and grazing varied with abiotic conditions and disturbance. Leaf harvest decreased with increasing grazing intensity, suggesting that the net effect of harvest on palm populations is less where it co‐occurs with grazing. In areas without fire, plots with lower soil moisture had higher grazing intensities.

4. We found multiple significant main and interactive effects of disturbance on palm vital rates. Palm mortality increased with fire and grazing. Grazing and harvest reduced growth, but growth increased following fire. The negative impact of harvest on palm individuals was reduced when harvest occurred in plots with fire.

5. We found evidence of non‐consumptive effects of grazing and harvest on palm growth, likely from trampling. Studies inferring the effects of grazing by comparing grazed and ungrazed individuals within an area where grazing occurs will likely underestimate grazing effects.

6. Synthesis. Our findings reveal that P. loureiri demographic rates are driven by interactive effects among multiple forms of disturbance and abiotic factors and that the intensities of disturbance are themselves driven by interactions between other forms of disturbance and abiotic factors. These results illustrate that understanding the effects of, and interactions among, multiple drivers will be key in attempts to mitigate the effects of environmental change on plant species declines.
Overcoming the issue of small sample sizes in fragmentation genetics
Authors: STRUEBIG MATTHEW J. , LE COMBER STEVEN C. , ROSSITER STEPHEN J.
Published: May 2012

Nazareno & Jump (2012) highlight potential issues with using small sample sizes in population genetic studies. By reanalysing allelic richness data from our recent publication on habitat fragmentation (Struebig et al. 2011), they assert that the observed relationship has been driven by three sites with the lowest number of individuals sampled. While sample size issues have been raised before in the genetic literature, Nazareno & Jump’s (2012) comment serves as a useful reminder to us all. Nevertheless, we disagree that our findings were significantly biased by sampling limitations. Here, we demonstrate by jackknifing that, contrary to the claims of Nazareno & Jump (2012), our correlations of allelic richness and fragment area are not driven solely by sites with low sample sizes. We maintain that small sample sizes can be accounted for in fragmentation studies and that sampling limitations should not detract from undertaking conservation genetic research.
Species–genetic diversity correlations in habitat fragmentation can be biased by small sample sizes
Authors: NAZARENO ALISON G. , JUMP ALISTAIR S.
Published: May 2012

Predicted parallel impacts of habitat fragmentation on genes and species lie at the core of conservation biology, yet tests of this rule are rare. In a recent article in Ecology Letters, Struebig et al. (2011) report that declining genetic diversity accompanies declining species diversity in tropical forest fragments. However, this study estimates diversity in many populations through extrapolation from very small sample sizes. Using the data of this recent work, we show that results estimated from the smallest sample sizes drive the species–genetic diversity correlation (SGDC), owing to a false‐positive association between habitat fragmentation and loss of genetic diversity. Small sample sizes are a persistent problem in habitat fragmentation studies, the results of which often do not fit simple theoretical models. It is essential, therefore, that data assessing the proposed SGDC are sufficient in order that conclusions be robust.
A Shift from Underweight to Overweight and Obesity in Asian Children and Adolescents with Congenital Heart Disease
Authors: Chen Chun‐An , Wang Jou‐Kou , Lue Hung‐Chi , Hua Yu‐Chuan , Chang Mei‐Hwei , Wu Mei‐Hwan
Published: May 2012

Background:  In Western countries, obesity is a common problem in children with congenital heart disease (CHD). However, this problem may have racial difference, and little is known about the shift of this trend as patients grow up. The present study sought to investigate the prevalence and trends of being underweight, overweight and obesity in an Asian CHD cohort using a 5‐year citywide school survey database.

Methods:  Patient group consisted of 705 first grade elementary school students (children) and 219 first grade senior high school students (adolescents), while 18753 healthy children and 15014 healthy adolescents served as controls. Body mass index (BMI) percentile was calculated to define underweight (BMI < 15th percentile) and overweight (BMI 85th–95th percentile)/obesity (BMI ≥ 95th percentile).

Results:  In CHD children, the prevalence of underweight and overweight/obesity was 21.0% (control 16%, P < 0.001) and 14.5% (control 19.8%, P < 0.001), respectively. Children with moderate to severe CHD, especially cyanotic CHD, were more underweight and less overweight/obese than children with non‐cyanotic CHD. The prevalence of underweight (23.3%) and overweight/obesity (26.5%) in CHD adolescents became close to that in controls. From childhood to adolescence, different shifts in BMI distribution were noted; controls became more underweight and overweight/obese for males and more underweight and less overweight/obese for females, while CHD patients became more overweight/obese for both genders, including cyanotic CHD.

Conclusions:  In this Asian CHD cohort, we demonstrates a shift of BMI distribution from more underweight and less overweight/obese compared with healthy children, to a pattern similar to that in healthy adolescents.
Functional analyses of AGAMOUS family members in Nicotiana benthamiana clarify the evolution of early and late roles of C‐function genes in eudicots
Authors: Fourquin Chloé , Ferrándiz Cristina
Published: May 2012

The C‐function, according to the ABC model of floral organ identity, is required for stamen and carpel development and to provide floral meristem determinacy. Members of the AG lineage of the large MADS box gene family specify the C‐function in a broadly conserved manner in angiosperms. In core eudicots, two sub‐lineages co‐exist, euAG and PLE, which have been extensively characterized in Antirrhinum majus and Arabidopsis thaliana, where strong sub‐functionalization has led to highly divergent contributions of the respective paralogs to the C‐function. Various scenarios have been proposed to reconstruct the evolutionary history of the euAG and PLE lineages in eudicots, but detailed functional analyses of the roles of these genes in additional representative species to validate evolutionary hypotheses are scarce. Here, we report functional characterization of euAG‐ and PLE‐like genes in Nicotiana benthamiana through expression analyses and phenotypic characterization of the defects caused by their specific down‐regulation. We show that both paralogs redundantly contribute to the C‐function in this species, providing insights on the likely evolution of these gene lineages following divergence of the major groups within the eudicots (rosids and asterids). Moreover, we have demonstrated a conserved role for the PLE‐like genes in controlling fruit dehiscence, which strongly supports the ancestral role of PLE‐like genes in late fruit development and suggests a common evolutionary origin of late developmental processes in dry (dehiscent) and fleshy (ripening) fruits.
Oxygen transport and mitochondrial function in porcine septic shock, cardiogenic shock, and hypoxaemia
Authors: REGUEIRA T. , DJAFARZADEH S. , BRANDT S. , GORRASI J. , BOROTTO E. , PORTA F. , TAKALA J. , BRACHT H. , SHAW S. , LEPPER P. M. , JAKOB S. M.
Published: May 2012

Introduction

The relevance of tissue oxygenation in the pathogenesis of organ dysfunction during sepsis is controversial. We compared oxygen transport, lactate metabolism, and mitochondrial function in pigs with septic shock, cardiogenic shock, or hypoxic hypoxia.

Methods

Thirty‐two anaesthetized, ventilated pigs were randomized to faecal peritonitis (P), cardiac tamponade (CT), hypoxic hypoxia (HH) or controls. Systemic and regional blood flows, lactate, mitochondrial respiration, and tissue hypoxia‐inducible factor 1 alpha (HIF‐1α) were measured for 24 h.

Results

Mortality was 50% in each intervention group. While systemic oxygen consumption (VO2) was maintained in all groups, hepatic VO2 tended to decrease in CT [0.84 (0.5–1.3) vs. 0.42 (0.06–0.8)/ml/min/kg; P = 0.06]. In P, fractional hepatic, celiac trunk, and portal vein blood flows, and especially renal blood flow [by 46 (14–91)%; P = 0.001] decreased. In CT, renal blood flow [by 50.4 (23–81)%; P = 0.004] and in HH, superior mesenteric blood flow decreased [by 38.9 (16–100)%, P = 0.009]. Hepatic lactate influx increased > 100% in P and HH, and > 200% in CT (all P < 0.02). Hepatic lactate uptake remained unchanged in P and HH and converted to release in CT. Mitochondrial respiration remained normal. Muscle adenosine triphosphate (ATP) concentrations decreased in P (5.9 ± 1.4 μmol/g wt vs. 2.8 ± 2.7 μmol/g wt, P = 0.04). HIF‐1α expression was not detectable in any group.

Conclusion

We conclude that despite shock and renal hypoperfusion, tissue hypoxia is not a major pathophysiological issue in early and established faecal peritonitis. The reasons for reduced skeletal muscle tissue ATP levels in the presence of well‐preserved in‐vitro muscle mitochondrial respiration should be further investigated.