bluuebunny/crossref_metadata_2025 huggingface dataset:
Diverse patterns of ocean export productivity change across the Cretaceous‐Paleogene boundary: New insights from biogenic barium
Authors: Hull Pincelli M. , Norris Richard D.
Published: July 2011

One of the best‐studied aspects of the K‐Pg mass extinction is the decline and subsequent recovery of open ocean export productivity (e.g., the flux of organic matter from the surface to deep ocean). Some export proxies, including surface‐to‐deep water δ13C gradients and carbonate sedimentation rates, indicate a global decline in export productivity triggered by the extinction. In contrast, benthic foraminiferal and other geochemical productivity proxies suggest spatially and temporally heterogeneous K‐Pg boundary effects. Here we address these conflicting export productivity patterns using new and compiled measurements of biogenic barium. Unlike a previous synthesis, we find that the boundary effect on export productivity and the timing of recovery varied considerably between different oceanic sites. The northeast and southwest Atlantic, Southern Ocean, and Indian Ocean records saw export production plummet and remain depressed for 350 thousand to 2 million years. Biogenic barium and other proxies in the central Pacific and some upwelling or neritic Atlantic sites indicate the opposite, with proxies recording either no change or increased export production in the early Paleocene. Our results suggest that widespread declines in surface‐to‐deep ocean δ13C do not record a global decrease in export productivity. Rather, independent proxies, including barium and other geochemical proxies, and benthic community structure, indicate that some regions were characterized by maintained or rapidly recovered organic flux from the surface ocean to the deep seafloor, while other regions had profound reductions in export productivity that persisted long into the Paleocene.
Development of a heterogeneous microwave network fade simulation tool applicable to networks that span Europe
Authors: Paulson Kevin S. , Basarudin Hafiz
Published: July 2011

Several research groups in Europe are developing joint channel simulators for arbitrarily complex networks of terrestrial and slant path, microwave telecommunications links. Currently, the Hull Rain Fade Network Simulator (HRFNS) developed at University of Hull can simulate rain fade on arbitrary terrestrial networks in the southern United Kingdom, producing joint rain fade time series with a 10 s integration time. This paper reports on work to broaden the function of the existing HRFNS to include slant paths such as Earth‐space links and communications to high altitude platforms and unmanned airborne systems. The area of application of the new simulation tool is being extended to the whole of Europe, and other fade mechanisms are being included. Nimrod/OPERA has been chosen as the input meteorological data sets for the new system to simulate rain fade. Zero‐degree isotherm heights taken from NCEP/NCAR Reanalysis Data are used in conjunction with the Eden‐Bacon sleet (wet snow) model to introduce melting layer effects. Other fading mechanisms, including cloud fade, scintillation and absorption losses by atmospheric gasses, can be added to the simulator. The simulator is tested against ITU‐R models for rain fade distribution experienced by terrestrial and Earth‐space links in the southern United Kingdom. Statistics of fade dynamics, i.e., fade slope and fade duration, for a simulated Earth‐space link are compared to International Telecommunication Union models.
Lateral extrusion in the Eastern Alps revisited: Refining the model by thermochronological, sedimentary, and seismic data
Authors: Wölfler Andreas , Kurz Walter , Fritz Harald , Stüwe Kurt
Published: July 2011

This study comprises a reassessment of the classical model of lateral extrusion in the Eastern Alps by using recently published geochronological data, sedimentary ages from intramontane basins, ages and distribution of magmatic rocks, and information from seismic profiles. Extrusion‐related faulting continuously propagated from the western toward the central eastern part of the Eastern Alps during Oligocene to Middle Miocene times. This is confined by oblique convergence between the Adriatic and European plates. During Middle Miocene times, extrusion became not only lateral in terms of parallel to the trend of the Eastern Alps, but was characterized by a displacement vector at a high angle to the strike of the orogen. This resulted in the exhumation of the Schladming and Pohorje blocks that were exhumed within extensional bridges at the northern and southern terminations of the Pöls‐Lavanttal fault system, respectively. From Middle Miocene to recent times, extrusion was controlled by overall extension between the Dinaric and Carpathian subduction zones. The influence of north directed compression triggered by the northward moving Adriatic plate diminished, and the influence of the retreating Carpathian subduction zone increased. This gave rise to Miocene volcanism that is exclusively found east of the Dinaric subduction zone. We therefore consider that lateral extrusion in the Eastern Alps can be subdivided into distinct tectonic phases, with less pronounced eastward extension‐related displacement between Late Oligocene and Middle Miocene times. As soon as the Eastern Alps passed the Dinaric subduction zone, the entire domain became highly extensive.
A long‐term data set for hydrologic modeling in a snow‐dominated mountain catchment
Authors: Reba Michele L. , Marks Danny , Seyfried Mark , Winstral Adam , Kumar Mukesh , Flerchinger Gerald
Published: July 2011

A modeling data set (meteorological forcing data, geographic information system data, and validation data) is presented for water years 1984 through 2008 for a snow‐dominated mountain catchment. The forcing data include hourly precipitation, wind speed and direction, air and soil temperature, relative humidity, dew point temperature, and incoming solar and thermal radiation from two sites. Validation data include stream discharge, snow water equivalent, snow depth, soil moisture, and groundwater elevation. These data will improve the development, testing, and application of the next generation of hydrologic models.
Freedom's roar
Authors: Jacobs Howy
Published: July 2011

Amidst the clamour for greater freedom represented by the ‘Arab Spring’, Howy argues that scientists have a special responsibility to stand on the side of liberty.
Nuclear transport of the serum response factor coactivator MRTF‐A is downregulated at tensional homeostasis
Authors: McGee Karen M , Vartiainen Maria K , Khaw Peng T , Treisman Richard , Bailly Maryse
Published: July 2011

The serum response factor (SRF) coactivator myocardin‐related transcription factor A (MAL/MKL1/MRTF‐A), the nuclear transport and activity of which is regulated by monomeric actin, has been implicated in tension‐based regulation of SRF‐mediated transcriptional activity. However, the mechanisms involved remain unclear. We used fibroblasts grown within collagen matrices to explore whether MRTF‐A transport is regulated by tissue tension. We show that MRTF‐A nuclear accumulation following stimulation with serum, actin drugs or acute mechanical stress is prevented within mechanically loaded, anchored matrices at tensional homeostasis. This is accompanied by a higher G/F actin ratio, defective nuclear import and increased cofilin expression. We propose that tension regulates MRTF‐A/SRF activity through cofilin‐mediated modulation of actin dynamics.
Mitochondria in innate immunity
Authors: Arnoult Damien , Soares Fraser , Tattoli Ivan , Girardin Stephen E
Published: July 2011

Mitochondria are cellular organelles involved in host‐cell metabolic processes and the control of programmed cell death. A direct link between mitochondria and innate immune signalling was first highlighted with the identification of MAVS—a crucial adaptor for RIGI‐like receptor signalling—as a mitochondria‐anchored protein. Recently, other innate immune molecules, such as NLRX1, TRAF6, NLRP3 and IRGM have been functionally associated with mitochondria. Furthermore, mitochondrial alarmins—such as mitochondrial DNA and formyl peptides—can be released by damaged mitochondria and trigger inflammation. Therefore, mitochondria emerge as a fundamental hub for innate immune signalling.
Swimming direction reversal of flagella through ciliary motion of mastigonemes
Authors: Namdeo S. , Khaderi S. N. , den Toonder J. M. J. , Onck P. R.
Published: July 2011

Bio-inspired designs can provide an answer to engineering problems such as swimming strategies at the micron or nano-scale. Scientists are now designing artificial micro-swimmers that can mimic flagella-powered swimming of micro-organisms. In an application such as lab-on-a-chip in which micro-object manipulation in small flow geometries could be achieved by micro-swimmers, control of the swimming direction becomes an important aspect for retrieval and control of the micro-swimmer. A bio-inspired approach for swimming direction reversal (a flagellum bearing mastigonemes) can be used to design such a system and is being explored in the present work. We analyze the system using a computational framework in which the equations of solid mechanics and fluid dynamics are solved simultaneously. The fluid dynamics of Stokes flow is represented by a 2D Stokeslets approach while the solid mechanics behavior is realized using Euler-Bernoulli beam elements. The working principle of a flagellum bearing mastigonemes can be broken up into two parts: (1) the contribution of the base flagellum and (2) the contribution of mastigonemes, which act like cilia. These contributions are counteractive, and the net motion (velocity and direction) is a superposition of the two. In the present work, we also perform a dimensional analysis to understand the underlying physics associated with the system parameters such as the height of the mastigonemes, the number of mastigonemes, the flagellar wave length and amplitude, the flagellum length, and mastigonemes rigidity. Our results provide fundamental physical insight on the swimming of a flagellum with mastigonemes, and it provides guidelines for the design of artificial flagellar systems.
Geometric phase of the gyromotion for charged particles in a time-dependent magnetic field
Authors: Liu Jian , Qin Hong
Published: July 2011

We study the dynamics of the gyrophase of a charged particle in a magnetic field which is uniform in space but changes slowly with time. As the magnetic field evolves slowly with time, the changing of the gyrophase is composed of two parts. The first part is the dynamical phase, which is the time integral of the instantaneous gyrofrequency. The second part, called geometric gyrophase, is more interesting, and it is an example of the geometric phase which has found many important applications in different branches of physics. If the magnetic field returns to the initial value after a loop in the parameter space, then the geometric gyrophase equals the solid angle spanned by the loop in the parameter space. This classical geometric gyrophase is compared with the geometric phase (the Berry phase) of the spin wave function of an electron placed in the same adiabatically changing magnetic field. Even though gyromotion is not the classical counterpart of the quantum spin, the similarities between the geometric phases of the two cases nevertheless reveal the similar geometric nature of the different physics laws governing these two physics phenomena.
Novel vibrational resonance in multistable systems
Authors: Rajasekar S. , Abirami K. , Sanjuan M. A. F.
Published: July 2011

We investigate the role of multistable states on the occurrence of vibrational resonance in a periodic potential system driven by both a low-frequency and a high-frequency periodic force in both underdamped and overdamped limits. In both cases, when the amplitude of the high-frequency force is varied, the response amplitude at the low-frequency exhibits a series of resonance peaks and approaches a limiting value. Using a theoretical approach, we analyse the mechanism of multiresonance in terms of the resonant frequency and the stability of the equilibrium points of the equation of motion of the slow variable. In the overdamped system, the response amplitude is always higher than in the absence of the high-frequency force. However, in the underdamped system, this happens only if the low-frequency is less than 1. In the underdamped system, the response amplitude is maximum when the equilibrium point around which slow oscillations take place is maximally stable and minimum at the transcritical bifurcation. And in the overdamped system, it is maximum at the transcritical bifurcation and minimum when the associated equilibrium point is maximally stable. When the periodicity of the potential is truncated, the system displays only a few resonance peaks.
Double tearing modes in the presence of internal transport barrier
Authors: Zhao X. M. , Peng X. D. , Tang C. J. , Qiu X. M.
Published: July 2011

The linear characteristics of double tearing modes (DTMs) in the presence of internal transport barrier (ITB) are investigated in a cylindrical tokamak plasma. A simple model describing density profile of ITB is suggested. Combining the safety factor profile given by Bierwage et al. [Phys. Plasmas 12, 082504 (2005); 14, 022107 (2007)], the DTMs spectra, scaling laws, and relationships between growth rate and density profile factor in the presence of ITB are studied, respectively. The results show that the resistive drift instability occurs in the case of high poloidal mode numbers. A transition from DTMs to the resistive drift instability is observed, and the dependence of DTMs growth rate on the magnetic Reynolds number has changed greatly due to the presence of ITB. In addition, the linear growth rates of the modes including those with low and high poloidal mode number increase when the plasma density profile steepens in the presence of ITB whatever the inter-resonant distance is smaller or larger.
On decomposing mixed-mode oscillations and their return maps
Authors: Kuehn Christian
Published: July 2011

Alternating patterns of small and large amplitude oscillations occur in a wide variety of physical, chemical, biological, and engineering systems. These mixed-mode oscillations (MMOs) are often found in systems with multiple time scales. Previous differential equation modeling and analysis of MMOs have mainly focused on local mechanisms to explain the small oscillations. Numerical continuation studies reported different MMO patterns based on parameter variation. This paper aims at improving the link between local analysis and numerical simulation. Our starting point is a numerical study of a singular return map for the Koper model which is a prototypical example for MMOs, which also relates to local normal form theory. We demonstrate that many MMO patterns can be understood geometrically by approximating the singular maps with affine and quadratic maps. Motivated by our numerical analysis we use abstract affine and quadratic return map models in combination with two local normal forms that generate small oscillations. Using this decomposition approach we can reproduce many classical MMO patterns and effectively decouple bifurcation parameters for local and global parts of the flow. The overall strategy we employ provides an alternative technique for understanding MMOs.
High conifer diversity in Oligo-Miocene New Zealand
Authors: Jordan Gregory J. , Carpenter Raymond J. , Bannister Jennifer M. , Lee Daphne E. , Mildenhall Dallas C. , Hill Robert S.
Published: July 2011

Eight species of Podocarpaceae foliage are recognised from the late Oligocene or early Miocene Newvale site, South Island, New Zealand, and the following five new species are described: two of Dacrydium Lamb. and one each of Dacrycarpus (Endl.) de Laub., Phyllocladus Rich. ex Mirb. and Halocarpus Quinn. The latter is the first macrofossil record of this New Zealand endemic genus. All these conifers, plus Agathis Salisb., Microcachrys Hook.f. and Podocarpus Pers., co-occurred in the local vegetation at Newvale. In conjunction with prior records of macrofossils and pollen, these fossils indicate that the late Paleogene to early Neogene conifer flora of New Zealand was very diverse, with all but one of the extant genera present, together with several regionally or globally extinct genera, and multiple species of many of these genera. This fossil diversity is similar to the Paleogene fossil conifer diversity observed in south-eastern Australia (and particularly Tasmania) and in parts of North America.
Nanoscale distribution of mitochondrial import receptor Tom20 is adjusted to cellular conditions and exhibits an inner-cellular gradient
Authors: Wurm Christian A. , Neumann Daniel , Lauterbach Marcel A. , Harke Benjamin , Egner Alexander , Hell Stefan W. , Jakobs Stefan
Published: July 2011

The translocase of the mitochondrial outer membrane (TOM) complex is the main import pore for nuclear-encoded proteins into mitochondria, yet little is known about its spatial distribution within the outer membrane. Super-resolution stimulated emission depletion microscopy was used to determine quantitatively the nanoscale distribution of Tom20, a subunit of the TOM complex, in more than 1,000 cells. We demonstrate that Tom20 is located in clusters whose nanoscale distribution is finely adjusted to the cellular growth conditions as well as to the specific position of a cell within a microcolony. The density of the clusters correlates to the mitochondrial membrane potential. The distributions of clusters of Tom20 and of Tom22 follow an inner-cellular gradient from the perinuclear to the peripheral mitochondria. We conclude that the nanoscale distribution of the TOM complex is finely adjusted to the cellular conditions, resulting in distribution gradients both within single cells and between adjacent cells.
Designed oligomers of cyanovirin-N show enhanced HIV neutralization
Authors: Keeffe Jennifer R. , Gnanapragasam Priyanthi N. P. , Gillespie Sarah K. , Yong John , Bjorkman Pamela J. , Mayo Stephen L.
Published: July 2011

Cyanovirin-N (CV-N) is a small, cyanobacterial lectin that neutralizes many enveloped viruses, including human immunodeficiency virus type I (HIV-1). This antiviral activity is attributed to two homologous carbohydrate binding sites that specifically bind high mannose glycosylation present on envelope glycoproteins such as HIV-1 gp120. We created obligate CV-N oligomers to determine whether increasing the number of binding sites has an effect on viral neutralization. A tandem repeat of two CV-N molecules (CVN
2
) increased HIV-1 neutralization activity by up to 18-fold compared to wild-type CV-N. In addition, the CVN
2
variants showed extensive cross-clade reactivity and were often more potent than broadly neutralizing anti-HIV antibodies. The improvement in activity and broad cross-strain HIV neutralization exhibited by these molecules holds promise for the future therapeutic utility of these and other engineered CV-N variants.
Observation of three-dimensional motion of the pellet ablatant in the Large Helical Device
Authors: Mishra J.S. , Sakamoto R. , Matsuyama A. , Motojima G. , Yamada H.
Published: July 2011

Application of two-point stereoscopic diagnostics using a fast camera and bundled fibre has enabled the observation of the three-dimensional nature of the pellet trajectory in the Large Helical Device. It has been observed that the pellet trajectory deviates from its injection direction, toroidally and vertically depending on the direction of the tangentially applied neutral beams. The magnitude of the toroidal deviation is similar in the clockwise as well as counter-clockwise neutral beam directions and is of 15–20 cm with a deflection speed of up to 400 m s−1. In contrast, an asymmetry in trajectory deflection has been observed in the vertical direction. Experimental results also indicate that the starting radius of the pellet trajectory bending in the counter-clockwise neutral beam case is more inward to that of the plasma. Collectively this leads to less penetration of the pellet inside the plasma and is prominent in the case of the clockwise neutral beam. Additionally, this fact supports evidence that the fast ion plays an important role in the pellet ablation process in the Large Helical Device. The pellet deflection is explained by the rocket effect due to unilateral ablation by the fast ions. The possible cause of the difference in the vertical deflection is explained by considering the geometrical aspects of the magnetic field structure.
Tissue-specific subnetworks and characteristics of publicly available human protein interaction databases
Authors: Lopes Tiago J. S. , Schaefer Martin , Shoemaker Jason , Matsuoka Yukiko , Fontaine Jean−Fred , Neumann Gabriele , Andrade-Navarro Miguel A. , Kawaoka Yoshihiro , Kitano Hiroaki
Published: July 2011

Motivation: Protein-protein interaction (PPI) databases are widely used tools to study cellular pathways and networks; however, there are several databases available that still do not account for cell type-specific differences. Here, we evaluated the characteristics of six interaction databases, incorporated tissue-specific gene expression information and finally, investigated if the most popular proteins of scientific literature are involved in good quality interactions.

Results: We found that the evaluated databases are comparable in terms of node connectivity (i.e. proteins with few interaction partners also have few interaction partners in other databases), but may differ in the identity of interaction partners. We also observed that the incorporation of tissue-specific expression information significantly altered the interaction landscape and finally, we demonstrated that many of the most intensively studied proteins are engaged in interactions associated with low confidence scores. In summary, interaction databases are valuable research tools but may lead to different predictions on interactions or pathways. The accuracy of predictions can be improved by incorporating datasets on organ- and cell type-specific gene expression, and by obtaining additional interaction evidence for the most ‘popular’ proteins.

Contact:  kitano@sbi.jp

Supplementary information:  Supplementary data are available at Bioinformatics online.
A powerful approach for association analysis incorporating imprinting effects
Authors: Xia Fan , Zhou Ji-Yuan , Fung Wing Kam
Published: July 2011

Motivation: For a diallelic marker locus, the transmission disequilibrium test (TDT) is a simple and powerful design for genetic studies. The TDT was originally proposed for use in families with both parents available (complete nuclear families) and has further been extended to 1-TDT for use in families with only one of the parents available (incomplete nuclear families). Currently, the increasing interest of the influence of parental imprinting on heritability indicates the importance of incorporating imprinting effects into the mapping of association variants.

Results: In this article, we extend the TDT-type statistics to incorporate imprinting effects and develop a series of new test statistics in a general two-stage framework for association studies. Our test statistics enjoy the nature of family-based designs that need no assumption of Hardy–Weinberg equilibrium. Also, the proposed methods accommodate complete and incomplete nuclear families with one or more affected children. In the simulation study, we verify the validity of the proposed test statistics under various scenarios, and compare the powers of the proposed statistics with some existing test statistics. It is shown that our methods greatly improve the power for detecting association in the presence of imprinting effects. We further demonstrate the advantage of our methods by the application of the proposed test statistics to a rheumatoid arthritis dataset.

Contact:  wingfung@hku.hk

Supplementary information:  Supplementary data are available at Bioinformatics online.
Enterohaemorrhagic, but not enteropathogenic, Escherichia coli infection of epithelial cells disrupts signalling responses to tumour necrosis factor-alpha
Authors: Gareau Mélanie G. , Ho Nathan K. , Brenner Dirk , Sousa Andrew J. , LeBourhis Lionel , Mak Tak W. , Girardin Stephen E. , Philpott Dana J. , Sherman Philip M.
Published: July 2011

Enterohaemorrhagic Escherichia coli (EHEC), serotype O157 : H7 is a non-invasive, pathogenic bacterium that employs a type III secretion system (T3SS) to inject effector proteins into infected cells. In this study, we demonstrate that EHEC blocks tumour necrosis factor-alpha (TNFα)-induced NF-κB signalling in infected epithelial cells. HEK293T and INT407 epithelial cells were challenged with EHEC prior to stimulation with TNFα. Using complementary techniques, stimulation with TNFα caused activation of NF-κB, as determined by luciferase reporter assay (increase in gene expression), Western blotting (phosphorylation of IκBα), immunofluorescence (p65 nuclear translocation) and immunoassay (CXCL-8 secretion), and each was blocked by EHEC O157 : H7 infection. In contrast, subversion of host cell signalling was not observed following exposure to either enteropathogenic E. coli, strain E2348/69 (O127 : H6) or the laboratory E. coli strain HB101. Heat-killed EHEC had no effect on NF-κB activation by TNFα. Inhibition was mediated, at least in part, by Shiga toxins and by the O157 plasmid, but not by the T3SS or flagellin, as demonstrated by using isogenic mutant strains. These findings indicate the potential for developing novel therapeutic targets to interrupt the infectious process.
Subjective measures of binge drinking and alcohol‐specific adverse health outcomes: a prospective cohort study
Authors: Paljärvi Tapio , Mäkelä Pia , Poikolainen Kari , Suominen Sakari , Car Josip , Koskenvuo Markku
Published: July 2011

Aim  To determine the performance of subjectively defined intoxications, hangovers and alcohol‐induced pass‐outs in identifying drinkers at risk for adverse health outcomes.

Design  Prospective population‐based cohort study.

Setting  Working‐aged Finnish general population.

Participants  A total of 21 204 alcohol‐drinking men and women aged 20–24, 30–34, 40–44 and 50–54 years at baseline who participated in the Health and Social Support (HeSSup) postal survey in 1998.

Measurements  Binge drinking was measured by subjectively defined intoxications/drunkenness, hangovers and alcohol‐induced pass‐outs. Hazardous drinking was defined according to Finnish guidelines as weekly total intake of >287 g of ethanol for men, and for women > 191 g of ethanol (≥24 and ≥16 standard drinks, respectively). Study participants were followed‐up for 7 years for alcohol‐specific hospitalizations and deaths. Proportional hazard models and areas under the receiver operating characteristics curves (AUC) were used to analyse the data.

Findings  Of the drinkers, 6.5% exceeded the weekly limit for hazardous drinking, and 1.5% experienced the alcohol‐specific end‐point during the follow‐up. Subjective intoxications, hangovers and alcohol‐induced pass‐outs all predicted future alcohol‐specific diagnoses independently of average intake and of several other potential confounders. In identifying baseline hazardous drinking, subjective intoxications had a superior performance in relation to other subjective measures of binge drinking. In identifying future alcohol‐specific hospitalizations or death, subjective intoxications had also the best performance, but this was not significantly different from the other binge drinking measures, or average intake.

Conclusions  Subjectively defined intoxications, hangovers and alcohol‐induced pass‐outs are population‐level proxy measures of at‐risk drinking patterns.
Kava hepatotoxicity in traditional and modern use: the presumed Pacific kava paradox hypothesis revisited
Authors: Teschke Rolf , Sarris Jerome , Schweitzer Isaac
Published: July 2011

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The rhizome of the Pacific kava plant (Piper methysticum) contains as its active constituents numerous kavalactones known for their relaxing properties. Kavalactones are found in aqueous, acetonic and ethanolic extracts of the kava rhizomes. These kava extracts are consumed worldwide and used for recreational purposes as well as to treat general anxiety. Kava use is associated with rare hepatotoxicity.

WHAT THIS PAPER ADDS

• Kava is a Pacific herb consumed worldwide and used for recreational purposes and to treat general anxiety. Kava use is associated with rare hepatotoxicity. The previously proposed Pacific kava paradox was based on kava hepatotoxicity, not observed following use of traditional aqueous extracts in the Pacific region but restricted to use of Western acetonic and ethanolic extracts. However, cases assessed by the WHO report and additional published case reports revealed that traditional aqueous extracts used in New Caledonia, Australia, the USA and Germany may also be hepatotoxic; hence, there is no longer a basis to sustain the previously proposed Pacific kava paradox. It appears that the primary cause of toxicity may be attributed to poor quality of the raw material caused by mould hepatotoxins.

Kava, a Pacific herb consumed worldwide for medicinal, recreational and cultural purposes, has been associated with rare hepatotoxicity, and there is currently a critical need to determine this causation. The previously proposed Pacific kava paradox was based on the theory that kava hepatotoxicity was not observed following use of traditional aqueous extracts in the Pacific region, but was restricted to use of Western acetonic and ethanolic extracts. Subsequent cases analyzed by the World Health Organization and published case reports revealed that traditional aqueous extracts used in New Caledonia, Australia, the USA and Germany may also be hepatotoxic; thus, there is no longer a basis to sustain the previously proposed Pacific kava paradox. It appears that the primary cause of toxicity may reside in the time before the preparation of the various kava extracts, possibly attributed to poor quality of the raw material caused by mould hepatotoxins. Rigorous testing of kava raw material is urgently advised, in addition to Pan‐Pacific kava manufacturing quality standards.
Clomipramine concentration and withdrawal symptoms in 10 neonates
Authors: ter Horst Peter G. J. , van der Linde Susanne , Smit Jan Pieter , den Boon Jan , van Lingen Richard A. , Jansman Frank G. A. , De Jong‐van den Berg Lolkje T. W. , Wilffert Bob
Published: July 2011

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Antidepressants are associated with withdrawal symptoms after in utero exposure.

• Half‐life of clomipramine in neonates is prolonged compared with that in adults.

WHAT THIS STUDY ADDS

• We present 10 cases of neonates exposed in utero to clomipramine, with detailed information about withdrawal symptoms and pharmacokinetics.

• There is a high and severe complication rate in our cohort regarding the mother and the neonate.

AIM After in utero exposure to tricyclic antidepressants, neonatal withdrawal symptoms have been reported with an estimated incidence between 20 and 50%; however, few data are available for clomipramine. This could also be the case for neonatal pharmacokinetic clomipramine parameters and so this study was set up.

METHODS Babies exposed to clomipramine in utero were included in an observational study, approved by the local ethics committee, after written informed consent. Withdrawal symptoms were scored at 12, 24 and 48 h after birth using the Finnegan score. Plasma concentrations were determined using an in‐house‐developed, validated liquid chromatography with mass detection (LC‐MSMS) method at 0, 12, 24 and 48 h after birth.

RESULTS We found that three of 11 pregnancies were complicated with pre‐eclampsia. Ten neonates were observed for clomipramine withdrawal symptoms. The observed withdrawal symptoms were too short a period of sleep after feeding (6), poor feeding (3), mild to severe tremors (6), hyperactive Moro reflex (3) and respiratory rate >60 breaths min−1. Serious withdrawal reactions, such as tachycardia and cyanosis, were seen. We calculated a half‐life value of 42 ± 16 h for clomipramine in neonates. Only a weak correlation was found between withdrawal reactions and clomipramine plasma concentration or desmethylclomipramine plasma concentration.

CONCLUSIONS In neonates, clomipramine is eliminated with a half‐life value of 42 h, compared with 20 h in adults. In two of 10 neonates, tachycardia and cyanosis were seen as serious withdrawal symptoms after maternal use of clomipramine.
The development of the Tuebingen Cushing’s disease quality of life inventory (Tuebingen CD‐25). Part I: construction and psychometric properties
Authors: Milian Monika , Teufel Philipp , Honegger Juergen , Gallwitz Baptist , Schnauder Guenter , Psaras Tsambika
Published: July 2011

Objective  To develop a disease‐specific questionnaire for Cushing’s disease (CD), the Tuebingen Cushing’s disease quality of life inventory (Tuebingen CD‐25).

Methods  Sources for item generation consisted of technical literature, interviews with patients and the rating of neurosurgeons, endocrinologists and a neuropsychologist. A preliminary inventory with 64 items was handed out to 63 CD patients. Twenty‐eight patients filled out the questionnaire preoperative, the remaining 35 patients evaluated their health‐related quality of life (HRQoL) retrospectively. Item reduction and scale generation followed the principles of classical test theory. Validation was performed with the WHOQoL‐BREF.

Results  The final version of the Tuebingen CD‐25 contained 25 items, showed high reliability (Cronbach’s alpha = 0·93) and validity (r = −0·65) and includes the subdomains Depression, Sexual Activity, Environment, Eating Behaviour, Bodily Restrictions and Cognition. The retrospective rating of the Tuebingen CD‐25 showed similar results compared to the pretreatment group. We found a non‐linear correlation between the Tuebingen CD‐25 scores and patients’ age, younger (21–30 years) and middle‐aged (51–60 years) patients having inferior HRQoL than patients between 31 and 50 years and older than 61 years. Preoperative 24 h urinary free cortisol (UFC) levels correlated significantly with the subscale Cognition and only marginally failed significance level for the subscale Eating Behaviour, while preoperative cortisol and ACTH levels did not correlate with any scale.

Conclusion  The Tuebingen CD‐25 is a valid and reliable instrument to evaluate HRQoL in CD. Based on impairment of HRQoL for the different subdimensions, specific support can be offered to the patients.
Estimated standard metabolic rate interacts with territory quality and density to determine the growth rates of juvenile Atlantic salmon
Authors: Reid Donald , Armstrong John D. , Metcalfe Neil B.
Published: July 2011

1. Physiological traits can vary greatly within a species and consequently have a significant impact on other aspects of performance. Many species exhibit substantial variation in basal or standard metabolic rate (SMR), even after controlling for body size and age, yet the ecological consequences of this are little known.

2. We examined the relationships between mass‐specific SMR of yearling salmon (estimated from their ventilation rate) and their feeding and growth rates across a range of natural population densities within a semi‐natural stream environment.

3. Standard metabolic rate was strongly correlated with dominance rank, and higher ranking fish were more likely to acquire good feeding territories. Despite this, there was no overall relationship between SMR and growth. We show for the first time that this paradox can be explained because within territories of a given quality, there was a negative correlation between SMR and growth rate, presumably owing to the costs of metabolism.

4. These effects were also influenced by density: lower densities led to reduced aggression and competition and hence higher average feeding and growth rates. Moreover, at low densities, where availability of good feeding locations was not limiting, there was no relationship between SMR and growth.

5. As a result of these processes, there was a context‐dependent trade‐off in energy budgets: the fish achieving the greatest growth were those with the lowest SMR that was necessary to achieve dominance over conspecifics (and hence acquire a good territory), but this minimum threshold SMR increased with population density. These relationships and trade‐offs can explain the persistence of variation in SMR within populations.
Body size and the division of niche space: food and predation differentially shape the distribution of Serengeti grazers
Authors: Hopcraft J. Grant C. , Anderson T. Michael , Pérez‐Vila Saleta , Mayemba Emilian , Olff Han
Published: July 2011

1. Theory predicts that small grazers are regulated by the digestive quality of grass, while large grazers extract sufficient nutrients from low‐quality forage and are regulated by its abundance instead. In addition, predation potentially affects populations of small grazers more than large grazers, because predators have difficulty capturing and handling large prey.

2. We analyse the spatial distribution of five grazer species of different body size in relation to gradients of food availability and predation risk. Specifically, we investigate how the quality of grass, the abundance of grass biomass and the associated risks of predation affect the habitat use of small, intermediate and large savanna grazers at a landscape level.

3. Resource selection functions of five mammalian grazer species surveyed over a 21‐year period in Serengeti are calculated using logistic regressions. Variables included in the analyses are grass nitrogen, rainfall, topographic wetness index, woody cover, drainage lines, landscape curvature, water and human habitation. Structural equation modelling (SEM) is used to aggregate predictor variables into ‘composites’ representing food quality, food abundance and predation risk. Subsequently, SEM is used to investigate species’ habitat use, defined as their recurrence in 5 × 5 km cells across repeated censuses.

4. The distribution of small grazers is constrained by predation and food quality, whereas the distribution of large grazers is relatively unconstrained. The distribution of the largest grazer (African buffalo) is primarily associated with forage abundance but not predation risk, while the distributions of the smallest grazers (Thomson’s gazelle and Grant’s gazelle) are associated with high grass quality and negatively with the risk of predation. The distributions of intermediate sized grazers (Coke’s hartebeest and topi) suggest they optimize access to grass biomass of sufficient quality in relatively predator‐safe areas.

5. The results illustrate how top‐down (vegetation‐mediated predation risk) and bottom‐up factors (biomass and nutrient content of vegetation) predictably contribute to the division of niche space for herbivores that vary in body size. Furthermore, diverse grazing assemblages are composed of herbivores of many body sizes (rather than similar body sizes), because these herbivores best exploit the resources of different habitat types.
Direct and indirect effects of landscape change on the reproduction of a temperate perennial herb
Authors: Valdés Alicia , García Daniel
Published: July 2011

1. The harmful effects of landscape change on species reproduction may be direct when habitat loss and fragmentation affect individual performance within habitat remnants, but also indirect when reproductive collapse derives from the effect of landscape alterations on population traits. Although the distinction between direct and indirect effects is crucial for the effective management of species, studies looking at both are scarce.

2. To assess the mechanisms and the temporal consistency of landscape change effects on reproduction, we quantified flowering, fruiting and seed set of the perennial herb Primula vulgaris through a gradient of forest loss and fragmentation, in 2 years with different climatic conditions. We used structural equation modelling to relate, at the landscape scale, forest habitat availability and subdivision, forest edge length, population size and subdivision, and flower, fruit and seed production. We also evaluated the effects of light availability, plant abundance and aggregation on reproduction at the local scale.

3. Flower and fruit production decreased in landscape regions with lower forest habitat availability, and fruit production decreased in areas with a smaller amount of forest edge. There was also a negative indirect effect of habitat loss on seed production, through population size reduction. These effects mostly emerged at the landscape scale and operated in all reproductive stages, but were also transmitted across stages, as flower and fruit production quantitatively influenced seed output.

4. Landscape change effects on reproduction differed between the 2 years, becoming evident after a mild winter that favoured long‐lasting flowering, but disappearing, or even changing sign, when winter harshness shortened flowering.

5. Synthesis and applications. Disentangling the relative importance of direct and indirect effects of landscape change in plant reproduction is a novel approach to distinguishing between populations and habitats as the required management targets. In our study system, increasing P. vulgaris population sizes within small forest patches seems less effective than increasing forest cover around existing populations (even small ones), to enhance individual reproduction. The contrasting effects of the different processes of landscape change and the potential additive role of climatic variability must also be considered in management purposes.
Progress in medicine: autonomy, oughtonomy and nudging
Authors: Devisch Ignaas
Published: July 2011

Rationale  In this article, I argue that we need a new perspective in the debate on autonomy in medicine, to understand many of the problems we face today – dilemmas that are situated at the intersection of autonomy and heteronomy, such as why well informed and autonomous people make unhealthy lifestyle choices. If people do not choose what they want, this is not simply caused by their lack of character or capability, but also by the fact that absolute autonomy is impossible; autonomous individuals are ‘contaminated’ by heteronymous aspects, by influences from ‘outside’. Consequently, there are many good reasons to question the widely accepted hierarchical opposition of autonomy (progress) versus heteronomy (paternalism) in medicine. In an earlier article an analysis is made of the neologism ‘oughtonomy’ to support the thesis that when it comes down to human existence, autonomy and heteronomy are intertwined, rather than being merely opposites.

Methods  In this article, I reflect upon how social conditions might improve our ‘choice architecture’, what Thaler & Sunstein have called ‘nudging’: how to change individual health choices without being paternalistic? I explore the extent to which both oughtonomy and nudging are able to challenge the question of autonomy in today's medicine.

Results and conclusions  Autonomy may and should be a shared target in today's medicine, but we should never forget that it is always intertwined with heteronomy. Starting from this perspective, progress in medicine demands far more than the increase of autonomy.
GRP78(BiP) facilitates the cytosolic delivery of anthrax lethal factor (LF) in vivo and functions as an unfoldase in vitro
Authors: Tamayo Alfred G. , Slater Louise , Taylor‐Parker Julian , Bharti Ajit , Harrison Robert , Hung Deborah T. , Murphy John R.
Published: July 2011

Anthrax toxin is an A/B bacterial protein toxin which is composed of the enzymatically active Lethal Factor (LF) and/or Oedema Factor (EF) bound to Protective Antigen 63 (PA63) which functions as both the receptor binding and transmembrane domains. Once the toxin binds to its cell surface receptors it is internalized into the cell and traffics through Rab5‐ and Rab7‐associated endosomal vesicles. Following acidification of the vesicle lumen, PA63 undergoes a dynamic change forming a beta‐barrel that inserts into and forms a pore through the endosomal membrane. It is widely recognized that LF, and the related fusion protein LFnDTA, must be completely denatured in order to transit through the PA63 formed pore and enter the eukaryotic cell cytosol. We demonstrate by protease protection assays that the molecular chaperone GRP78 mediates the unfolding of LFnDTA and LF at neutral pH and thereby converts these proteins from a trypsin resistant to sensitive conformation. We have used immunoelectron microscopy and gold‐labelled antibodies to demonstrate that both GRP78 and GRP94 chaperones are present in the lumen of endosomal vesicles. Finally, we have used siRNA to demonstrate that knock‐down of GRP78 results in the emergence of resistance to anthrax lethal toxin and oedema toxin action.
Potential susceptibility of Australian native plant species to branch dieback and bole canker diseases caused by Phytophthora ramorum
Authors: Ireland K. B. , Hüberli D. , Dell B. , Smith I. W. , Rizzo D. M. , Hardy G. E. St. J.
Published: July 2011

Susceptibility to branch dieback caused by Phytophthora ramorum was tested using a detached branch assay for 66 Australian native plant species sourced from established gardens and arboreta in California. Six of these species were further tested for their susceptibility to bole cankers caused by P. ramorum using a sealed log assay. Isopogon formosus and Eucalyptus denticulata were identified as potentially highly susceptible Australian branch dieback hosts. Thirteen potentially tolerant Australian host species included Banksia attenuata, B. marginata, E. haemastoma, E. regnans, Pittosporum undulatum and Billardiera heterophylla. Eucalyptus regnans was identified as a potentially highly susceptible bole canker host, while E. diversicolor and E. viminalis were considered potentially tolerant species to bole cankers caused by P. ramorum. Phytophthora ramorum was able to infect all 66 species, as confirmed by reisolation. These results extend the known potential host range for P. ramorum, confirm it as a possible threat to Australian plant industries and ecosystems and highlight additional associated hosts that are important in the global horticultural trade, native forests and plantation forestry.
Genetic population structure and trichothecene genotypes of Fusarium graminearum isolated from wheat in southern Brazil
Authors: Astolfi P. , Reynoso M. M. , Ramirez M. L. , Chulze S. N. , Alves T. C. A. , Tessmann D. J. , Del Ponte E. M.
Published: July 2011

A sample of 140 Fusarium graminearum isolates from Rio Grande do Sul, Brazil, representing three populations at least 150 km from one another, were examined for trichothecene genotype based on PCR amplification of portions of the Tri3 and Tri12 genes and a species‐specific (Fg16F/R) primer pair. Genetic diversity was assessed in a sample of 103 F. graminearum lineage 7 (F. graminearum sensu stricto) isolates using amplified fragment length polymorphism (AFLP) markers. The 15‐ADON genotype was dominant, followed by the NIV genotype (2–18% prevalence), across all three populations. All NIV‐type isolates were in lineage 2 (F. meridionale) and all 15‐ADON‐type isolates were in lineage 7. Isolates with the same haplotype were rare and genotypic diversity was uniformly high (≥98% of the count), suggesting that recombination has played a significant role. The number of migrants (Nm) was estimated between 5 and 6 across all loci and all populations, but the high frequency of private alleles (up to 30%) suggests a historical, rather than contemporary, gene flow. Regarding linkage disequilibrium, 0·8, 1·5 and 2·2% of the locus pairs from the three populations were in disequilibrium, which is lower than values reported in other locations. Thus, Brazilian populations differ from those found in Europe, North America and most of Asia in the presence of a significant frequency (7·8%) of isolates of the NIV genotype in lineage 2.