bluuebunny/crossref_metadata_2025 huggingface dataset:
Rab5c promotes AMAP1–PRKD2 complex formation to enhance β1 integrin recycling in EGF-induced cancer invasion
Authors: Onodera Yasuhito , Nam Jin-Min , Hashimoto Ari , Norman Jim C. , Shirato Hiroki , Hashimoto Shigeru , Sabe Hisataka
Published: June 2012

Epidermal growth factor receptor (EGFR) signaling is one of the crucial factors in breast cancer malignancy. Breast cancer cells often overexpress Arf6 and its effector, AMAP1/ASAP1/DDEF1; in these cells, EGFR signaling may activate the Arf6 pathway to induce invasion and metastasis. Active recycling of some integrins is crucial for invasion and metastasis. Here, we show that the Arf6–AMAP1 pathway links to the machinery that recycles β1 integrins, such as α3β1, to promote cell invasion upon EGFR stimulation. We found that AMAP1 had the ability to bind directly to PRKD2 and hence to make a complex with the cytoplasmic tail of the β1 subunit. Moreover, GTP-Rab5c also bound to AMAP1, and activation of Rab5c by EGFR signaling was necessary to promote the intracellular association of AMAP1 and PRKD2. Our results suggest a novel mechanism by which EGFR signaling promotes the invasiveness of some breast cancer cells via integrin recycling.
Calcium-activated chloride channels in the apical region of mouse vomeronasal sensory neurons
Authors: Dibattista Michele , Amjad Asma , Maurya Devendra Kumar , Sagheddu Claudia , Montani Giorgia , Tirindelli Roberto , Menini Anna
Published: June 2012

The rodent vomeronasal organ plays a crucial role in several social behaviors. Detection of pheromones or other emitted signaling molecules occurs in the dendritic microvilli of vomeronasal sensory neurons, where the binding of molecules to vomeronasal receptors leads to the influx of sodium and calcium ions mainly through the transient receptor potential canonical 2 (TRPC2) channel. To investigate the physiological role played by the increase in intracellular calcium concentration in the apical region of these neurons, we produced localized, rapid, and reproducible increases in calcium concentration with flash photolysis of caged calcium and measured calcium-activated currents with the whole cell voltage-clamp technique. On average, a large inward calcium-activated current of −261 pA was measured at −50 mV, rising with a time constant of 13 ms. Ion substitution experiments showed that this current is anion selective. Moreover, the chloride channel blockers niflumic acid and 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid partially inhibited the calcium-activated current. These results directly demonstrate that a large chloride current can be activated by calcium in the apical region of mouse vomeronasal sensory neurons. Furthermore, we showed by immunohistochemistry that the calcium-activated chloride channels TMEM16A/anoctamin1 and TMEM16B/anoctamin2 are present in the apical layer of the vomeronasal epithelium, where they largely colocalize with the TRPC2 transduction channel. Immunocytochemistry on isolated vomeronasal sensory neurons showed that TMEM16A and TMEM16B coexpress in the neuronal microvilli. Therefore, we conclude that microvilli of mouse vomeronasal sensory neurons have a high density of calcium-activated chloride channels that may play an important role in vomeronasal transduction.
An integrated catch-and-hold mechanism activates nicotinic acetylcholine receptors
Authors: Jadey Snehal , Auerbach Anthony
Published: June 2012

In neuromuscular acetylcholine (ACh) receptor channels (AChRs), agonist molecules bind with a low affinity (LA) to two sites that can switch to high affinity (HA) and increase the probability of channel opening. We measured (by using single-channel kinetic analysis) the rate and equilibrium constants for LA binding and channel gating for several different agonists of adult-type mouse AChRs. Almost all of the variation in the equilibrium constants for LA binding was from differences in the association rate constants. These were consistently below the limit set by diffusion and were substantially different even though the agonists had similar sizes and the same charge. This suggests that binding to resting receptors is not by diffusion alone and, hence, that each binding site can undergo two conformational changes (“catch” and “hold”) that connect three different structures (apo-, LA-bound, and HA-bound). Analyses of ACh-binding protein structures suggest that this binding site, too, may adopt three discrete structures having different degrees of loop C displacement (“capping”). For the agonists we tested, the logarithms of the equilibrium constants for LA binding and LA↔HA gating were correlated. Although agonist binding and channel gating have long been considered to be separate processes in the activation of ligand-gated ion channels, this correlation implies that the catch-and-hold conformational changes are energetically linked and together comprise an integrated process having a common structural basis. We propose that loop C capping mainly reflects agonist binding, with its two stages corresponding to the formation of the LA and HA complexes. The catch-and-hold reaction coordinate is discussed in terms of preopening states and thermodynamic cycles of activation.
Whose Probabilities? Predicting Climate Change with Ensembles of Models
Authors: Parker Wendy S.
Published: June 2012

Today's most sophisticated simulation studies of future climate employ not just one climate model but a number of models. I explain why this “ensemble” approach has been adopted—namely, as a means of taking account of uncertainty—and why a comprehensive investigation of uncertainty remains elusive. I then defend a middle ground between two camps in an ongoing debate over the transformation of ensemble results into probabilistic predictions of climate change, highlighting requirements that I refer to as ownership, justification, and robustness.
Adaptation to Global Warming: Do Climate Models Tell Us What We Need to Know?
Authors: Oreskes Naomi , Stainforth David A. , Smith Leonard A.
Published: June 2012

Scientific experts have confirmed that anthropogenic warming is underway, and some degree of adaptation is now unavoidable. However, the details of impacts on the scale of climate change at which humans would have to prepare for and adjust to them are still the subject of considerable research, inquiry, and debate. Planning for adaptation requires information on the scale over which human organizations and institutions have authority and capacity, yet the general circulation models lack forecasting skill at these scales, and attempts to “downscale” climate models are still in the early stages of development. Because we do not know what adaptations will be required, we cannot say whether they will be harder or easier—more expensive or less—than emissions control. Whatever improvements in regional predictive capacity may come about in the future, the lack of current predictive capacity on the relevant scale is a strong argument for why we must both control greenhouse gas emissions and prepare to adapt.
Relevance and formation mechanisms of negative ions upon ablation of Al2O3
Authors: Peláez R J , Afonso C N , Chen J , Esposito M , Lippert Th , Stender D , Wokaun A
Published: June 2012

The aim of this work is to study the significance of negative ions in the plasma produced by ablation of a simple oxide ceramic target (Al2O3) at distances and fluences typically used in pulsed-laser deposition processes. The results show that negative ions are indeed produced, the majority of which (>82%) being O− that are predominantly produced by neutralization of O+ followed by electron attachment. They represent one third of the O+ population at low fluences for a distance of 4 cm from the target at which most deposition experiments are performed. AlO− represents up to 15% of the negative ions and their amount increases at the expense of O− as fluence is increased. The most abundant as well as the fastest species in the plasma is by far Al+ that represent >80% of ions having kinetic energy <100 eV at low fluences. This result is consistent with earlier discussion on the possible existence of direct photoionization processes due to the high (6.4 eV) photon energy. Saturation effects, the formation mechanism for AlO− and Al2+, and expansion dynamics for negative ions are finally discussed.
cis-Golgi proteins accumulate near the ER exit sites and act as the scaffold for Golgi regeneration after brefeldin A treatment in tobacco BY-2 cells
Authors: Ito Yoko , Uemura Tomohiro , Shoda Keiko , Fujimoto Masaru , Ueda Takashi , Nakano Akihiko
Published: June 2012

The Golgi apparatus forms stacks of cisternae in many eukaryotic cells. However, little is known about how such a stacked structure is formed and maintained. To address this question, plant cells provide a system suitable for live-imaging approaches because individual Golgi stacks are well separated in the cytoplasm. We established tobacco BY-2 cell lines expressing multiple Golgi markers tagged by different fluorescent proteins and observed their responses to brefeldin A (BFA) treatment and BFA removal. BFA treatment disrupted cis, medial, and trans cisternae but caused distinct relocalization patterns depending on the proteins examined. Medial- and trans-Golgi proteins, as well as one cis-Golgi protein, were absorbed into the endoplasmic reticulum (ER), but two other cis-Golgi proteins formed small punctate structures. After BFA removal, these puncta coalesced first, and then the Golgi stacks regenerated from them in the cis-to-trans order. We suggest that these structures have a property similar to the ER-Golgi intermediate compartment and function as the scaffold of Golgi regeneration.
The nucleoporin Nup205/NPP-3 is lost near centrosomes at mitotic onset and can modulate the timing of this process inCaenorhabditis elegansembryos
Authors: Hachet Virginie , Busso Coralie , Toya Mika , Sugimoto Asako , Askjaer Peter , Gönczy Pierre
Published: June 2012

Regulation of mitosis in time and space is critical for proper cell division. We conducted an RNA interference–based modifier screen to identify novel regulators of mitosis in Caenorhabditis elegans embryos. Of particular interest, this screen revealed that the Nup205 nucleoporin NPP-3 can negatively modulate the timing of mitotic onset. Furthermore, we discovered that NPP-3 and nucleoporins that are associated with it are lost from the nuclear envelope (NE) in the vicinity of centrosomes at the onset of mitosis. We demonstrate that centrosomes are both necessary and sufficient for NPP-3 local loss, which also requires the activity of the Aurora-A kinase AIR-1. Our findings taken together support a model in which centrosomes and AIR-1 promote timely onset of mitosis by locally removing NPP-3 and associated nucleoporins from the NE.
The CSC connects three major axonemal complexes involved in dynein regulation
Authors: Heuser Thomas , Dymek Erin E. , Lin Jianfeng , Smith Elizabeth F. , Nicastro Daniela
Published: June 2012

Motile cilia and flagella are highly conserved organelles that play important roles in human health and development. We recently discovered a calmodulin- and spoke-associ­ated complex (CSC) that is required for wild-type motility and for the stable assembly of a subset of radial spokes. Using cryo–electron tomography, we present the first structure-based localization model of the CSC. Chlamydomonas flagella have two full-length radial spokes, RS1 and RS2, and a shorter RS3 homologue, the RS3 stand-in (RS3S). Using newly developed techniques for analyzing samples with structural heterogeneity, we demonstrate that the CSC connects three major axonemal complexes involved in dynein regulation: RS2, the nexin–dynein regulatory complex (N-DRC), and RS3S. These results provide insights into how signals from the radial spokes may be transmitted to the N-DRC and ultimately to the dynein motors. Our results also indicate that although structurally very similar, RS1 and RS2 likely serve different functions in regulating flagellar motility.
RESQUE: Network reduction using semi-Markov random walk scores for efficient querying of biological networks
Authors: Sahraeian Sayed Mohammad Ebrahim , Yoon Byung-Jun
Published: June 2012

Motivation: Recent technological advances in measuring molecular interactions have resulted in an increasing number of large-scale biological networks. Translation of these enormous network data into meaningful biological insights requires efficient computational techniques that can unearth the biological information that is encoded in the networks. One such example is network querying, which aims to identify similar subnetwork regions in a large target network that are similar to a given query network. Network querying tools can be used to identify novel biological pathways that are homologous to known pathways, thereby enabling knowledge transfer across different organisms.

Results: In this article, we introduce an efficient algorithm for querying large-scale biological networks, called RESQUE. The proposed algorithm adopts a semi-Markov random walk (SMRW) model to probabilistically estimate the correspondence scores between nodes that belong to different networks. The target network is iteratively reduced based on the estimated correspondence scores, which are also iteratively re-estimated to improve accuracy until the best matching subnetwork emerges. We demonstrate that the proposed network querying scheme is computationally efficient, can handle any network query with an arbitrary topology and yields accurate querying results.

Availability: The source code of RESQUE is freely available at http://www.ece.tamu.edu/~bjyoon/RESQUE/

Contact:  bjyoon@ece.tamu.edu

Supplementary Information:  Supplementary data are available at Bioinformatics online.
Identification of feedback loops in neural networks based on multi-step Granger causality
Authors: Dong Chao-Yi , Shin Dongkwan , Joo Sunghoon , Nam YoonKey , Cho Kwang-Hyun
Published: June 2012

Motivation: Feedback circuits are crucial network motifs, ubiquitously found in many intra- and inter-cellular regulatory networks, and also act as basic building blocks for inducing synchronized bursting behaviors in neural network dynamics. Therefore, the system-level identification of feedback circuits using time-series measurements is critical to understand the underlying regulatory mechanism of synchronized bursting behaviors.

Results: Multi-Step Granger Causality Method (MSGCM) was developed to identify feedback loops embedded in biological networks using time-series experimental measurements. Based on multivariate time-series analysis, MSGCM used a modified Wald test to infer the existence of multi-step Granger causality between a pair of network nodes. A significant bi-directional multi-step Granger causality between two nodes indicated the existence of a feedback loop. This new identification method resolved the drawback of the previous non-causal impulse response component method which was only applicable to networks containing no co-regulatory forward path. MSGCM also significantly improved the ratio of correct identification of feedback loops. In this study, the MSGCM was testified using synthetic pulsed neural network models and also in vitro cultured rat neural networks using multi-electrode array. As a result, we found a large number of feedback loops in the in vitro cultured neural networks with apparent synchronized oscillation, indicating a close relationship between synchronized oscillatory bursting behavior and underlying feedback loops. The MSGCM is an efficient method to investigate feedback loops embedded in in vitro cultured neural networks. The identified feedback loop motifs are considered as an important design principle responsible for the synchronized bursting behavior in neural networks.

Contact:  ckh@kaist.ac.kr

Availability: The software implementing MSGCM is available at Supplementary Information.

Supplementary Information:  Supplementary material are available at Bioinformatics online.
DySC: software for greedy clustering of 16S rRNA reads
Authors: Zheng Zejun , Kramer Stefan , Schmidt Bertil
Published: June 2012

Summary: Pyrosequencing technologies are frequently used for sequencing the 16S ribosomal RNA marker gene for profiling microbial communities. Clustering of the produced reads is an important but time-consuming task. We present Dynamic Seed-based Clustering (DySC), a new tool based on the greedy clustering approach that uses a dynamic seeding strategy. Evaluations based on the normalized mutual information (NMI) criterion show that DySC produces higher quality clusters than UCLUST and CD-HIT at a comparable runtime.

Availability and implementation: DySC, implemented in C, is available at http://code.google.com/p/dysc/ under GNU GPL license.

Contact:  bertil.schmidt@uni-mainz.de

Supplementary Information:  Supplementary data are available at Bioinformatics online.
Bendix: intuitive helix geometry analysis and abstraction
Authors: Dahl Anna Caroline E. , Chavent Matthieu , Sansom Mark S. P.
Published: June 2012

Summary: The flexibility of α-helices is important for membrane protein function and calls for better visualization and analysis. Software is presented that quantifies and projects the helix axis evolution over time, with the choice of uniform or analytic heatmap graphics according to the local geometry. Bendix supports static, molecular dynamics, atomistic and coarse-grained input.

Availability and implementation: Bendix source code and documentation, including installation instructions, are freely available at http://sbcb.bioch.ox.ac.uk/Bendix. Bendix is written in Tcl as an extension to VMD and is supported by all major operating systems.

Contact:  mark.sansom@bioch.ox.ac.uk
gSearch: a fast and flexible general search tool for whole-genome sequencing
Authors: Song Taemin , Hwang Kyu-Baek , Hsing Michael , Lee Kyungjoon , Bohn Justin , Kong Sek Won
Published: June 2012

Background: Various processes such as annotation and filtering of variants or comparison of variants in different genomes are required in whole-genome or exome analysis pipelines. However, processing different databases and searching among millions of genomic loci is not trivial.

Results: gSearch compares sequence variants in the Genome Variation Format (GVF) or Variant Call Format (VCF) with a pre-compiled annotation or with variants in other genomes. Its search algorithms are subsequently optimized and implemented in a multi-threaded manner. The proposed method is not a stand-alone annotation tool with its own reference databases. Rather, it is a search utility that readily accepts public or user-prepared reference files in various formats including GVF, Generic Feature Format version 3 (GFF3), Gene Transfer Format (GTF), VCF and Browser Extensible Data (BED) format. Compared to existing tools such as ANNOVAR, gSearch runs more than 10 times faster. For example, it is capable of annotating 52.8 million variants with allele frequencies in 6 min.

Availability: gSearch is available at http://ml.ssu.ac.kr/gSearch. It can be used as an independent search tool or can easily be integrated to existing pipelines through various programming environments such as Perl, Ruby and Python.

Contacts:
BIDDSAT: visualizing the content of biodiversity data publishers in the Global Biodiversity Information Facility network
Authors: Otegui Javier , Ariño Arturo H.
Published: June 2012

Summary: In any data quality workflow, data publishers must become aware of issues in their data so these can be corrected. User feedback mechanisms provide one avenue, while global assessments of datasets provide another. To date, there is no publicly available tool to allow both biodiversity data institutions sharing their data through the Global Biodiversity Information Facility network and its potential users to assess datasets as a whole. Contributing to bridge this gap both for publishers and users, we introduce BIoDiversity DataSets Assessment Tool, an online tool that enables selected diagnostic visualizations on the content of data publishers and/or their individual collections.

Availability and implementation: The online application is accessible at http://www.unav.es/unzyec/mzna/biddsat/ and is supported by all major browsers. The source code is licensed under the GNU GPLv3 license (http://www.gnu.org/licenses/gpl-3.0.txt) and is available at https://github.com/jotegui/BIDDSAT.

Contact:  jotellechea@alumni.unav.es
Predicting drug–target interactions from chemical and genomic kernels using Bayesian matrix factorization
Authors: Gönen Mehmet
Published: June 2012

Motivation: Identifying interactions between drug compounds and target proteins has a great practical importance in the drug discovery process for known diseases. Existing databases contain very few experimentally validated drug–target interactions and formulating successful computational methods for predicting interactions remains challenging.

Results: In this study, we consider four different drug–target interaction networks from humans involving enzymes, ion channels, G-protein-coupled receptors and nuclear receptors. We then propose a novel Bayesian formulation that combines dimensionality reduction, matrix factorization and binary classification for predicting drug–target interaction networks using only chemical similarity between drug compounds and genomic similarity between target proteins. The novelty of our approach comes from the joint Bayesian formulation of projecting drug compounds and target proteins into a unified subspace using the similarities and estimating the interaction network in that subspace. We propose using a variational approximation in order to obtain an efficient inference scheme and give its detailed derivations. Finally, we demonstrate the performance of our proposed method in three different scenarios: (i) exploratory data analysis using low-dimensional projections, (ii) predicting interactions for the out-of-sample drug compounds and (iii) predicting unknown interactions of the given network.

Availability: Software and Supplementary Material are available at http://users.ics.aalto.fi/gonen/kbmf2k.

Contact:  mehmet.gonen@aalto.fi

Supplementary information:  Supplementary data are available at Bioinformatics online.
Corporate Fraud, Governance, and Auditing
Authors: Pagano Marco , Immordino Giovanni
Published: June 2012

We analyze corporate fraud in a setting in which managers have superior information but are biased against liquidation because of their private benefits from empire building. This may induce them to misreport information and even bribe auditors when liquidation would be value-increasing. To curb fraud, shareholders optimally design corporate governance by jointly choosing audit quality and managerial compensation. We analyze how country-level rules affect these firm-level choices. Our analysis underscores that different country-level governance provisions have different effects on firm-level governance: Some act as substitutes of internal governance mechanisms, whereas others enhance their effectiveness and therefore complement them. (JEL G28, K22, M42)
New thinking: the evolution of human cognition
Authors: Heyes Cecilia
Published: June 2012

Humans are animals that specialize in thinking and knowing, and our extraordinary cognitive abilities have transformed every aspect of our lives. In contrast to our chimpanzee cousins and Stone Age ancestors, we are complex political, economic, scientific and artistic creatures, living in a vast range of habitats, many of which are our own creation. Research on the evolution of human cognition asks what types of thinking make us such peculiar animals, and how they have been generated by evolutionary processes. New research in this field looks deeper into the evolutionary history of human cognition, and adopts a more multi-disciplinary approach than earlier ‘Evolutionary Psychology’. It is informed by comparisons between humans and a range of primate and non-primate species, and integrates findings from anthropology, archaeology, economics, evolutionary biology, neuroscience, philosophy and psychology. Using these methods, recent research reveals profound commonalities, as well striking differences, between human and non-human minds, and suggests that the evolution of human cognition has been much more gradual and incremental than previously assumed. It accords crucial roles to cultural evolution, techno-social co-evolution and gene–culture co-evolution. These have produced domain-general developmental processes with extraordinary power—power that makes human cognition, and human lives, unique.
Embodied cognitive evolution and the cerebellum
Authors: Barton Robert A.
Published: June 2012

Much attention has focused on the dramatic expansion of the forebrain, particularly the neocortex, as the neural substrate of cognitive evolution. However, though relatively small, the cerebellum contains about four times more neurons than the neocortex. I show that commonly used comparative measures such as neocortex ratio underestimate the contribution of the cerebellum to brain evolution. Once differences in the scaling of connectivity in neocortex and cerebellum are accounted for, a marked and general pattern of correlated evolution of the two structures is apparent. One deviation from this general pattern is a relative expansion of the cerebellum in apes and other extractive foragers. The confluence of these comparative patterns, studies of ape foraging skills and social learning, and recent evidence on the cognitive neuroscience of the cerebellum, suggest an important role for the cerebellum in the evolution of the capacity for planning, execution and understanding of complex behavioural sequences—including tool use and language. There is no clear separation between sensory–motor and cognitive specializations underpinning such skills, undermining the notion of executive control as a distinct process. Instead, I argue that cognitive evolution is most effectively understood as the elaboration of specialized systems for embodied adaptive control.
New thinking, innateness and inherited representation
Authors: Shea Nicholas
Published: June 2012

The New Thinking contained in this volume rejects an Evolutionary Psychology that is committed to innate domain-specific psychological mechanisms: gene-based adaptations that are unlearnt, developmentally fixed and culturally universal. But the New Thinking does not simply deny the importance of innate psychological traits. The problem runs deeper: the concept of innateness is not suited to distinguishing between the New Thinking and Evolutionary Psychology. That points to a more serious problem with the concept of innateness as it is applied to human psychological phenotypes. This paper argues that the features of recent human evolution highlighted by the New Thinking imply that the concept ofinherited representation, set out here, is a better tool for theorizing about human cognitive evolution.
Dining hall at sea: feeding migrations of nektonic predators to the eastern Patagonian Shelf
Authors: Arkhipkin A. , Brickle P. , Laptikhovsky V. , Winter A.
Published: June 2012

Seasonal changes in relative abundance and biomass of nektonic predators were analysed on the eastern Patagonian Shelf and continental slope; one of the most productive large marine ecosystems of the southern hemisphere. Several migratory types were revealed for species belonging to either temperate or sub‐Antarctic faunas. Despite high productivity, only a few large nektonic predators spend their entire life cycle on the eastern Patagonian Shelf and use only a small proportion of the meso‐nektonic resource. Most of the resource is exploited by non‐resident nektonic migrants, which move to the area from distant spawning grounds. Pelagic and demersal sharks and skates, the squid Illex argentinus, tunas and gadoids migrate to the eastern part of the Patagonian Shelf to feed at different times of the year; arriving in seasonal waves according to their life cycle and spawning seasonality. Some deepwater fishes and squid migrate onto the shelf as juveniles to harvest the resource, and then return to deepwater habitat as adults. It is hypothesized that the large biomass of meso‐planktonic and meso‐nektonic consumers prevents most higher‐trophic level predators from establishing spawning populations in this area, as their larvae and fry would be overwhelmed by predation. Instead, the higher‐trophic level predators establish spawning and nursery grounds elsewhere and arrive to feed on the meso‐planktonic and meso‐nektonic resources after they have outgrown their own stages of predation vulnerability.
How clinical decisions are made
Authors: Bate Louise , Hutchinson Andrew , Underhill Jonathan , Maskrey Neal
Published: June 2012

There is much variation in the implementation of the best available evidence into clinical practice. These gaps between evidence and practice are often a result of multiple individual decisions. When making a decision, there is so much potentially relevant information available, it is impossible to know or process it all (so called ‘bounded rationality’). Usually, a limited amount of information is selected to reach a sufficiently satisfactory decision, a process known as satisficing. There are two key processes used in decision making: System 1 and System 2. System 1 involves fast, intuitive decisions; System 2 is a deliberate analytical approach, used to locate information which is not instantly recalled. Human beings unconsciously use System 1 processing whenever possible because it is quicker and requires less effort than System 2. In clinical practice, gaps between evidence and practice can occur when a clinician develops a pattern of knowledge, which is then relied on for decisions using System 1 processing, without the activation of a System 2 check against the best available evidence from high quality research. The processing of information and decision making may be influenced by a number of cognitive biases, of which the decision maker may be unaware. Interventions to encourage appropriate use of System 1 and System 2 processing have been shown to improve clinical decision making. Increased understanding of decision making processes and common sources of error should help clinical decision makers to minimize avoidable mistakes and increase the proportion of decisions that are better.
Harmonising the bioassessment of large rivers in the absence of near‐natural reference conditions – a case study of the Danube River
Authors: BIRK SEBASTIAN , van KOUWEN LEON , WILLBY NIGEL
Published: June 2012

1. International river catchments pose challenges for effective water resource management. Catchment‐wide strategies are often complicated by differences in national bioassessment and quality classification. Intercalibration efforts aim to harmonise these differences, but rely on the consistent delineation of near‐natural reference sites that are almost unavailable in today’s landscape, especially for large rivers.

2. We introduce the concept of alternative benchmarking that is based on the notion of aquatic communities at similar (low) levels of impairment associated with least‐disturbed conditions (LDC) as defined by abiotic criteria. Using data acquired during the second Joint Danube Survey, we defined LDC sites based on a multivariate gradient of anthropogenic pressures, mostly related to morphological deterioration, that spans the entire navigable Danube.

3. The river was subdivided into four stretches, each featuring homogeneous biological assemblages. Indirect gradient analysis revealed relationships between the pressure gradient and selected features of the macroinvertebrate and macrophyte community but not for diatoms or phytoplankton.

4. We identified biological metrics suitable for the quality classification of individual stretches or the entire river. Impoundment is the major hydromorphological alteration on the Danube but various metrics still responded significantly to differences in the morphological condition of sites not affected by impoundment.

5. A comparison of macroinvertebrate sampling techniques (airlift versus kick‐and‐sweep) revealed differences in how the acquired data reflect the effects of anthropogenic pressure. Biological metrics based only on kick‐and‐sweep sample data were insensitive to habitat deterioration in the heavily modified Upper Danube.

6. This study exemplifies the empirical approach of alternative benchmarking in intercalibration and offers practical solutions to some of the challenges of large river bioassessment.
Gene therapy for haemophilia B
Authors: TUDDENHAM E.
Published: June 2012

Summary.  AAV virus mediated transfer of factor IX to humans is safe and effective at three dose levels. Two subjects treated at highest dose level developed immune mediated transaminitis which resolved on a short course of Prednisolone. Beneficial effects in terms of continuous elevation of factor IX level above base line was seen in all subjects, continuing for over 18 months. Further study of this treatment method is warranted.
Standards and monitoring treatment
Authors: BARROWCLIFFE T. W. , HUBBARD A. R. , KITCHEN S.
Published: June 2012

Summary.  Accuracy and reproducibility of laboratory measurements are important in the diagnosis and treatment of bleeding disorders. This article describes the process of establishment of international standards and some of the problems that have arisen in standardization of these measurements.
Personalized prophylaxis
Authors: COLLINS P. W.
Published: June 2012

Summary.  Prophylaxis is the recommended treatment for people with severe haemophilia. It is unlikely that a single prophylactic regimen, for example based on weight, would be optimal for all patients and therefore each individual should have a personalized regimen, agreed between themselves and their haemophilia centre. This regimen should take into account the individual’s bleeding pattern, the condition of their musculoskeletal system, level and timing of physical activity and measurement of coagulation factor in their blood. It is important to recognize that prophylactic regimens are likely to need to change with time as the circumstances of an individual change. For example, activity may change with age or with the season and an individual’s factor VIII pharmacokinetics vary with age. Knowledge of a patient’s pharmacokinetics is likely to help personalize prophylaxis when combined with other information. Factor VIII pharmacokinetics are simple to measure in routine clinical practice and can be adequately calculated from 2 to 3 blood samples combined with a simple to use computer program. Prophylaxis is expensive and, in countries with a limited health care budget, ways to improve its cost effectiveness need to be considered to allow increased access to this treatment. For example, increasing the frequency of prophylaxis can dramatically reduce the amount of treatment required to sustain measureable factor levels and hence reduce cost. The introduction of longer‐acting coagulation factors may necessitate a change in concepts about prophylaxis because whilst these agents may sustain an apparently adequate trough level with fewer infusions, the length of time a person spends at a low level will be increased and this could increase the risk of bleeding, especially at the time of increased physical activity. There is convincing evidence that prophylaxis is the optimal therapy for severe haemophilia, optimizing treatment for each individual and increasing access to this treatment modality are important goals for the future.
Invasion history of North American Canada thistle, Cirsium arvense
Authors: Guggisberg Alessia , Welk Erik , Sforza René , Horvath David P. , Anderson James V. , Foley Michael E. , Rieseberg Loren H.
Published: June 2012

Aim  Canada thistle (Cirsium arvense– Cardueae, Asteraceae) is one of the worst invasive plants world‐wide. Native to Eurasia, its unintentional introduction into North America now threatens the native flora and is responsible for enormous agricultural losses. The goals of this study are to: (1) reconstruct the evolutionary history of C. arvense and estimate how often it may have colonized North America, (2) compare the genetic diversity between European and North American populations to detect signs of demographic bottlenecks and/or patterns of population admixture, and (3) conduct bioclimatic comparisons to infer eventual niche shifts following this species’ introduction into North America.

Location  Europe and North America.

Methods  A total of 1522 individuals from 58 populations were investigated with six microsatellite markers. Estimates of heterozygosity (HE) and allelic richness (RS) were quantified for each population, and population structure was inferred via analyses of molecular variance (AMOVAs), principal components analyses (PCAs), Mantel tests and Bayesian clustering analyses. Climatic niche spaces were based on 19 bioclimatic variables extracted from approximately 32,000 locations covering the entire range, and compared using PCA and hierarchical cluster analysis.

Results  Although there is evidence of multiple introductions from divergent European lineages, North American populations of C. arvense exhibited significantly lower levels of genetic diversity than their putative ancestors. Bioclimatic comparisons pointed to a high degree of niche conservatism during invasion, but indicated that genotypes from the former USSR and Central European mountain chains were probably best adapted to invade North America upon entry into the continent.

Main conclusions  Genetic and historical data suggest that C. arvense first entered North America from Western Europe with the first European settlers, and was later introduced from Eastern Europe into the prairie states during the agricultural boom. The species went through a significant bottleneck following its introduction into the New World, but the level of genetic diversity remained high owing to admixture between genetically differentiated lineages and to a highly efficient outcrossing breeding system.
The effects of fasting duration on gastric emptying in man, an exploration of the role of the endocannabinoid system and inter‐individual responsiveness
Authors: Jones R. B. , Dockray G. J. , Thompson D. G.
Published: June 2012

Background  In animal studies, gut vagal afferent neurons express cannabinoid (CB1) receptors, whose expression is increased by fasting. We aimed to explore the possibility that similar effects might be relevant in man in controlling gastric emptying.

Methods  Fourteen healthy volunteers underwent measurements of gastric emptying using the 13C acetate breath test, after either a nutrient (skimmed milk) or non‐nutrient (water) meal following both a 12 and 24 h fast. Further gastric emptying studies were performed with and without the CB1 receptor antagonist Rimonabant (20 mg or 80 mg). Because of the inter‐individual variations observed, two subjects underwent additional studies with and without Rimonabant to determine intra‐individual consistency. Gastric emptying was evaluated as cumulative C13 : C12 ratio values, measured at 5 min intervals for 30 min.

Key Results  In the group as a whole, fasting duration slowed gastric emptying for both the nutrient [120 ± 30 (mean ± SD) vs 101 ± 34, P < 0.05] and non‐nutrient [226 ± 62 vs 177 ± 47, P < 0.05] meals, but there was no effect of Rimonabant. However, there was consistent inter individual variation; thus while 12 subjects showed a slowing, two (14%) exhibited accelerated gastric emptying for both the nutrient and the non‐nutrient meal after 24 h fasting and in one of whom, Rimonabant consistently reversed the fasting effect on the non‐nutrient meal.

Conclusions & Inferences  Extended fasting alters the gastric emptying of liquid meals but there are consistent differences between individuals. Where there is an accelerated response to fasting, Rimonabant appears to reverse the effect.
Interventions with Vitamins B6, B12 and C in Pregnancy
Authors: Dror Daphna K. , Allen Lindsay H.
Published: June 2012

The water‐soluble vitamins B6, B12 and C play important roles in maternal health as well as fetal development and physiology during gestation. This systematic review evaluates the risks and benefits of interventions with vitamins B6, B12 and C during pregnancy on maternal, neonatal and child health and nutrition outcomes. Relevant publications were identified by searching PubMed, Popline and Web of Science databases. Meta‐analyses were conducted for outcomes where results from at least three controlled trials were available. Potential benefits of vitamin B6 supplementation were reduction in nausea and vomiting, improvement in dental health, and treatment of some cases of anaemia. In meta‐analysis based on three small studies, vitamin B6 supplementation had a significant positive effect on birthweight (d = 217 g [95% confidence interval (CI) 130, 304]). Interventions with vitamin C alone or combined with vitamin E did not systematically reduce the incidence of pre‐eclampsia, premature rupture of membranes, or other adverse pregnancy outcomes. In meta‐analyses, vitamins C and E increased the risk of pregnancy‐related hypertension (relative risk 1.10 [95% CI 1.02, 1.19]). Effects of vitamin B6 or C intervention on other neonatal outcomes, including preterm birth, low birthweight, and perinatal morbidity and mortality, were not significant. Data on child health outcomes were lacking. Despite the prevalence of vitamin B12 deficiency amongst populations with limited intake of animal source foods, no intervention trials have evaluated vitamin B12 supplementation before or during pregnancy. In conclusion, existing evidence does not justify vitamin C supplementation during pregnancy. Additional studies are needed to confirm positive effects of vitamin B6 supplementation on infant birthweight and other outcomes. While vitamin B12 supplementation may reduce the incidence of neural tube defects in the offspring based on theoretical considerations, research is needed to support this hypothesis.
Perceived hazards of transfusion: can a clinician tool help patients' understanding?
Authors: Khan M. H. , Watson H. G. , Dombrowski S. U.
Published: June 2012

Objective

To evaluate the use of a tool prompting counselling behaviour for blood transfusion by assessing clinicians' self‐reported counselling behaviours, and changes in patients' beliefs about transfusion.

Methods and materials

Mixed quantitative and qualitative methodology undertaken in two phases. In phase 1, clinicians' responses (n = 12) to a semi‐structured questionnaire were analysed to identify the content of discussions with patients about different aspects of receiving a blood transfusion. The content of discussions was coded using illness representation concepts from the Common Sense Self‐Regulation Model. Phase 2 included patients (n = 14) scheduled for elective surgery who completed a questionnaire on their beliefs about transfusion before and after counselling.

Results

The most frequently coded illness representations targeted by clinicians using the tool were ‘consequence of treatment’ (32%) and ‘cure/control’ (30·5%). Two patient beliefs showed significant change following counselling using the checklist. After counselling, patients were more likely to disagree/strongly disagree with the statement that doctors relied too much on transfusion (P = 0·034) and more likely to agree/strongly agree that blood transfusion can result in new health problems (P = 0·041).

Conclusion

This pilot study provides insight into how clinicians use a tool for blood transfusion counselling and shows the potential to influence patients' beliefs about transfusion. Whilst the checklist has a role in standardising practice, this pilot study highlights the need for optimising its use before undertaking a fully randomised evaluation of the tool.
Detection of bacterial contamination in platelet concentrates by a sensitive flow cytometric assay (BactiFlow): a multicentre validation study
Authors: Vollmer T. , Dreier J. , Schottstedt V. , Bux J. , Tapernon K. , Sibrowski W. , Kleesiek K. , Knabbe C.
Published: June 2012

abstract

Background

Bacterial contamination of platelet concentrates (PCs) still represents an ongoing risk. As a result of septic complications, particularly observed with older PCs, the shelf life of PCs has been reduced in Germany to 4 days. In this study, bacterial screening of PCs by BactiFlow (BF) flow cytometry was introduced in three German blood services to evaluate the robustness and applicability of the assay. Results were used to discuss the potential for the extension of PC shelf life to 5 days.

Study design and methods

A total of 1956 PCs were tested on days 4 or 5+ after PC production using the BF, whereas the BacT/Alert culture system served as reference method.

Results

Two PCs were confirmed positive by culture only and were identified as Propionibacterium acnes and Staphylococcus species. Two PCs were confirmed positive for Streptococcus mitis by BF and culture. Additionally, two PCs were culture‐positive only in one culture bottle (aerobic: S. mitis and anaerobic: S. hominis). Retrospective analysis of bacterial growth kinetics provide the indication that corresponding bacterial titres were most likely below the BF analytical detection limit (<150 CFU mL−1) and had probably no transfusion relevance. All remaining specimens were tested negative.

Conclusions

Testing of PCs by BF was successfully implemented. The BF proved sufficient as a rapid screening method to improve PC safety. This study further provides data supporting the extension of PC shelf life to 5 days after negative BF testing on day 4.
Transfusion‐associated necrotising enterocolitis in very low birth weight premature infants
Authors: Demirel G. , Celik I. H. , Aksoy H. T. , Erdeve O. , Oguz S. S. , Uras N. , Dilmen U.
Published: June 2012

Objective

Our aim was to determine the relationship between red blood cell transfusion and necrotising enterocolitis (NEC) in all admitted very low birth weight (VLBW) infants with or without transfusion.

Study Design

All VLBW neonates were categorised into five groups: (i) subjects that developed NEC <48 h after transfusion (n = 15); (ii) subjects that developed NEC >48 h after transfusion (n = 31); (iii) subjects that were never transfused but developed NEC, (n = 50); (iv) subjects that were transfused but did not develop NEC, (n = 250) and (v) subjects that were neither transfused nor developed NEC (n = 301).

Results

A group of 647 infants were enrolled in the study. Mean gestational age and birth weight of the patients were 29 ± 3·1 weeks and 1157 ± 237 g, respectively. The mean age at the onset of NEC in the NEC groups were 20 ± 2·3 days, 12 ± 3 days and 11 ± 2·6 days, respectively (P < 0·05). The mean interval from the last transfusion to the onset of NEC was 16·8 ± 8·8 h in group 1 and 240 ± 50 h in group 2 (P < 0·05).

Conclusion

In this study, we sought to evaluate all VLBW infants, whether they received a transfusion or not. We suggest that transfusion associated NEC exists, but many other factors influence this multifactorial disease. The age of NEC onset was later in transfused vs non‐transfused patients, whereas the interval between transfusion and NEC was shorter in transfused vs non‐transfused patients.