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1.  Effects of added involvement from concerned significant others in internet-delivered CBT treatments for problem gambling: study protocol for a randomised controlled trial 
BMJ Open  2016;6(9):e011974.
Problem gambling is a public health concern affecting ∼2.3% of the Swedish population. Problem gambling also severely affects concerned significant others (CSOs). Several studies have investigated the effect of individual treatments based on cognitive–behavioural therapy (CBT), but less is known of the effect of involving CSOs in treatment. This study aims to compare an intervention based on behavioural couples therapy (BCT), involving a CSO, with an individual CBT treatment to determine their relative efficacy. BCT has shown promising results in working with substance abuse, but this is the first time it is used as an intervention for problem gambling. Both interventions will be internet-delivered, and participants will receive written support and telephone support.
Methods and analysis
A sample of 120 couples will be randomised to either the BCT condition, involving the gambler and the CSO, or the CBT condition, involving the gambler alone. Measures will be conducted weekly and at 3, 6 and 12 months follow-up. The primary outcome measure is gambling behaviour, as measured by Timeline Followback for Gambling. This article describes the outline of the research methods, interventions and outcome measures used to evaluate gambling behaviour, mechanisms of change and relationship satisfaction. This study will be the first study on BCT for problem gambling.
Ethics and dissemination
This study has been given ethical approval from the regional ethics board of Stockholm, Sweden. It will add to the body of knowledge as to how to treat problem gambling and how to involve CSOs in treatment. The findings of this study will be published in peer-reviewed journals and published at international and national conferences.
Trial registration number
NCT02543372; Pre-results.
PMCID: PMC5051398  PMID: 27670519
problem gambling; Internet based interventions; concerned significant others; cognitive behavioral therapy; behavioral couples therapy
2.  Adapting Drug Approval Pathways for Bacteriophage-Based Therapeutics 
The global rise of multi-drug resistant bacteria has resulted in the notion that an “antibiotic apocalypse” is fast approaching. This has led to a number of well publicized calls for global funding initiatives to develop new antibacterial agents. The long clinical history of phage therapy in Eastern Europe, combined with more recent in vitro and in vivo success, demonstrates the potential for whole phage or phage based antibacterial agents. To date, no whole phage or phage derived products are approved for human therapeutic use in the EU or USA. There are at least three reasons for this: (i) phages possess different biological, physical, and pharmacological properties compared to conventional antibiotics. Phages need to replicate in order to achieve a viable antibacterial effect, resulting in complex pharmacodynamics/pharmacokinetics. (ii) The specificity of individual phages requires multiple phages to treat single species infections, often as part of complex cocktails. (iii) The current approval process for antibacterial agents has evolved with the development of chemically based drugs at its core, and is not suitable for phages. Due to similarities with conventional antibiotics, phage derived products such as endolysins are suitable for approval under current processes as biological therapeutic proteins. These criteria render the approval of phages for clinical use theoretically possible but not economically viable. In this review, pitfalls of the current approval process will be discussed for whole phage and phage derived products, in addition to the utilization of alternative approval pathways including adaptive licensing and “Right to try” legislation.
PMCID: PMC4971087  PMID: 27536293
bacteriophage; phage therapy; adaptive pathways; alternative licensing; pharmaceutical regulation
3.  The activity of HYDROPEROXIDE LYASE 1 regulates accumulation of galactolipids containing 12-oxo-phytodienoic acid in Arabidopsis 
Journal of Experimental Botany  2016;67(17):5133-5144.
The ability to accumulate OPDA-containing galactoplids in response to wounding was investigated in Arabidopsis accessions and found to correlate with the expression level of the HYDROPEROXIDE LYASE 1 gene.
Arabidopsis produces galactolipids containing esters of 12-oxo-phytodienoic acid (OPDA) and dinor-12-oxo-phytodienoic acid (dnOPDA). These lipids are referred to as arabidopsides and accumulate in response to abiotic and biotic stress. We explored the natural genetic variation found in 14 different Arabidopsis accessions to identify genes involved in the formation of arabidopsides. The accession C24 was identified as a poor accumulator of arabidopsides whereas the commonly used accession Col-0 was found to accumulate comparably large amounts of arabidopsides in response to tissue damage. A quantitative trait loci analysis of an F2 population created from a cross between C24 and Col-0 located a region on chromosome four strongly linked to the capacity to form arabidopsides. Expression analysis of HYDROPEROXIDE LYASE 1 (HPL1) showed large differences in transcript abundance between accessions. Transformation of Col-0 plants with the C24 HPL1 allele under transcriptional regulation of the 35S promoter revealed a strong negative correlation between HPL1 expression and arabidopside accumulation after tissue damage, thereby strengthening the view that HPL1 competes with ALLENE OXIDE SYNTHASE (AOS) for lipid-bound hydroperoxide fatty acids. We further show that the last step in the synthesis of galactolipid-bound OPDA and dnOPDA from unstable allene oxides is exclusively enzyme-catalyzed and not the result of spontaneous cyclization. Thus, the results presented here together with previous studies suggest that all steps in arabidopside biosynthesis are enzyme-dependent and apparently all reactions can take place with substrates being esterified to galactolipids.
PMCID: PMC5014160  PMID: 27422994
Acyl-MGDG; arabidopsides; Arabidopsis accessions; hydroperoxide lyase; jasmonates; OPDA; natural variation.
4.  A voltage-dependent chloride channel fine-tunes photosynthesis in plants 
Nature Communications  2016;7:11654.
In natural habitats, plants frequently experience rapid changes in the intensity of sunlight. To cope with these changes and maximize growth, plants adjust photosynthetic light utilization in electron transport and photoprotective mechanisms. This involves a proton motive force (PMF) across the thylakoid membrane, postulated to be affected by unknown anion (Cl−) channels. Here we report that a bestrophin-like protein from Arabidopsis thaliana functions as a voltage-dependent Cl− channel in electrophysiological experiments. AtVCCN1 localizes to the thylakoid membrane, and fine-tunes PMF by anion influx into the lumen during illumination, adjusting electron transport and the photoprotective mechanisms. The activity of AtVCCN1 accelerates the activation of photoprotective mechanisms on sudden shifts to high light. Our results reveal that AtVCCN1, a member of a conserved anion channel family, acts as an early component in the rapid adjustment of photosynthesis in variable light environments.
Plants have evolved to maximize energy capture while protecting their photosynthetic machinery in response to rapid variation in light conditions. Here, the authors describe a chloroplast voltage-dependent anion channel that contributes to photoprotection by fine-tuning the ion balance across the thylakoid membrane.
PMCID: PMC4890181  PMID: 27216227
5.  Morphologically Distinct Escherichia coli Bacteriophages Differ in Their Efficacy and Ability to Stimulate Cytokine Release In Vitro 
Due to a global increase in the range and number of infections caused by multi-resistant bacteria, phage therapy is currently experiencing a resurgence of interest. However, there are a number of well-known concerns over the use of phages to treat bacterial infections. In order to address concerns over safety and the poorly understood pharmacokinetics of phages and their associated cocktails, immunological characterization is required. In the current investigation, the immunogenicity of four distinct phages (taken from the main families that comprise the Caudovirales order) and their interaction with donor derived peripheral blood mononuclear cells and immortalized cell lines (HT-29 and Caco-2 intestinal epithelial cells) were investigated using standard immunological techniques. When exposed to high phage concentrations (109 PFU/well), cytokine driven inflammatory responses were induced from all cell types. Although phages appeared to inhibit the growth of intestinal epithelial cell lines, they also appear to be non-cytotoxic. Despite co-incubation with different cell types, phages maintained a high killing efficiency, reducing extended-spectrum beta-lactamase-producing Escherichia coli numbers by 1–4 log10 compared to untreated controls. When provided with a suitable bacterial host, phages were also able to actively reproduce in the presence of human cells resulting in an approximately 2 log10 increase in phage titer compared to the initial inoculum. Through an increased understanding of the complex pharmacokinetics of phages, it may be possible to address some of the safety concerns surrounding phage preparations prior to creating new therapeutic strategies.
PMCID: PMC4814447  PMID: 27065990
pharmacokinetics; phage therapy; cytokines; immune response; multi-resistant bacteria
6.  Species delimitation in northern European water scavenger beetles of the genus Hydrobius (Coleoptera, Hydrophilidae) 
ZooKeys  2016;71-120.
The chiefly Holarctic Hydrobius species complex (Coleoptera, Hydrophilidae) currently consists of Hydrobius arcticus Kuwert, 1890, and three morphological variants of Hydrobius fuscipes (Linnaeus, 1758): var. fuscipes, var. rottenbergii and var. subrotundus in northern Europe. Here molecular and morphological data are used to test the species boundaries in this species complex. Three gene segments (COI, H3 and ITS2) were sequenced and analyzed with Bayesian methods to infer phylogenetic relationships. The Generalized Mixed Yule Coalescent (GMYC) model and two versions of the Bayesian species delimitation method BPP, with or without an a priori defined guide tree (v2.2 & v3.0), were used to evaluate species limits. External and male genital characters of primarily Fennoscandian specimens were measured and statistically analyzed to test for significant differences in quantitative morphological characters. The four morphotypes formed separate genetic clusters on gene trees and were delimited as separate species by GMYC and by both versions of BPP, despite specimens of Hydrobius fuscipes var. fuscipes and Hydrobius fuscipes var. subrotundus being sympatric. Hydrobius arcticus and Hydrobius fuscipes var. rottenbergii could only be separated genetically with ITS2, and were delimited statistically with GMYC on ITS2 and with BPP on the combined data. In addition, six or seven potentially cryptic species of the Hydrobius fuscipes complex from regions outside northern Europe were delimited genetically. Although some overlap was found, the mean values of six male genital characters were significantly different between the morphotypes (p < 0.001). Morphological characters previously presumed to be diagnostic were less reliable to separate Hydrobius fuscipes var. fuscipes from Hydrobius fuscipes var. subrotundus, but characters in the literature for Hydrobius arcticus and Hydrobius fuscipes var. rottenbergii were diagnostic. Overall, morphological and molecular evidence strongly suggest that Hydrobius arcticus and the three morphological variants of Hydrobius fuscipes are separate species and Hydrobius rottenbergii Gerhardt, 1872, stat. n. and Hydrobius subrotundus Stephens, 1829, stat. n. are elevated to valid species. An identification key to northern European species of Hydrobius is provided.
PMCID: PMC4820092  PMID: 27081333
GMYC; species complex; BPP; guide tree; Fennoscandia; morphometrics; Bayesian; genitalia; molecular phylogeny; species boundaries; morphology; cryptic species; integrative taxonomy; DNA barcoding; identification key; taxonomy; checklist
7.  The structural origin of anomalous properties of liquid water 
Nature Communications  2015;6:8998.
Water is the most common liquid in nature, with unusual properties that could be linked to the peculiar hydrogen-bonding network holding the molecules together. Here, Nilsson and Pettersson review recent progress in searching the connections between local configurations and thermodynamic responses of water.
Water is unique in its number of unusual, often called anomalous, properties. When hot it is a normal simple liquid; however, close to ambient temperatures properties, such as the compressibility, begin to deviate and do so increasingly on further cooling. Clearly, these emerging properties are connected to its ability to form up to four well-defined hydrogen bonds allowing for different local structural arrangements. A wealth of new data from various experiments and simulations has recently become available. When taken together they point to a heterogeneous picture with fluctuations between two classes of local structural environments developing on temperature-dependent length scales.
PMCID: PMC4686860  PMID: 26643439
8.  Internet-delivered cognitive-behavioural therapy for concerned significant others of people with problem gambling: study protocol for a randomised wait-list controlled trial 
BMJ Open  2015;5(12):e008724.
About 2.3% of the adult population in Sweden are considered to suffer from problem gambling, and it is estimated that only 5% of those seek treatment. Problem gambling can have devastating effects on the economy, health and relationship, both for the individual who gambles and their concerned significant other (CSO). No empirically supported treatment exists for the CSOs of people with problem gambling. Consequently, the aim of this study is to develop and evaluate a programme aimed at CSOs of treatment-refusing problem gamblers. The programme will be based on principles from cognitive behavioural therapy (CBT) and motivational interviewing. To benefit as many CSOs as possible, the programme will be delivered via the internet with therapist support via encrypted email and short weekly conversations via telephone.
Methods and analysis
This will be a randomised wait-list controlled internet-delivered treatment trial. A CBT programme for the CSOs of people with problem gambling will be developed and evaluated. The participants will work through nine modules over 10 weeks in a secure online environment, and receive support via secure emails and over the telephone. A total of 150 CSOs over 18 years of age will be included. Measures will be taken at baseline and at 3, 6 and 12 months. Primary outcomes concern gambling-related harm. Secondary outcomes include the treatment entry of the individual who gambles, the CSO's levels of depression, anxiety, as well as relationship satisfaction and quality of life.
Ethics and dissemination
The protocol has been approved by the regional ethics board of Stockholm, Sweden. This study will add to the body of knowledge on how to protect CSOs from gambling-related harm, and how to motivate treatment-refusing individuals to seek professional help for problem gambling.
Trial registration number
PMCID: PMC4680021  PMID: 26656017
concerned significant other; pathological gambling; cognitive behavior therapy; randomized controlled trial
9.  Taxonomic revision of Afrotropical Laccophilus Leach, 1815 (Coleoptera, Dytiscidae) 
ZooKeys  2015;1-379.
The African species of the genus Laccophilus Leach, 1815, are revised, on the basis of study of adult specimens. In all, 105 species are now recognized. A phenetic character-analysis was undertaken, which resulted in a split of the genus into 17 species groups. Diagnoses and a description of each species are given together with keys for identification of species groups and species. We also provide habitus photos, illustration of male genitalia and distribution maps for all species. New species are described as follows: Laccophilus grossus sp. n. (Angola, Namibia), Laccophilus rocchii sp. n. (Tanzania, Namibia, Botswana, Mozambique), Laccophilus ferrugo sp. n. (Mozambique), Laccophilus furthi sp. n. (Madagascar), Laccophilus isamberti sp. n. (Madagascar), Laccophilus inobservatus sp. n. (Gambia, Senegal, Mali, Niger, Sudan, Chad, Ethiopia, Burkina Faso, Ivory Coast, Ghana, Nigeria, Cameroon, Zaire and Asia: Yemen), Laccophilus cryptos sp. n. (Zaire, Mozambique, Zimbabwe, Namibia, Botswana, South Africa), Laccophilus enigmaticus sp. n. (Nigeria, Sudan), Laccophilus bellus sp. n. (Benin, Nigeria), Laccophilus guentheri sp. n. (Guinea, Ghana), Laccophilus guineensis sp. n. (Guinea), Laccophilus decorosus sp. n. (Uganda), Laccophilus empheres sp. n. (Kenya), Laccophilus inconstans sp. n. (Guinea, Ivory Coast, Ghana, Nigeria, Cameroon), Laccophilus brancuccii sp. n. (Central African Republic), Laccophilus incomptus sp. n. (Cameroon), Laccophilus australis sp. n. (Tanzania, South Africa), Laccophilus minimus sp. n. (Namibia), Laccophilus eboris sp. n. (Ivory Coast), Laccophilus insularum sp. n. (Madagascar), Laccophilus occidentalis sp. n. (Gambia, Senegal, Mali, Guinea, Sierra Leone, Ivory Coast, Ghana, Benin, Nigeria, Central African Republic, Zaire) and Laccophilus transversovittatus sp. n. (Madagascar). Laccophilus restrictus Sharp, 1882, is restored as good species; not junior synonym of Laccophilus pictipennis Sharp, 1882. New synonyms are established as follows: Laccophilus continentalis Gschwendtner, 1935 = Laccophilus perplexus Omer-Cooper, 1970, syn. n., Laccophilus taeniolatus Régimbart, 1889 = Laccophilus congener Omer-Cooper, 1957, syn. n., Laccophilus adspersus Boheman, 1848 = Laccophilus vitshumbii Guignot, 1959, syn. n. = Laccophilus adspersus nigeriensis Omer-Cooper, 1970, syn. n. = Laccophilus adspersus sudanensis Omer-Cooper, 1970, syn. n., Laccophilus modestus Régimbart, 1895 = Laccophilus espanyoli Hernando, 1990, syn. n., Laccophilus flaveolus Régimbart, 1906 = Laccophilus pampinatus Guignot, 1941, syn. n., Laccophilus trilineola Régimbart, 1889 = Laccophilus simulator Omer-Cooper, 1958, syn. n., Laccophilus mediocris Guignot, 1952 = Laccophilus meii Rocchi, 2000, syn. n., Laccophilus epinephes Guignot, 1955 = Laccophilus castaneus Guignot, 1956, syn. n., Laccophilus saegeri Guignot, 1958 = Laccophilus comoensis Pederzani & Reintjes, 2002, syn. n., Laccophilus restrictus Sharp, 1882 = Laccophilus evanescens Régimbart, 1895, syn. n., Laccophilus incrassatus Gschwendtner, 1933 = Laccophilus virgatus Guignot, 1953, syn. n., Laccophilus cyclopis Sharp, 1882 = Laccophilus shephardi Omer-Cooper, 1965, syn. n., Laccophilus burgeoni Gschwendtner, 1930 = Laccophilus wittei Guignot, 1952, syn. n., Laccophilus secundus Régimbart, 1895 = Laccophilus torquatus Guignot, 1956, syn. n., Laccophilus desintegratus Régimbart, 1895 = Laccophilus sanguinosus Régimbart, 1895, syn. n. and Laccophilus flavopictus Régimbart, 1889 = Laccophilus bergeri Guignot, 1953, syn. n. = Laccophilus segmentatus Omer-Cooper, 1957, syn. n. Lectotypes are designated for the following taxa: Laccophilus productus Régimbart, 1906, Laccophilus ruficollis Zimmermann, 1919, Laccophilus sordidus Sharp, 1882, Laccophilus alluaudi Régimbart, 1899, Laccophilus pictipennis Sharp, 1882, Laccophilus wehnckei Sharp, 1882, Laccophilus continentalis Gschwendtner, 1935, Laccophilus simplicistriatus Gschwendtner, 1932, Laccophilus complicatus Sharp, 1882, Laccophilus rivulosus Klug, 1833, Laccophilus ampliatus Régimbart, 1895, Laccophilus pilitarsis Régimbart, 1906, Laccophilus adspersus Boheman, 1848, Laccophilus livens Régimbart, 1895, Laccophilus modestus Régimbart, 1895, Laccophilus nodieri Régimbart, 1895, Laccophilus flaveolus Régimbart, 1906, Laccophilus pallescens Régimbart, 1903, Laccophilus restrictus Sharp, 1882, Laccophilus vermiculosus Gerstaecker, 1867, Laccophilus mocquerysi Régimbart, 1895, Laccophilus bizonatus Régimbart, 1895, Laccophilus tschoffeni Régimbart, 1895, Laccophilus persimilis Régimbart, 1895, Laccophilus poecilus Klug, 1834, Laccophilus lateralis Sharp, 1882, Laccophilus lateralis var. polygrammus Régimbart, 1903, Laccophilus cyclopis Sharp, 1882, Laccophilus shephardi Omer-Cooper, 1965, Laccophilus conjunctus Guignot, 1950, Laccophilus grammicus Sharp, 1882, Laccophilus flavoscriptus Régimbart, 1895, Laccophilus flavosignatus Régimbart, 1895, Laccophilus brevicollis Sharp, 1882, Laccophilus secundus Régimbart, Laccophilus desintegratus Régimbart, 1895, Laccophilus gutticollis Régimbart, 1895, Laccophilus luctuosus Sharp, 1882 and Laccophilus inornatus Zimmermann, 1926. Laccophilus remex Guignot, 1952, comprises a species complex with uncertain taxonomic delimitation; the complex includes Laccophilus concisus Guignot, 1953, Laccophilus turneri Omer-Cooper, 1957 and Laccophilus praeteritus Omer-Cooper, 1957, as tentative synonyms of Laccophilus remex Guignot, 1952.
PMCID: PMC4714360  PMID: 26798285
Coleoptera; Dytiscidae; Laccophilus; Africa; Madagascar; taxonomy; revision; description; new species
10.  Changing Names with Changed Address: Integrated Taxonomy and Species Delimitation in the Holarctic Colymbetes paykulli Group (Coleoptera: Dytiscidae) 
PLoS ONE  2015;10(11):e0143577.
Species delimitation of geographically isolated forms is a long-standing problem in less studied insect groups. Often taxonomic decisions are based directly on morphologic variation, and lack a discussion regarding sample size and the efficiency of migration barriers or dispersal/migration capacity of the studied species. These problems are here exemplified in a water beetle complex from the Bering Sea region that separates North America from Eurasia. Only a few sampled specimens occur from this particular area and they are mostly found in museum and private collections. Here we utilize the theory of integrated taxonomy to discuss the speciation of the Holarctic Colymbetes paykulli water beetle complex, which historically has included up to five species of which today only two are recognized. Three delimitation methods are used; landmark based morphometry of body shape, variation in reticulation patterns of the pronotum exo-skeleton and sequence variation of the partial mitochondrial gene Cyt b. Our conclusion is that the Palearctic and Nearctic populations of C. paykulli are given the status of separate species, based on the fact that all methods showed significant separation between populations. As a consequence the name of the Palearctic species is C. paykulli Erichson and the Nearctic species should be known as C. longulus LeConte. There is no clear support for delineation between Palearctic and Nearctic populations of C. dahuricus based on mtDNA. However, significant difference in size and reticulation patterns from the two regions is shown. The combined conclusion is that the C. dahuricus complex needs a more thorough investigation to fully disentangle its taxonomic status. Therefore it is here still regarded as a Holarctic species. This study highlights the importance to study several diagnosable characters that has the potential to discriminate evolutionary lineage during speciation.
PMCID: PMC4664258  PMID: 26619278
11.  The Evolution of Functionally Redundant Species; Evidence from Beetles 
PLoS ONE  2015;10(10):e0137974.
While species fulfill many different roles in ecosystems, it has been suggested that numerous species might actually share the same function in a near neutral way. So-far, however, it is unclear whether such functional redundancy really exists. We scrutinize this question using extensive data on the world’s 4168 species of diving beetles. We show that across the globe these animals have evolved towards a small number of regularly-spaced body sizes, and that locally co-existing species are either very similar in size or differ by at least 35%. Surprisingly, intermediate size differences (10–20%) are rare. As body-size strongly reflects functional aspects such as the food that these generalist predators can eat, these beetles thus form relatively distinct groups of functional look-a-likes. The striking global regularity of these patterns support the idea that a self-organizing process drives such species-rich groups to self-organize evolutionary into clusters where functional redundancy ensures resilience through an insurance effect.
PMCID: PMC4598105  PMID: 26447476
13.  Anomalous Behavior of the Homogeneous Ice Nucleation Rate in “No-Man’s Land” 
We present an analysis of ice nucleation kinetics from near-ambient pressure water as temperature decreases below the homogeneous limit TH by cooling micrometer-sized droplets (microdroplets) evaporatively at 103–104 K/s and probing the structure ultrafast using femtosecond pulses from the Linac Coherent Light Source (LCLS) free-electron X-ray laser. Below 232 K, we observed a slower nucleation rate increase with decreasing temperature than anticipated from previous measurements, which we suggest is due to the rapid decrease in water’s diffusivity. This is consistent with earlier findings that microdroplets do not crystallize at <227 K, but vitrify at cooling rates of 106–107 K/s. We also hypothesize that the slower increase in the nucleation rate is connected with the proposed “fragile-to-strong” transition anomaly in water.
PMCID: PMC4507474  PMID: 26207172
15.  Fauna Europaea: Coleoptera 2 (excl. series Elateriformia, Scarabaeiformia, Staphyliniformia and superfamily Curculionoidea) 
Fauna Europaea provides a public web-service with an index of scientific names (including synonyms) of all living European land and freshwater animals, their geographical distribution at country level (up to the Urals, excluding the Caucasus region), and some additional information. The Fauna Europaea project covers about 230,000 taxonomic names, including 130,000 accepted species and 14,000 accepted subspecies, which is much more than the originally projected number of 100,000 species. This represents a huge effort by more than 400 contributing specialists throughout Europe and is a unique (standard) reference suitable for many users in science, government, industry, nature conservation and education.
Coleoptera represent a huge assemblage of holometabolous insects, including as a whole more than 200 recognized families and some 400,000 described species worldwide. Basic information is summarized on their biology, ecology, economic relevance, and estimated number of undescribed species worldwide. Little less than 30,000 species are listed from Europe. The Coleoptera 2 section of the Fauna Europaea database (Archostemata, Myxophaga, Adephaga and Polyphaga excl. the series Elateriformia, Scarabaeiformia, Staphyliniformia and the superfamily Curculionoidea) encompasses 80 families (according to the previously accepted family-level systematic framework) and approximately 13,000 species. Tabulations included a complete list of the families dealt with, the number of species in each, the names of all involved specialists, and, when possible, an estimate of the gaps in terms of total number of species at an European level. A list of some recent useful references is appended. Most families included in the Coleoptera 2 Section have been updated in the most recent release of the Fauna Europaea index, or are ready to be updated as soon as the FaEu data management environment completes its migration from Zoological Museum Amsterdam to Berlin Museum für Naturkunde.
PMCID: PMC4399155  PMID: 25892924
Biodiversity Informatics;  Coleoptera ; Fauna Europaea; Taxonomic indexing.
16.  A Suggested New Bacteriophage Genus, “Kp34likevirus”, within the Autographivirinae Subfamily of Podoviridae 
Viruses  2015;7(4):1804-1822.
Klebsiella pneumoniae phages vB_KpnP_SU503 (SU503) and vB_KpnP_SU552A (SU552A) are virulent viruses belonging to the Autographivirinae subfamily of Podoviridae that infect and kill multi-resistant K. pneumoniae isolates. Phages SU503 and SU552A show high pairwise nucleotide identity to Klebsiella phages KP34 (NC_013649), F19 (NC_023567) and NTUH-K2044-K1-1 (NC_025418). Bioinformatic analysis of these phage genomes show high conservation of gene arrangement and gene content, conserved catalytically active residues of their RNA polymerase, a common and specific lysis cassette, and form a joint cluster in phylogenetic analysis of their conserved genes. Also, we have performed biological characterization of the burst size, latent period, host specificity (together with KP34 and NTUH-K2044-K1-1), morphology, and structural genes as well as sensitivity testing to various conditions. Based on the analyses of these phages, the creation of a new phage genus is suggested within the Autographivirinae, called “Kp34likevirus” after their type phage, KP34. This genus should encompass the recently genome sequenced Klebsiella phages KP34, SU503, SU552A, F19 and NTUH-K2044-K1-1.
PMCID: PMC4411677  PMID: 25853484
“Kp34likevirus”; phikmvlikevirus; Autographivirinae; Klebsiella pneumoniae; bacteriophage; phage; Podoviridae
17.  Isolation of Phages for Phage Therapy: A Comparison of Spot Tests and Efficiency of Plating Analyses for Determination of Host Range and Efficacy 
PLoS ONE  2015;10(3):e0118557.
Phage therapy, treating bacterial infections with bacteriophages, could be a future alternative to antibiotic treatment of bacterial infections. There are, however, several problems to be solved, mainly associated to the biology of phages, the interaction between phages and their bacterial hosts, but also to the vast variation of pathogenic bacteria which implies that large numbers of different phages are going to be needed. All of these phages must under present regulation of medical products undergo extensive clinical testing before they can be applied. It will consequently be of great economic importance that effective and versatile phages are selected and collected into phage libraries, i.e., the selection must be carried out in a way that it results in highly virulent phages with broad host ranges. We have isolated phages using the Escherichia coli reference (ECOR) collection and compared two methods, spot testing and efficiency of plating (EOP), which are frequently used to identify phages suitable for phage therapy. The analyses of the differences between the two methods show that spot tests often overestimate both the overall virulence and the host range and that the results are not correlated to the results of EOP assays. The conclusion is that single dilution spot tests cannot be used for identification and selection of phages to a phage library and should be replaced by EOP assays. The difference between the two methods can be caused by many factors. We have analysed if the differences and lack of correlation could be caused by lysis from without, bacteriocins in the phage lysate, or by the presence of prophages harbouring genes coding for phage resistance systems in the genomes of the bacteria in the ECOR collection.
PMCID: PMC4356574  PMID: 25761060
18.  Genomic, Proteomic, Morphological, and Phylogenetic Analyses of vB_EcoP_SU10, a Podoviridae Phage with C3 Morphology 
PLoS ONE  2014;9(12):e116294.
A recently isolated phage, vB_EcoP_SU10 (SU10), with the unusual elongated C3 morphotype, can infect a wide range of Escherichia coli strains. We have sequenced the genome of this phage and characterized it further by mass spectrometry based proteomics, transmission electron microscopy (TEM), scanning electron microscopy (SEM), and ultra-thin section electron microscopy. The genome size is 77,327 base pairs and its genes, and genome architecture, show high similarity to the phiEco32 phage genes and genome. The TEM images reveal that SU10 have a quite long tail for being a Podoviridae phage, and that the tail also changes conformation upon infection. The ultra-thin section electron microscopy images of phages at the stage of replication within the host cell show that the phages form a honeycomb-like structure under packaging of genomes and assembly of mature capsids. This implies a tight link between the replication and cutting of the concatemeric genome, genome packaging, and capsid assembly. We have also performed a phylogenetic analysis of the structural genes common between Podoviridae phages of the C1 and C3 morphotypes. The result shows that the structural genes have coevolved, and that they form two distinct groups linked to their morphotypes. The structural genes of C1 and C3 phages appear to have diverged around 280 million years ago applying a molecular clock calibrated according to the presumed split between the Escherichia – Salmonella genera.
PMCID: PMC4281155  PMID: 25551446
19.  Severe complications with irreversible electroporation of the pancreas in the presence of a metallic stent: a warning of a procedure that never should be performed 
Acta Radiologica Short Reports  2014;3(11):2047981614556409.
Irreversible electroporation (IRE) is an ablation technique that is being investigated as a potential treatment of pancreatic cancer. However, many of these patients have a metallic stent in the bile duct, which is recognized as a contraindication for IRE ablation. We report a case in which an IRE ablation in the region of the pancreatic head was performed on a patient with a metallic stent which led to severe complications. After the treatment, the patient suffered from several complications including perforation of the duodenum and transverse colon, and bleeding from a branch of the superior mesenteric artery which eventually lead to her death. Therefore, we believe it is important to be aware of this if an IRE ablation close to a metallic stent is considered.
PMCID: PMC4271709  PMID: 25535573
IRE; irreversible electroporation; pancreatic cancer; metallic stent; bowel perforation; bleeding; artery injury
20.  Low concentrations of citrate reduce complement and granulocyte activation in vitro in human blood 
Clinical Kidney Journal  2014;8(1):31-37.
The use of acetate in haemodialysis fluids may induce negative effects in patients including nausea and increased inflammation. Therefore, haemodialysis fluids where acetate is substituted with citrate have recently been developed. In this study, we investigated the biocompatibility of citrate employing concentrations used in haemodialysis.
The effects of citrate and acetate were investigated in human whole blood in vitro under conditions promoting biomaterial-induced activation. Complement activation was measured as generation of C3a, C5a and the sC5b-9 complex, and granulocyte activation as up-regulation of CD11b expression. For the experimental set-up, a mathematical model was created to calculate the concentrations of acetate and citrate attained during haemodialysis.
Citrate reduced granulocyte activation and did not induce higher complement activation compared with acetate at concentrations attained during haemodialysis. Investigating different citrate concentrations clearly showed that citrate is a potent complement inhibitor already at low concentrations, i.e. 0.25 mM, which is comparable with concentrations detected in the blood of patients during dialysis with citrate-containing fluids. Increased citrate concentration up to 6 mM further reduced the activation of C3a, C5a and sC5b-9, as well as the expression of CD11b.
Our results suggest that citrate is a promising substitute for acetate for a more biocompatible dialysis, most likely resulting in less adverse effects for the patients.
PMCID: PMC4310429  PMID: 25713707
acetate; biocompatibility; citrate; complement; haemodialysis
21.  Phage therapy—constraints and possibilities 
Upsala Journal of Medical Sciences  2014;119(2):192-198.
The rise of antibiotic-resistant bacterial strains, causing intractable infections, has resulted in an increased interest in phage therapy. Phage therapy preceded antibiotic treatment against bacterial infections and involves the use of bacteriophages, bacterial viruses, to fight bacteria. Virulent phages are abundant and have proven to be very effective in vitro, where they in most cases lyse any bacteria within the hour. Clinical trials on animals and humans show promising results but also that the treatments are not completely effective. This is partly due to the studies being carried out with few phages, and with limited experimental groups, but also the fact that phage therapy has limitations in vivo. Phages are large compared with small antibiotic molecules, and each phage can only infect one or a few bacterial strains. A very large number of different phages are needed to treat infections as these are caused by genetically different strains of bacteria. Phages are effective only if enough of them can reach the bacteria and increase in number in situ. Taken together, this entails high demands on resources for the construction of phage libraries and the testing of individual phages. The effectiveness and host range must be characterized, and immunological risks must be assessed for every single phage.
PMCID: PMC4034558  PMID: 24678769
Antibiotic resistance; bacteriophage; phage; phage therapy
22.  Redundancy among phospholipase D isoforms in resistance triggered by recognition of the Pseudomonas syringae effector AvrRpm1 in Arabidopsis thaliana 
Plants possess a highly sophisticated system for defense against microorganisms. So called MAMP (microbe-associated molecular patterns) triggered immunity (MTI) prevents the majority of non-adapted pathogens from causing disease. Adapted plant pathogens use secreted effector proteins to interfere with such signaling. Recognition of microbial effectors or their activity by plant resistance (R)-proteins triggers a second line of defense resulting in effector triggered immunity (ETI). The latter usually comprises the hypersensitive response (HR) which includes programmed cell death at the site of infection. Phospholipase D (PLD) mediated production of phosphatidic acid (PA) has been linked to both MTI and ETI in plants. Inhibition of PLD activity has been shown to attenuate MTI as well as ETI. In this study, we systematically tested single and double knockouts in all 12 genes encoding PLDs in Arabidopsis thaliana for effects on ETI and MTI. No single PLD could be linked to ETI triggered by recognition of effectors secreted by the bacterium Pseudomonas syringae. However, repression of PLD dependent PA production by n-butanol strongly inhibited the HR following Pseudomonas syringae effector recognition. In addition some pld mutants were more sensitive to n-butanol than wild type. Thus, the effect of mutations of PLDs could become detectable, and the corresponding genes can be proposed to be involved in the HR. Only knockout of PLDδ caused a loss of MTI-induced cell wall based defense against the non-host powdery mildew Erysiphe pisi. This is thus in stark contrast to the involvement of a multitude of PLD isoforms in the HR triggered by AvrRpm1 recognition.
PMCID: PMC4230166  PMID: 25431578
phospholipase D; hypersensitive response; Pseudomonas syringae; Arabidopsis thaliana; phosphatidic acid; pathogen defense
23.  Bayesian Tests of Topology Hypotheses with an Example from Diving Beetles 
Systematic Biology  2013;62(5):660-673.
We review Bayesian approaches to model testing in general and to the assessment of topological hypotheses in particular. We show that the standard way of setting up Bayes factor tests of the monophyly of a group, or the placement of a sample sequence in a known reference tree, can be misleading. The reason for this is related to the well-known dependency of Bayes factors on model-specific priors. Specifically, when testing tree hypotheses it is important that each hypothesis is associated with an appropriate tree space in the prior. This can be achieved by using appropriately constrained searches or by filtering trees in the posterior sample, but in a more elaborate way than typically implemented. If it is difficult to find the appropriate tree sets to be contrasted, then the posterior model odds may be more informative than the Bayes factor. We illustrate the recommended techniques using an empirical test case addressing the issue of whether two genera of diving beetles (Coleoptera: Dytiscidae), Suphrodytes and Hydroporus, should be synonymized. Our refined Bayes factor tests, in contrast to standard analyses, show that there is strong support for Suphrodytes nesting inside Hydroporus, and the genera are therefore synonymized. [Bayes factor; Coleoptera; Dytiscidae; marginal likelihood; model testing; posterior odds; reversible-jump MCMC; stepping-stone sampling.]
PMCID: PMC3739882  PMID: 23628960
24.  Fms-Like Tyrosine Kinase 3 Ligand Controls Formation of Regulatory T Cells in Autoimmune Arthritis 
PLoS ONE  2013;8(1):e54884.
Fms-like tyrosine kinase 3 ligand (Flt3L) is known as the primary differentiation and survival factor for dendritic cells (DCs). Furthermore, Flt3L is involved in the homeostatic feedback loop between DCs and regulatory T cell (Treg). We have previously shown that Flt3L accumulates in the synovial fluid in rheumatoid arthritis (RA) and that local exposure to Flt3L aggravates arthritis in mice, suggesting a possible involvement in RA pathogenesis. In the present study we investigated the role of Flt3L on DC populations, Tregs as well as inflammatory responses in experimental antigen-induced arthritis. Arthritis was induced in mBSA-immunized mice by local knee injection of mBSA and Flt3L was provided by daily intraperitoneal injections. Flow cytometry analysis of spleen and lymph nodes revealed an increased formation of DCs and subsequently Tregs in mice treated with Flt3L. Flt3L-treatment was also associated with a reduced production of mBSA specific antibodies and reduced levels of the pro-inflammatory cytokines IL-6 and TNF-α. Morphological evaluation of mBSA injected joints revealed reduced joint destruction in Flt3L treated mice. The role of DCs in mBSA arthritis was further challenged in an adoptive transfer experiment. Transfer of DCs in combination with T-cells from mBSA immunized mice, predisposed naïve recipients for arthritis and production of mBSA specific antibodies. We provide experimental evidence that Flt3L has potent immunoregulatory properties. Flt3L facilitates formation of Treg cells and by this mechanism reduces severity of antigen-induced arthritis in mice. We suggest that high systemic levels of Flt3L have potential to modulate autoreactivity and autoimmunity.
PMCID: PMC3549988  PMID: 23349985
25.  Highly Compressed Two-Dimensional Form of Water at Ambient Conditions 
Scientific Reports  2013;3:1074.
The structure of thin-film water on a BaF2(111) surface under ambient conditions was studied using x-ray absorption spectroscopy from ambient to supercooled temperatures at relative humidity up to 95%. No hexagonal ice-like structure was observed in spite of the expected templating effect of the lattice-matched (111) surface. The oxygen K-edge x-ray absorption spectrum of liquid thin-film water on BaF2 exhibits, at all temperatures, a strong resemblance to that of high-density phases for which the observed spectroscopic features correlate linearly with the density. Surprisingly, the highly compressed, high-density thin-film liquid water is found to be stable from ambient (300 K) to supercooled (259 K) temperatures, although a lower-density liquid would be expected at supercooled conditions. Molecular dynamics simulations indicate that the first layer water on BaF2(111) is indeed in a unique local structure that resembles high-density water, with a strongly collapsed second coordination shell.
PMCID: PMC3545261  PMID: 23323216

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