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1.  Polymorphisms at the innate immune receptor TLR2 are associated with Borrelia infection in a wild rodent population 
The discovery of the key role of Toll-like receptors (TLRs) in initiating innate immune responses and modulating adaptive immunity has revolutionized our understanding of vertebrate defence against pathogens. Yet, despite their central role in pathogen recognition and defence initiation, there is little information on how variation in TLRs influences disease susceptibility in natural populations. Here, we assessed the extent of naturally occurring polymorphisms at TLR2 in wild bank voles (Myodes glareolus) and tested for associations between TLR2 variants and infection with Borrelia afzelii, a common tick-transmitted pathogen in rodents and one of the causative agents of human Lyme disease. Bank voles in our population had 15 different TLR2 haplotypes (10 different haplotypes at the amino acid level), which grouped in three well-separated clusters. In a large-scale capture–mark–recapture study, we show that voles carrying TLR2 haplotypes of one particular cluster (TLR2c2) were almost three times less likely to be Borrelia infected than animals carrying other haplotypes. Moreover, neutrality tests suggested that TLR2 has been under positive selection. This is, to our knowledge, the first demonstration of an association between TLR polymorphism and parasitism in wildlife, and a striking example that genetic variation at innate immune receptors can have a large impact on host resistance.
doi:10.1098/rspb.2013.0364
PMCID: PMC3619520  PMID: 23554395
wildlife disease; host–parasite interactions; Borrelia; innate immune defence; Toll-like receptors; disease resistance
2.  Direct observation of ionic structure at solid-liquid interfaces: a deep look into the Stern Layer 
Scientific Reports  2014;4:4956.
The distribution of ions and charge at solid-water interfaces plays an essential role in a wide range of processes in biology, geology and technology. While theoretical models of the solid-electrolyte interface date back to the early 20th century, a detailed picture of the structure of the electric double layer has remained elusive, largely because of experimental techniques have not allowed direct observation of the behaviour of ions, i.e. with subnanometer resolution. We have made use of recent advances in high-resolution Atomic Force Microscopy to reveal, with atomic level precision, the ordered adsorption of the mono- and divalent ions that are common in natural environments to heterogeneous gibbsite/silica surfaces in contact with aqueous electrolytes. Complemented by density functional theory, our experiments produce a detailed picture of the formation of surface phases by templated adsorption of cations, anions and water, stabilized by hydrogen bonding.
doi:10.1038/srep04956
PMCID: PMC4030399  PMID: 24850566
3.  Nano in Implant Dentistry 
doi:10.1155/2014/314819
PMCID: PMC3963107  PMID: 24729785
4.  Evaluation of Bone Healing on Sandblasted and Acid Etched Implants Coated with Nanocrystalline Hydroxyapatite: An In Vivo Study in Rabbit Femur 
This study aimed at investigating if a coating of hydroxyapatite nanocrystals would enhance bone healing over time in trabecular bone. Sandblasted and acid etched titanium implants with and without a submicron thick coat of hydroxyapatite nanocrystals (nano-HA) were implanted in rabbit femur with healing times of 2, 4, and 9 weeks. Removal torque analyses and histological evaluations were performed. The torque analysis did not show any significant differences between the implants at any healing time. The control implant showed a tendency of more newly formed bone after 4 weeks of healing and significantly higher bone area values after 9 weeks of healing. According to the results from this present study, both control and nano-HA surfaces were biocompatible and osteoconductive. A submicron thick coating of hydroxyapatite nanocrystals deposited onto blasted and acid etched screw shaped titanium implants did not enhance bone healing, as compared to blasted and etched control implants when placed in trabecular bone.
doi:10.1155/2014/197581
PMCID: PMC3958713  PMID: 24723952
5.  The Effect of Hydroxyapatite Nanocrystals on Osseointegration of Titanium Implants: An In Vivo Rabbit Study 
Osseointegration is dependent on implant surface characteristics, including surface chemistry and topography. The presence of nanosized calcium phosphates on the implant surface is interesting to investigate since they affect both the nanotopography and surface chemistry, forming a bone mineral resembling surface. In this work, the osseointegration of titanium implants with and without the presence of hydroxyapatite (HA) nanocrystals has been evaluated in vivo. The integration was examined using removal torque measurements and real-time polymerase chain reaction (RT-PCR) analysis. The study was performed using two healing time points, 3 and 12 weeks. The results showed that the torque needed to remove the implants was insignificant between the non- and HA-coated implants, both at weeks 3 and 12. The RT-PCR, however, showed significant differences for osteoblast, osteoclast, and proinflammation markers when HA nanocrystals were present.
doi:10.1155/2014/171305
PMCID: PMC3915854  PMID: 24563651
6.  Non-Host Volatile Blend Optimization for Forest Protection against the European Spruce Bark Beetle, Ips typographus 
PLoS ONE  2014;9(1):e85381.
Conifer feeding bark beetles (Coleoptera, Curculionidae, Scolytinae) pose a serious economic threat to forest production. Volatiles released by non-host angiosperm plants (so called non-host volatiles, NHV) have been shown to reduce the risk of attack by many bark beetle species, including the European spruce bark beetle, Ips typographus. However, the most active blend for I. typographus, containing three green leaf volatiles (GLVs) in addition to the key compounds trans-conophthorin (tC) and verbenone, has been considered too expensive for use in large-scale management. To lower the cost and improve the applicability of NHV, we aim to simplify the blend without compromising its anti-attractant potency. Since the key compound tC is expensive in pure form, we also tested a crude version: technical grade trans-conophthorin (T-tC). In another attempt to find a more cost effective substitute for tC, we evaluated a more readily synthesized analog: dehydro-conophthorin (DHC). Our results showed that 1-hexanol alone could replace the three-component GLV blend containing 1-hexanol, (3Z)-hexen-1-ol, and (2E)-hexen-1-ol. Furthermore, the release rate of tC could be reduced from 5 mg/day to 0.5 mg/day in a blend with 1-hexanol and (–)-verbenone without compromising the anti-attractant activity. We further show that T-tC was comparable with tC, whereas DHC was a less effective anti-attractant. DHC also elicited weaker physiological responses in the tC-responding olfactory receptor neuron class, providing a likely mechanistic explanation for its weaker anti-attractive effect. Our results suggest a blend consisting of (–)-verbenone, 1-hexanol and technical trans-conophthorin as a cost-efficient anti-attractant for forest protection against I. typographus.
doi:10.1371/journal.pone.0085381
PMCID: PMC3891852  PMID: 24454855
7.  Predicting pKa for proteins using COSMO-RS 
PeerJ  2013;1:e198.
We have used the COSMO-RS implicit solvation method to calculate the equilibrium constants, pKa, for deprotonation of the acidic residues of the ovomucoid inhibitor protein, OMTKY3. The root mean square error for comparison with experimental data is only 0.5 pH units and the maximum error 0.8 pH units. The results show that the accuracy of pKa prediction using COSMO-RS is as good for large biomolecules as it is for smaller inorganic and organic acids and that the method compares very well to previous pKa predictions of the OMTKY3 protein using Quantum Mechanics/Molecular Mechanics. Our approach works well for systems of about 1000 atoms or less, which makes it useful for small proteins as well as for investigating portions of larger proteins such as active sites in enzymes.
doi:10.7717/peerj.198
PMCID: PMC3817581  PMID: 24244915
Proteins; pKa; COSMO-RS; OMTKY3; Quantum mechanics; Implicit solvent; Semi-empirical methods
8.  Characteristics of 2 Different Commercially Available Implants with or without Nanotopography 
The aim of this study was to assess histologically and histomorphometrically the early bone forming properties after 3 weeks for 2 commercially available implants, one supposedly possessing nanotopography and one without, in a rabbit femur model. Twenty-four implants divided equally into 2 groups were utilized in this study. The first group (P-I MICRO+NANO) was a titanium oxide (TiO2) microblasted and noble gas ion bombarded surface while the second group (Ospol) was anodic oxidized surface with calcium and phosphate incorporation. The implants were placed in the rabbit femur unicortically and were allowed to heal for 3 weeks. After euthanasia, the samples were subjected to histologic sectioning and bone-implant contact and bone area were evaluated histomorphometrically under an optical microscope. The histomorphometric evaluation presented that the P-I MICRO+NANO implants demonstrated significantly higher new bone formation as compared to the Ospol implants. Within the limitations of this study, the results suggested that nanostructures presented significantly higher bone formation after 3 weeks in vivo, and the effect of chemistry was limited, which is indicative that nanotopography is effective at early healing periods.
doi:10.1155/2013/769768
PMCID: PMC3808707  PMID: 24223592
9.  The Advantages of Micro-Cal™ Auto-iTC200 for Secondary Screening in a Fragment-based Drug Discovery Campaign 
Background: Recent developments in ITC instrumentation, namely MicroCal iTC200 and MicroCal Auto-iTC200 have led to an increase in the throughput and decrease in the protein consumption of the technique. In addition, there have been recent methodological Advancements 1 that have extended the affinity range that ITC can measure into the mM range. The combination of all these factors has made the technique ideal for fragment-based drug discovery (FBDD) campaigns. Method: This work outlines the role of MicroCal Auto-iTC200, in the fragment based drug discovery program of Sprint Bioscience, to identify and optimize potential drug candidates that will inhibit the activity of Vps34. This class phosphatidylinositol3-kinase is central to autophagy and has been shown to play an important role in resistance to cancer drugs2, 3. As such it has been identified as a target for therapeutic intervention. ITC is a generic assay without the need for assay development and as such the affinity of all 50 compounds was measured in less than three days after receiving the purified protein. Conclusion: This approach was fast and proved very successful for identifying fragments that co crystallized with the target protein. Of the14 compounds chosen, based on the ITC data, 12 formed crystals that could be used in the optimization process.
PMCID: PMC3635267
10.  Antennal transcriptome analysis of the chemosensory gene families in the tree killing bark beetles, Ips typographus and Dendroctonus ponderosae (Coleoptera: Curculionidae: Scolytinae) 
BMC Genomics  2013;14:198.
Background
The European spruce bark beetle, Ips typographus, and the North American mountain pine beetle, Dendroctonus ponderosae (Coleoptera: Curculionidae: Scolytinae), are severe pests of coniferous forests. Both bark beetle species utilize aggregation pheromones to coordinate mass-attacks on host trees, while odorants from host and non-host trees modulate the pheromone response. Thus, the bark beetle olfactory sense is of utmost importance for fitness. However, information on the genes underlying olfactory detection has been lacking in bark beetles and is limited in Coleoptera. We assembled antennal transcriptomes from next-generation sequencing of I. typographus and D. ponderosae to identify members of the major chemosensory multi-gene families.
Results
Gene ontology (GO) annotation indicated that the relative abundance of transcripts associated with specific GO terms was highly similar in the two species. Transcripts with terms related to olfactory function were found in both species. Focusing on the chemosensory gene families, we identified 15 putative odorant binding proteins (OBP), 6 chemosensory proteins (CSP), 3 sensory neuron membrane proteins (SNMP), 43 odorant receptors (OR), 6 gustatory receptors (GR), and 7 ionotropic receptors (IR) in I. typographus; and 31 putative OBPs, 11 CSPs, 3 SNMPs, 49 ORs, 2 GRs, and 15 IRs in D. ponderosae. Predicted protein sequences were compared with counterparts in the flour beetle, Tribolium castaneum, the cerambycid beetle, Megacyllene caryae, and the fruit fly, Drosophila melanogaster. The most notable result was found among the ORs, for which large bark beetle-specific expansions were found. However, some clades contained receptors from all four beetle species, indicating a degree of conservation among some coleopteran OR lineages. Putative GRs for carbon dioxide and orthologues for the conserved antennal IRs were included in the identified receptor sets.
Conclusions
The protein families important for chemoreception have now been identified in three coleopteran species (four species for the ORs). Thus, this study allows for improved evolutionary analyses of coleopteran olfaction. Identification of these proteins in two of the most destructive forest pests, sharing many semiochemicals, is especially important as they might represent novel targets for population control.
doi:10.1186/1471-2164-14-198
PMCID: PMC3610139  PMID: 23517120
Ips typographus; Dendroctonus ponderosae; Gene ontology; Transcriptome; Odorant receptor; Ionotropic receptor; Gustatory receptor; Odorant binding protein; Chemosensory Protein; Sensory neuron membrane protein
11.  Heavy vehicle traffic is related to wheeze among schoolchildren: a population-based study in an area with low traffic flows 
Environmental Health  2011;10:91.
Background
An association between traffic air pollution and respiratory symptoms among children has been reported. However, the effects of traffic air pollution on asthma and wheeze have been very sparsely studied in areas with low traffic intensity in cold climate with poor dispersion. We evaluated the impact of vehicle traffic on childhood asthma and wheeze by objective exposure assessment.
Methods
As a part of the Obstructive Lung Disease in Northern Sweden (OLIN) studies, a questionnaire was sent to the families of all children attending first or second grade in Luleå (72,000 inhabitants) in Northern Sweden in 2006. The age of the children was 7-8 years and the participation rate was 98% (n = 1357). Skin prick tests were performed in 1224 (89%) children. The home addresses were given geographical coordinates and traffic counts were obtained from the local traffic authorities. A proximity model of average daily traffic and average daily heavy vehicle traffic within 200 meters from each participant's home address was used. The associations between traffic exposure and asthma and wheeze, respectively, were analysed in an adjusted multiple logistic regression model.
Results
Exposure to high traffic flows was uncommon in the study area; only 15% of the children lived within 200 meters from a road with a traffic flow of ≥8000 vehicles per day. Living closer than 200 meters from a road with ≥500 heavy vehicles daily was associated with current wheeze, odds ratio 1.7 (confidence interval 1.0-2.7). A dose-response relation was indicated. An increased risk of asthma was also seen, however not significant, odds ratio 1.5 (confidence interval 0.8-2.9). Stratified analyses revealed that the effect of traffic exposure was restricted to the non-sensitized phenotype of asthma and wheeze. The agreement between self-reported traffic exposure and objective measurements of exposure was moderate.
Conclusions
This study showed that already at low levels of exposure, vehicle traffic is related to an increased risk of wheeze among children. Thus, the global burden of traffic air pollution may be underestimated.
doi:10.1186/1476-069X-10-91
PMCID: PMC3206415  PMID: 21995638
12.  Wild Rodents and Novel Human Pathogen Candidatus Neoehrlichia mikurensis, Southern Sweden 
Emerging Infectious Diseases  2011;17(9):1716-1718.
We examined small mammals as hosts for Anaplasmataceae in southern Sweden. Of 771 rodents, 68 (8.8%) were infected by Candidatus Neoehrlichia mikurensis, but no other Anaplasmataceae were found. Candidatus N. mikurensis has recently been found in human patients in Germany, Switzerland, and Sweden, which suggests that this could be an emerging pathogen in Europe.
doi:10.3201/eid1709.101058
PMCID: PMC3322053  PMID: 21888802
Anaplasmataceae; Candidatus Neoehrlichia mikurensis; Anaplasma phagocytophilum; Bartonella; bacteria; tick-borne disease; zoonotic disease; wild rodents; Rickettsia; Sweden; dispatch
13.  Effects of synovial fluid from aseptic prosthesis loosening on collagen production in osteoblasts 
International Orthopaedics  2008;33(3):873-877.
Synovial fluid from a loose prosthesis may act as a vehicle for factors that regulate bone turnover. The effect of such synovial fluid on osteoblasts has been studied. Synovial fluid obtained from patients who underwent revision hip arthroplasty because of aseptic prosthesis loosening was studied regarding the effect on protein synthesis, procollagen I mRNA expression, the secretion of procollagen I carboxyterminal propeptide (PICP) and osteocalcin in MG63 osteoblasts. Protein synthesis was increased and procollagen I mRNA expression was decreased by synovial fluid from patients with prosthesis loosening. Synovial fluid stimulated the total PICP in cell medium, but there was no change after correction for cell protein content in the cells. Synovial fluid in patients with prosthesis loosening has a general stimulatory effect on collagen formation and osteoblast proliferation because of a stimulatory effect on cell growth. Aseptic prosthesis loosening may be associated with an increase in bone formation.
doi:10.1007/s00264-008-0533-z
PMCID: PMC2903105  PMID: 18350290
14.  Correlations between measures of executive attention and cortical thickness of left posterior middle frontal gyrus - a dichotic listening study 
Background
The frontal lobe has been associated to a wide range of cognitive control functions and is also vulnerable to degeneration in old age. A recent study by Thomsen and colleagues showed a difference between a young and old sample in grey matter density and activation in the left middle frontal cortex (MFC) and performance on a dichotic listening task. The present study investigated this brain behaviour association within a sample of healthy older individuals, and predicted a positive correlation between performance in a condition requiring executive attention and measures of grey matter structure of the posterior left MFC.
Methods
A dichotic listening forced attention paradigm was used to measure attention control functions. Subjects were instructed to report only the left or the right ear syllable of a dichotically presented consonant-vowel syllable pair. A conflict situation appears when subjects are instructed to report the left ear stimulus, caused by the conflict with the bottom-up, stimulus-driven right ear advantage. Overcoming this processing conflict was used as a measure of executive attention. Thickness and volumes of frontal lobe regions were derived from automated segmentation of 3D magnetic resonance image acquisitions.
Results
The results revealed a statistically significant positive correlation between the thickness measure of the left posterior MFC and performance on the dichotic listening measures of executive attention. Follow-up analyses showed that this correlation was only statistically significant in the subgroup that showed the typical bottom-up, stimulus-driven right ear advantage.
Conclusion
The results suggest that the left MFC is a part of an executive attention network, and that the dichotic listening forced attention paradigm may be a feasible tool for assessing subtle attentional dysfunctions in older adults.
doi:10.1186/1744-9081-5-41
PMCID: PMC2761925  PMID: 19796388
15.  Hippocampal volumes are important predictors for memory function in elderly women 
BMC Medical Imaging  2009;9:17.
Background
Normal aging involves a decline in cognitive function that has been shown to correlate with volumetric change in the hippocampus, and with genetic variability in the APOE-gene. In the present study we utilize 3D MR imaging, genetic analysis and assessment of verbal memory function to investigate relationships between these factors in a sample of 170 healthy volunteers (age range 46–77 years).
Methods
Brain morphometric analysis was performed with the automated segmentation work-flow implemented in FreeSurfer. Genetic analysis of the APOE genotype was determined with polymerase chain reaction (PCR) on DNA from whole-blood. All individuals were subjected to extensive neuropsychological testing, including the California Verbal Learning Test-II (CVLT). To obtain robust and easily interpretable relationships between explanatory variables and verbal memory function we applied the recent method of conditional inference trees in addition to scatterplot matrices and simple pairwise linear least-squares regression analysis.
Results
APOE genotype had no significant impact on the CVLT results (scores on long delay free recall, CVLT-LD) or the ICV-normalized hippocampal volumes. Hippocampal volumes were found to decrease with age and a right-larger-than-left hippocampal asymmetry was also found. These findings are in accordance with previous studies. CVLT-LD score was shown to correlate with hippocampal volume. Multivariate conditional inference analysis showed that gender and left hippocampal volume largely dominated predictive values for CVLT-LD scores in our sample. Left hippocampal volume dominated predictive values for females but not for males. APOE genotype did not alter the model significantly, and age was only partly influencing the results.
Conclusion
Gender and left hippocampal volumes are main predictors for verbal memory function in normal aging. APOE genotype did not affect the results in any part of our analysis.
doi:10.1186/1471-2342-9-17
PMCID: PMC2743662  PMID: 19698138
16.  Effects on osteoclast and osteoblast activities in cultured mouse calvarial bones by synovial fluids from patients with a loose joint prosthesis and from osteoarthritis patients 
Aseptic loosening of a joint prosthesis is associated with remodelling of bone tissue in the vicinity of the prosthesis. In the present study, we investigated the effects of synovial fluid (SF) from patients with a loose prosthetic component and periprosthetic osteolysis on osteoclast and osteoblast activities in vitro and made comparisons with the effects of SF from patients with osteoarthritis (OA). Bone resorption was assessed by the release of calcium 45 (45Ca) from cultured calvariae. The mRNA expression in calvarial bones of molecules known to be involved in osteoclast and osteoblast differentiation was assessed using semi-quantitative reverse transcription-polymerase chain reaction (PCR) and real-time PCR. SFs from patients with a loose joint prosthesis and patients with OA, but not SFs from healthy subjects, significantly enhanced 45Ca release, effects associated with increased mRNA expression of calcitonin receptor and tartrate-resistant acid phosphatase. The mRNA expression of receptor activator of nuclear factor-kappa-B ligand (rankl) and osteoprotegerin (opg) was enhanced by SFs from both patient categories. The mRNA expressions of nfat2 (nuclear factor of activated T cells 2) and oscar (osteoclast-associated receptor) were enhanced only by SFs from patients with OA, whereas the mRNA expressions of dap12 (DNAX-activating protein 12) and fcrγ (Fc receptor common gamma subunit) were not affected by either of the two SF types. Bone resorption induced by SFs was inhibited by addition of OPG. Antibodies neutralising interleukin (IL)-1α, IL-1β, soluble IL-6 receptor, IL-17, or tumour necrosis factor-α, when added to individual SFs, only occasionally decreased the bone-resorbing activity. The mRNA expression of alkaline phosphatase and osteocalcin was increased by SFs from patients with OA, whereas only osteocalcin mRNA was increased by SFs from patients with a loose prosthesis. Our findings demonstrate the presence of a factor (or factors) stimulating both osteoclast and osteoblast activities in SFs from patients with a loose joint prosthesis and periprosthetic osteolysis as well as in SFs from patients with OA. SF-induced bone resorption was dependent on activation of the RANKL/RANK/OPG pathway. The bone-resorbing activity could not be attributed solely to any of the known pro-inflammatory cytokines, well known to stimulate bone resorption, or to RANKL or prostaglandin E2 in SFs. The data indicate that SFs from patients with a loose prosthesis or with OA stimulate bone resorption and that SFs from patients with OA are more prone to enhance bone formation.
doi:10.1186/ar2127
PMCID: PMC1860076  PMID: 17316439

Results 1-16 (16)