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1.  Development of the “Highly Sensitive Dog” questionnaire to evaluate the personality dimension “Sensory Processing Sensitivity” in dogs 
PLoS ONE  2017;12(5):e0177616.
In humans, the personality dimension ‘sensory processing sensitivity (SPS)’, also referred to as “high sensitivity”, involves deeper processing of sensory information, which can be associated with physiological and behavioral overarousal. However, it has not been studied up to now whether this dimension also exists in other species. SPS can influence how people perceive the environment and how this affects them, thus a similar dimension in animals would be highly relevant with respect to animal welfare. We therefore explored whether SPS translates to dogs, one of the primary model species in personality research. A 32-item questionnaire to assess the “highly sensitive dog score” (HSD-s) was developed based on the “highly sensitive person” (HSP) questionnaire. A large-scale, international online survey was conducted, including the HSD questionnaire, as well as questions on fearfulness, neuroticism, “demographic” (e.g. dog sex, age, weight; age at adoption, etc.) and “human” factors (e.g. owner age, sex, profession, communication style, etc.), and the HSP questionnaire. Data were analyzed using linear mixed effect models with forward stepwise selection to test prediction of HSD-s by the above-mentioned factors, with country of residence and dog breed treated as random effects. A total of 3647 questionnaires were fully completed. HSD-, fearfulness, neuroticism and HSP-scores showed good internal consistencies, and HSD-s only moderately correlated with fearfulness and neuroticism scores, paralleling previous findings in humans. Intra- (N = 447) and inter-rater (N = 120) reliabilities were good. Demographic and human factors, including HSP score, explained only a small amount of the variance of HSD-s. A PCA analysis identified three subtraits of SPS, comparable to human findings. Overall, the measured personality dimension in dogs showed good internal consistency, partial independence from fearfulness and neuroticism, and good intra- and inter-rater reliability, indicating good construct validity of the HSD questionnaire. Human and demographic factors only marginally affected the HSD-s suggesting that, as hypothesized for human SPS, a genetic basis may underlie this dimension within the dog species.
doi:10.1371/journal.pone.0177616
PMCID: PMC5433715  PMID: 28520773
2.  The antifungal caspofungin increases fluoroquinolone activity against Staphylococcus aureus biofilms by inhibiting N-acetylglucosamine transferase 
Nature Communications  2016;7:13286.
Biofilms play a major role in Staphylococcus aureus pathogenicity but respond poorly to antibiotics. Here, we show that the antifungal caspofungin improves the activity of fluoroquinolones (moxifloxacin, delafloxacin) against S. aureus biofilms grown in vitro (96-well plates or catheters) and in vivo (murine model of implanted catheters). The degree of synergy among different clinical isolates is inversely proportional to the expression level of ica operon, the products of which synthesize poly-N-acetyl-glucosamine polymers, a major constituent of biofilm matrix. In vitro, caspofungin inhibits the activity of IcaA, which shares homology with β-1-3-glucan synthase (caspofungin's pharmacological target in fungi). This inhibition destructures the matrix, reduces the concentration and polymerization of exopolysaccharides in biofilms, and increases fluoroquinolone penetration inside biofilms. Our study identifies a bacterial target for caspofungin and indicates that IcaA inhibitors could potentially be useful in the treatment of biofilm-related infections.
Biofilms formed by Staphylococcus aureus are poorly responsive to antibiotics. Here, Siala et al. show that an antifungal drug (caspofungin) enhances the activity of fluoroquinolone antibiotics against S. aureus biofilms by inhibiting an enzyme involved in synthesis of the biofilm matrix.
doi:10.1038/ncomms13286
PMCID: PMC5097165  PMID: 27808087
3.  The Effect of Physical Therapy Treatment in Patients with Subjective Tinnitus: A Systematic Review 
Background: Tinnitus is a very common symptom that often causes distress and decreases the patient's quality of life. Apart from the well-known causes, tinnitus can in some cases be elicited by dysfunctions of the cervical spine or the temporomandibular joint (TMJ). To date however, it is unclear whether alleviation of these dysfunctions, by physical therapy treatment, also decreases the tinnitus complaints. Such physical therapy could be an interesting treatment option for patients that are now often left without treatment.
Objectives: The aim of this review was to investigate the current evidence regarding physical therapy treatment in patients with tinnitus.
Data sources: The online databases Pubmed, Web of Science, Cochrane, and Embase were searched up to March 2016. Two independent reviewers conducted the data extraction and methodological quality assessment.
Study eligibility criteria: Only randomized controlled trials and quasi-experimental trials were included in the review. Studies had to be written in English, French, Dutch, or German.
Participants and interventions: The included studies investigated the effect of physical therapy treatment modalities on tinnitus severity in patients suffering from subjective tinnitus.
Results: Six studies were included in this review, four investigating cervical spine treatment and two investigating TMJ treatment. These studies show positive effects of cervical spine treatment (manipulations, exercises, triggerpoint treatment) on tinnitus severity. Additionally, decrease in tinnitus severity and intensity was demonstrated after TMJ treatment, following splints, occlusal adjustments as well as jaw exercises.
Limitations: The risk of bias in the included studies was high, mainly due to lack of randomization, lack of blinding of subjects, therapists, and/or investigators. Additionally, risk of bias is present due to incomplete presentation of the data and selective reporting. A major issue of the reviewed papers is the heterogeneity of the included study populations, treatments and outcome measures, which inhibit data pooling and meta-analysis.
Conclusions: Despite the methodological issues in the included studies and the consequent low quality evidence, it is noteworthy that all included studies show positive treatment effects. Before recommendations can be made, these results need to be confirmed in larger, high quality studies, using unambiguous inclusion criteria, state-of-the-art treatment, and high quality outcome measures.
doi:10.3389/fnins.2016.00545
PMCID: PMC5126072  PMID: 27965530
somatic tinnitus; physical therapy; treatment; cervical spine; temporomandibular joint disorders
4.  Fungal β-1,3-Glucan Increases Ofloxacin Tolerance of Escherichia coli in a Polymicrobial E. coli/Candida albicans Biofilm 
In the past, biofilm-related research has focused mainly on axenic biofilms. However, in nature, biofilms are often composed of multiple species, and the resulting polymicrobial interactions influence industrially and clinically relevant outcomes such as performance and drug resistance. In this study, we show that Escherichia coli does not affect Candida albicans tolerance to amphotericin or caspofungin in an E. coli/C. albicans biofilm. In contrast, ofloxacin tolerance of E. coli is significantly increased in a polymicrobial E. coli/C. albicans biofilm compared to its tolerance in an axenic E. coli biofilm. The increased ofloxacin tolerance of E. coli is mainly biofilm specific, as ofloxacin tolerance of E. coli is less pronounced in polymicrobial E. coli/C. albicans planktonic cultures. Moreover, we found that ofloxacin tolerance of E. coli decreased significantly when E. coli/C. albicans biofilms were treated with matrix-degrading enzymes such as the β-1,3-glucan-degrading enzyme lyticase. In line with a role for β-1,3-glucan in mediating ofloxacin tolerance of E. coli in a biofilm, we found that ofloxacin tolerance of E. coli increased even more in E. coli/C. albicans biofilms consisting of a high-β-1,3-glucan-producing C. albicans mutant. In addition, exogenous addition of laminarin, a polysaccharide composed mainly of poly-β-1,3-glucan, to an E. coli biofilm also resulted in increased ofloxacin tolerance. All these data indicate that β-1,3-glucan from C. albicans increases ofloxacin tolerance of E. coli in an E. coli/C. albicans biofilm.
doi:10.1128/AAC.04650-14
PMCID: PMC4432160  PMID: 25753645
5.  Synergistic Activity of the Plant Defensin HsAFP1 and Caspofungin against Candida albicans Biofilms and Planktonic Cultures 
PLoS ONE  2015;10(8):e0132701.
Plant defensins are small, cysteine-rich peptides with antifungal activity against a broad range of yeast and fungi. In this study we investigated the antibiofilm activity of a plant defensin from coral bells (Heuchera sanguinea), i.e. HsAFP1. To this end, HsAFP1 was heterologously produced using Pichia pastoris as a host. The recombinant peptide rHsAFP1 showed a similar antifungal activity against the plant pathogen Fusarium culmorum as native HsAFP1 purified from seeds. NMR analysis revealed that rHsAFP1 consists of an α-helix and a triple-stranded antiparallel β-sheet stabilised by four intramolecular disulfide bonds. We found that rHsAFP1 can inhibit growth of the human pathogen Candida albicans as well as prevent C. albicans biofilm formation with a BIC50 (i.e. the minimum rHsAFP1 concentration required to inhibit biofilm formation by 50% as compared to control treatment) of 11.00 ± 1.70 μM. As such, this is the first report of a plant defensin exhibiting inhibitory activity against fungal biofilms. We further analysed the potential of rHsAFP1 to increase the activity of the conventional antimycotics caspofungin and amphotericin B towards C. albicans. Synergistic effects were observed between rHsAFP1 and these compounds against both planktonic C. albicans cells and biofilms. Most notably, concentrations of rHsAFP1 as low as 0.53 μM resulted in a synergistic activity with caspofungin against pre-grown C. albicans biofilms. rHsAFP1 was found non-toxic towards human HepG2 cells up to 40 μM, thereby supporting the lack of a general cytotoxic activity as previously reported for HsAFP1. A structure-function study with 24-mer synthetic peptides spanning the entire HsAFP1 sequence revealed the importance of the γ-core and its adjacent regions for HsAFP1 antibiofilm activity. These findings point towards broad applications of rHsAFP1 and its derivatives in the field of antifungal and antibiofilm drug development.
doi:10.1371/journal.pone.0132701
PMCID: PMC4527839  PMID: 26248029
6.  In vitro retention of a new thermoplastic titratable mandibular advancement device 
F1000Research  2015;4:56.
Oral appliance (OA) therapy with a mandibular advancement device (OAm) is a non-invasive, alternative approach to maintaining upper airway patency. The main requirement for an OAm to be effective is the adequate retention on the teeth while the patient is asleep. We evaluated the retentive forces of a new low-cost, customizable, titratable, thermoplastic OAm (BluePro ®; BlueSom, France). Dental impressions and casts were made for one patient with complete upper and lower dental arches including the third molars and class II bite proportions. A setup based on Frasaco ANA-4 models was also used. Two protrusive positions of the mandible were investigated: 3 mm and 8 mm, representing respectively 25% and 65% of the maximal protrusion. The forces required to remove the BluePro ® device from the carriers were recorded continuously over 730 cycles (=365 days, twice a day) to simulate 1 year of clinical use. At 8 mm protrusion the BluePro ® device showed retentive forces of ~27N. There was a slight but non-significant decrease in retentive forces in the tests on the epoxified carriers which was not found on the ANA-4 carriers. There were no significant differences between the carriers as a function of protrusion. The BluePro ® device tested in the present study possesses sufficient retention forces to resist initial jaw opening forces and full mouth opening forces estimated to be ~20N. It could therefore broaden the indications for use of thermoplastic OAms. It could provide a temporary OAm while a custom-made OAm is being manufactured or repaired. Patients could be provided with a low-cost try-out device capable of reliable titration, providing an indication of effectiveness and of patient acceptance of an OAm, although the effect of device shape and size on therapeutic outcome is not yet known. Finally it could provide an affordable OAm solution in resource-restricted healthcare settings.
doi:10.12688/f1000research.6061.1
PMCID: PMC4392831  PMID: 25901281
mandibular advancement device; obstructive sleep apnoea; oral appliance; retention force
7.  Experience a conflict—either consciously or not (commentary on Desender, Van Opstal, and Van den Bussche, 2014) 
doi:10.3389/fpsyg.2015.00179
PMCID: PMC4333772  PMID: 25745411
conflict adaptation; cognitive control; response conflict; consciousness; conflict monitoring
8.  The Congruency Sequence Effect 3.0: A Critical Test of Conflict Adaptation 
PLoS ONE  2014;9(10):e110462.
Over the last two decades, the congruency sequence effect (CSE) –the finding of a reduced congruency effect following incongruent trials in conflict tasks– has played a central role in advancing research on cognitive control. According to the influential conflict-monitoring account, the CSE reflects adjustments in selective attention that enhance task focus when needed, often termed conflict adaptation. However, this dominant interpretation of the CSE has been called into question by several alternative accounts that stress the role of episodic memory processes: feature binding and (stimulus-response) contingency learning. To evaluate the notion of conflict adaptation in accounting for the CSE, we construed versions of three widely used experimental paradigms (the colour-word Stroop, picture-word Stroop and flanker task) that effectively control for feature binding and contingency learning. Results revealed that a CSE can emerge in all three tasks. This strongly suggests a contribution of attentional control to the CSE and highlights the potential of these unprecedentedly clean paradigms for further examining cognitive control.
doi:10.1371/journal.pone.0110462
PMCID: PMC4207697  PMID: 25340396
9.  A promising concept of combination therapy for positional obstructive sleep apnea 
Purpose
The objective of this randomized controlled trial was to assess the additional effect of a chest-worn sleep position trainer (SPT) in patients with residual supine-dependent obstructive sleep apnea (sdOSA) under mandibular advancement device (MAD) therapy.
Methods
Baseline and follow-up polysomnography with MAD were performed. Twenty patients with sdOSA under MAD therapy underwent two consecutive randomized polysomnographies: one with SPT and one with combination of SPT + MAD. Data are presented as median (quartile 1, quartile 3).
Results
The SPT reduced the time spent in supine sleeping position compared to baseline and MAD therapy. Both MAD and SPT were individually effective in reducing the overall apnea/hypopnea index (AHI) significantly when compared to baseline from 20.8 (15.1; 33.6)/h at baseline to 11.0 (6.7; 13.8)/h and to 11.1 (3.5; 17.7)/h with MAD or SPT, respectively. The combination of SPT + MAD further reduced the overall AHI to 5.7 (3.6; 7.4), which was significantly lower than with MAD alone (p < 0.001) and SPT alone (p < 0.008), respectively.
Conclusions
The results of this study indicate that combination of SPT + MAD leads to a higher therapeutic efficacy in patients with sdOSA under MAD therapy when compared to one of the treatment modalities alone.
doi:10.1007/s11325-014-1068-8
PMCID: PMC4873543  PMID: 25335642
Obstructive sleep apnea/hypopnea syndrome; Sleep-disordered breathing; Supine-dependent
10.  What determines the specificity of conflict adaptation? A review, critical analysis, and proposed synthesis 
Frontiers in Psychology  2014;5:1134.
Over the past decade, many cognitive control researchers have studied to what extent adaptations to conflict are domain-general or rather specific, mostly by testing whether or not the congruency sequence effect (CSE) transfers across different conditions (e.g., conflict type, task sets, contexts, et cetera). The CSE refers to the observation that congruency effects in conflict tasks tend to be reduced following incongruent relative to following congruent trials, and is considered a prime measure of cognitive control. By investigating the transfer of this CSE across different conflict types, tasks, or contexts, researchers made several inferences about the scope of cognitive control. This method gained popularity during the last few years, spawning an interesting, yet seemingly inconsistent set of results. Consequently, these observations gave rise to a number of equally divergent theories about the determinants and scope of conflict adaptation. In this review, we offer a systematic overview of these past studies, as well as an evaluation of the theories that have been put forward to account for the results. Finally, we propose an integration of these various theoretical views in a unifying framework that centers on the role of context (dis)similarity. This framework allows us to generate new predictions about the relation between task or context similarity and the scope of cognitive control. Specifically, while most theories imply that increasing contextual differences will result in reduced transfer of the CSE, we propose that context similarity and across-context control follow a U-shaped function instead.
doi:10.3389/fpsyg.2014.01134
PMCID: PMC4189611  PMID: 25339930
cognitive control; congruency sequence effect; task structure; associative learning
11.  The heterogeneous world of congruency sequence effects: an update 
Frontiers in Psychology  2014;5:1001.
Congruency sequence effects (CSEs) refer to the observation that congruency effects in conflict tasks are typically smaller following incongruent compared to following congruent trials. This measure has long been thought to provide a unique window into top-down attentional adjustments and their underlying brain mechanisms. According to the renowned conflict monitoring theory, CSEs reflect enhanced selective attention following conflict detection. Still, alternative accounts suggested that bottom-up associative learning suffices to explain the pattern of reaction times and error rates. A couple of years ago, a review by Egner (2007) pitted these two rivalry accounts against each other, concluding that both conflict adaptation and feature integration contribute to the CSE. Since then, a wealth of studies has further debated this issue, and two additional accounts have been proposed, offering intriguing alternative explanations. Contingency learning accounts put forward that predictive relationships between stimuli and responses drive the CSE, whereas the repetition expectancy hypothesis suggests that top-down, expectancy-driven control adjustments affect the CSE. In the present paper, we build further on the previous review (Egner, 2007) by summarizing and integrating recent behavioral and neurophysiological studies on the CSE. In doing so, we evaluate the relative contribution and theoretical value of the different attentional and memory-based accounts. Moreover, we review how all of these influences can be experimentally isolated, and discuss designs and procedures that can critically judge between them.
doi:10.3389/fpsyg.2014.01001
PMCID: PMC4158803  PMID: 25250005
cognitive control; congruency sequence effect; contingency learning; feature integration; conflict adaptation; repetition expectancy
12.  Conscious and unconscious context-specific cognitive control 
A key feature of the human cognitive system is its ability to deal with an ever-changing environment. One prototypical example is the observation that we adjust our information processing depending on the conflict-likelihood of a context (context-specific proportion congruency effect, CSPC, Crump etal., 2006). Recently, empirical studies started to question the role of consciousness in these strategic adaptation processes (for reviews, see Desender and Van den Bussche, 2012; Kunde etal., 2012). However, these studies have not yielded unequivocal results (e.g., Kunde, 2003; Heinemann etal., 2009; Van Gaal etal., 2010a; Desender etal., 2013; Reuss etal., 2014). In the present study, we aim at replicating the experiment of Heinemann etal. (2009) in which the proportion of congruent and incongruent trials between different contexts was varied in a masked priming task. Their results showed a reduction of the congruency effect for the context with more incongruent trials. However, this CSPC effect was only observed when the prime–target conflict was conscious, rather than unconscious, suggesting that context-specific control operates within the boundaries of awareness. Our replication attempt however contrasts these findings. In the first experiment we found no evidence for a CSPC effect in reaction times (RTs), neither in the conscious nor in the unconscious condition. The error rate analysis did show a CSPC effect, albeit not one modulated by consciousness. In the second experiment we found an overall CSPC effect in RTs, independent of consciousness. The error rates did not display a CSPC pattern. These mixed results seem to nuance the findings of Heinemann etal. (2009) and highlight the need for replication studies in psychology research.
doi:10.3389/fpsyg.2014.00539
PMCID: PMC4045158  PMID: 24926275
masked priming; consciousness; cognitive control; CSPC effect; context
13.  Affective Modulation of Cognitive Control is Determined by Performance-Contingency and Mediated by Ventromedial Prefrontal and Cingulate Cortex 
The Journal of Neuroscience  2013;33(43):16961-16970.
Cognitive control requires a fine balance between stability, the protection of an on-going task-set, and flexibility, the ability to update a task-set in line with changing contingencies. It is thought that emotional processing modulates this balance, but results have been equivocal regarding the direction of this modulation. Here, we tested the hypothesis that a crucial determinant of this modulation is whether affective stimuli represent performance-contingent or task-irrelevant signals. Combining functional magnetic resonance imaging with a conflict task-switching paradigm, we contrasted the effects of presenting negative- and positive-valence pictures on the stability/flexibility trade-off in humans, depending on whether picture presentation was contingent on behavioral performance. Both the behavioral and neural expressions of cognitive control were modulated by stimulus valence and performance contingency: in the performance-contingent condition, cognitive flexibility was enhanced following positive pictures, whereas in the nonperformance-contingent condition, positive stimuli promoted cognitive stability. The imaging data showed that, as anticipated, the stability/flexibility trade-off per se was reflected in differential recruitment of dorsolateral frontoparietal and striatal regions. In contrast, the affective modulation of stability/flexibility shifts was mirrored, unexpectedly, by neural responses in ventromedial prefrontal and posterior cingulate cortices, core nodes of the “default mode” network. Our results demonstrate that the affective modulation of cognitive control depends on the performance contingency of the affect-inducing stimuli, and they document medial default mode regions to mediate the flexibility-promoting effects of performance-contingent positive affect, thus extending recent work that recasts these regions as serving a key role in on-task control processes.
doi:10.1523/JNEUROSCI.1208-13.2013
PMCID: PMC3807025  PMID: 24155301
14.  Epstein-Barr Virus Large Tegument Protein BPLF1 Contributes to Innate Immune Evasion through Interference with Toll-Like Receptor Signaling 
PLoS Pathogens  2014;10(2):e1003960.
Viral infection triggers an early host response through activation of pattern recognition receptors, including Toll-like receptors (TLR). TLR signaling cascades induce production of type I interferons and proinflammatory cytokines involved in establishing an anti-viral state as well as in orchestrating ensuing adaptive immunity. To allow infection, replication, and persistence, (herpes)viruses employ ingenious strategies to evade host immunity. The human gamma-herpesvirus Epstein-Barr virus (EBV) is a large, enveloped DNA virus persistently carried by more than 90% of adults worldwide. It is the causative agent of infectious mononucleosis and is associated with several malignant tumors. EBV activates TLRs, including TLR2, TLR3, and TLR9. Interestingly, both the expression of and signaling by TLRs is attenuated during productive EBV infection. Ubiquitination plays an important role in regulating TLR signaling and is controlled by ubiquitin ligases and deubiquitinases (DUBs). The EBV genome encodes three proteins reported to exert in vitro deubiquitinase activity. Using active site-directed probes, we show that one of these putative DUBs, the conserved herpesvirus large tegument protein BPLF1, acts as a functional DUB in EBV-producing B cells. The BPLF1 enzyme is expressed during the late phase of lytic EBV infection and is incorporated into viral particles. The N-terminal part of the large BPLF1 protein contains the catalytic site for DUB activity and suppresses TLR-mediated activation of NF-κB at, or downstream of, the TRAF6 signaling intermediate. A catalytically inactive mutant of this EBV protein did not reduce NF-κB activation, indicating that DUB activity is essential for attenuating TLR signal transduction. Our combined results show that EBV employs deubiquitination of signaling intermediates in the TLR cascade as a mechanism to counteract innate anti-viral immunity of infected hosts.
Author Summary
Epstein-Barr virus (EBV) is a human herpesvirus that persistently infects >90% of adults worldwide. One factor underlying the ability of EBV to establish such widespread and lifelong infections is its capacity to escape elimination by the human immune system. Among the first lines of defense against viral infection is the human Toll-like receptor (TLR) system. These receptors can detect the presence of viruses and initiate an intracellular protein signaling cascade that leads to the expression of immune response genes. The activation status of many proteins in this signaling cascade is regulated by the addition of ubiquitin tags. EBV has previously been reported to encode enzymes, called deubiquitinases (DUBs), which are capable of removing such ubiquitin tags from substrate proteins. In our study, we found that one of these enzymes, BPLF1, functions as an active DUB during EBV production in infected cells before being packaged into newly produced viral particles. Furthermore, our study provides insight into the way in which EBV can subvert the human immune response, as we show that BPLF1 can remove ubiquitin tags from proteins in the TLR signaling cascade. This inhibits TLR signaling and decreases the expression of immune response genes.
doi:10.1371/journal.ppat.1003960
PMCID: PMC3930590  PMID: 24586164
15.  Modified Titanium Surface-Mediated Effects on Human Bone Marrow Stromal Cell Response 
Materials  2013;6(12):5533-5548.
Surface modification of titanium implants is used to enhance osseointegration. The study objective was to evaluate five modified titanium surfaces in terms of cytocompatibility and pro-osteogenic/pro-angiogenic properties for human mesenchymal stromal cells: amorphous microporous silica (AMS), bone morphogenetic protein-2 immobilized on AMS (AMS + BMP), bio-active glass (BAG) and two titanium coatings with different porosity (T1; T2). Four surfaces served as controls: uncoated Ti (Ti), Ti functionalized with BMP-2 (Ti + BMP), Ti surface with a thickened titanium oxide layer (TiO2) and a tissue culture polystyrene surface (TCPS). The proliferation of eGFP-fLuc (enhanced green fluorescence protein-firefly luciferase) transfected cells was tracked non-invasively by fluorescence microscopy and bio-luminescence imaging. The implant surface-mediated effects on cell differentiation potential was tracked by determination of osteogenic and angiogenic parameters [alkaline phosphatase (ALP); osteocalcin (OC); osteoprotegerin (OPG); vascular endothelial growth factor-A (VEGF-A)]. Unrestrained cell proliferation was observed on (un)functionalized Ti and AMS surfaces, whereas BAG and porous titanium coatings T1 and T2 did not support cell proliferation. An important pro-osteogenic and pro-angiogenic potential of the AMS + BMP surface was observed. In contrast, coating the Ti surface with BMP did not affect the osteogenic differentiation of the progenitor cells. A significantly slower BMP-2 release from AMS compared to Ti supports these findings. In the unfunctionalized state, Ti was found to be superior to AMS in terms of OPG and VEGF-A production. AMS is suggested to be a promising implant coating material for bioactive agents delivery.
doi:10.3390/ma6125533
PMCID: PMC5452737
titanium; surface coating; human bone marrow stromal cells; in vitro cytocompatibility; osteogenic differentiation; osseointegration
16.  Punishment Sensitivity Predicts the Impact of Punishment on Cognitive Control 
PLoS ONE  2013;8(9):e74106.
Cognitive control theories predict enhanced conflict adaptation after punishment. However, no such effect was found in previous work. In the present study, we demonstrate in a flanker task how behavioural adjustments following punishment signals are highly dependent on punishment sensitivity (as measured by the Behavioural Inhibition System (BIS) scale): Whereas low punishment-sensitive participants do show increased conflict adaptation after punishment, high punishment-sensitive participants show no such modulation. Interestingly, participants with a high punishment-sensitivity showed an overall reaction time increase after punishments. Our results stress the role of individual differences in explaining motivational modulations of cognitive control.
doi:10.1371/journal.pone.0074106
PMCID: PMC3772886  PMID: 24058520
17.  Retention of mandibular advancement devices in the treatment of obstructive sleep apnea: an in vitro pilot study 
Purpose
In order for a mandibular advancement device (MAD) to be efficacious, it must remain seated on the teeth during sleep. Quantitative data on the retentive characteristics of MADs are currently unavailable. The present pilot study is the first to describe an in vitro setup testing the retentive characteristics of different monobloc MADs.
Methods
A hydraulic cyclic test machine was used with MADs seated on dental casts to measure retention forces upon removal of the MADs. A custom-made monobloc (CM-mono), a thermoplastic monobloc (TP-mono), and a thermoplastic duobloc (TP-duo) configured as a monobloc were tested. Two protrusions were investigated, representing 25 and 65 % of the maximal protrusion. The effects of the type of MAD, duration of the test, and amount of protrusion on removal forces were measured.
Results
The measured removal forces of all three MADs tested differed significantly, with the TP-duo showing the highest values (P < 0.0001). The effects of wear due to the repetitive cyclic loading became obvious by the production of wear particles in all MADs tested. However, only the TP-duo showed a significant reduction in time in removal forces for both protrusion positions (P < 0.0001; P = 0.0011). The effect of the amount of protrusion on the removal forces differed significantly between all three MADs tested (P = 0.0074).
Conclusions
This in vitro pilot study reveals significant differences in retention forces for the MADs tested. The findings are consistent with clinical effects of nightly loss of MADs as reported in the literature and are within the range of reported physiological mouth-opening forces. Future research is needed to determine the key design features of MADs that explain these differences.
doi:10.1007/s11325-013-0886-4
PMCID: PMC4006122  PMID: 23963782
Obstructive sleep apnea; Oral appliance design; Therapy; Retention; Oral appliance
18.  Interactions between Genetic Variants in AMH and AMHR2 May Modify Age at Natural Menopause 
PLoS ONE  2013;8(3):e59819.
The onset of menopause has important implications on women’s fertility and health. We previously identified genetic variants in genes involved in initial follicle recruitment as potential modifiers of age at natural menopause. The objective of this study was to extend our previous study, by searching for pairwise interactions between tagging single nucleotide polymorphisms (tSNPs) in the 5 genes previously selected (AMH, AMHR2, BMP15, FOXL2, GDF9). We performed a cross-sectional study among 3445 women with a natural menopause participating in the Prospect-EPIC study, a population-based prospective cohort study, initiated between 1993 and 1997. Based on the model-based multifactor dimensionality reduction (MB-MDR) test with a permutation-based maxT correction for multiple testing, we found a statistically significant interaction between rs10407022 in AMH and rs11170547 in AMHR2 (p = 0.019) associated with age at natural menopause. Rs10407022 did not have a statistically significant main effect. However, rs10407022 is an eQTL SNP that has been shown to influence mRNA expression levels in lymphoblastoid cell lines. This study provides additional insights into the genetic background of age at natural menopause and suggests a role of the AMH signaling pathway in the onset of natural menopause. However, these results remain suggestive and replication by independent studies is necessary.
doi:10.1371/journal.pone.0059819
PMCID: PMC3609726  PMID: 23544102
19.  Spontaneous arthritis and ankylosis in male DBA/1 mice: further evidence for a role of behavioral factors in “stress-induced arthritis” 
Background
Ageing male DBA/1 mice spontaneously develop arthritis in the hind paws. We and others have demonstrated that this model shares striking features with human spondyloarthritis, in particular entheseal involvement, progressive ankylosis but also dactylitis. Here, we report on our recent experience with this model highlighting how changes in the animal facility affect the development of the disease.
Findings
Ageing male DBA/1 mice from different litters were caged together (6 mice per cage) at the age of 10 weeks. The mice were checked twice a week for clinical signs of arthritis. Disease severity was assessed in further detail post-mortem by scoring for histomorphological characteristics. DBA/1 mice spontaneously develop macroscopically detectable arthritis, presenting as joint swelling or toe stiffness. Standard settings with open cages lead to an almost 100% incidence by the age of 26 weeks. The introduction of larger cages and filter tops reducing exposure to other cages dramatically affected incidence. Other negative factors include excess bedding material reducing the impact of walking and running. Switching back to the original conditions resulted again in a high incidence, further optimized by sensory exposure to female mice. We also showed that the related DBA/2 strain is sensitive to the disease.
Conclusions
Changing environmental factors in the housing conditions of DBA/1 mice severely affects the spontaneous development of arthritis. This points out that the model is very sensitive to external stress and sensory factors that are likely affecting the behavior of the male mice and that the model needs to be optimized in different situations.
doi:10.1186/1480-9222-14-10
PMCID: PMC3537550  PMID: 23253472
Spondyloarthritis; Spontaneous arthritis; Behavioral factors; Ankylosis
20.  Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European Prospective Investigation into Cancer and Nutrition 
British Journal of Cancer  2011;105(9):1436-1442.
Background:
It is well established that parity and use of oral contraceptives reduce the risk of ovarian cancer, but the associations with other reproductive variables are less clear.
Methods:
We examined the associations of oral contraceptive use and reproductive factors with ovarian cancer risk in the European Prospective Investigation into Cancer and Nutrition. Among 327 396 eligible women, 878 developed ovarian cancer over an average of 9 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models stratified by centre and age, and adjusted for smoking status, body mass index, unilateral ovariectomy, simple hysterectomy, menopausal hormone therapy, and mutually adjusted for age at menarche, age at menopause, number of full-term pregnancies and duration of oral contraceptive use.
Results:
Women who used oral contraceptives for 10 or more years had a significant 45% (HR, 0.55; 95% CI, 0.41–0.75) lower risk compared with users of 1 year or less (P-trend, <0.01). Compared with nulliparous women, parous women had a 29% (HR, 0.71; 95% CI, 0.59–0.87) lower risk, with an 8% reduction in risk for each additional pregnancy. A high age at menopause was associated with a higher risk of ovarian cancer (>52 vs ⩽45 years: HR, 1.46; 95% CI, 1.06–1.99; P-trend, 0.02). Age at menarche, age at first full-term pregnancy, incomplete pregnancies and breastfeeding were not associated with risk.
Conclusion:
This study shows a strong protective association of oral contraceptives and parity with ovarian cancer risk, a higher risk with a late age at menopause, and no association with other reproductive factors.
doi:10.1038/bjc.2011.371
PMCID: PMC3241548  PMID: 21915124
reproductive history; oral contraceptive use; ovarian cancer; cohort study
21.  The role of bone morphogenetic proteins in ankylosing spondylitis 
Ankylosing spondylitis (AS), the best-known form of spondyloarthritis (SpA), is a remodelling arthritis characterized by chronic inflammation and bone formation. Ankylosis of the axial skeleton and sacroiliac joints leads to an impairment of spinal mobility, progressive spinal fusion and an increased risk of spinal fractures. The nature of the relationship between inflammation and new bone formation in AS has been controversial and questions remain as to whether there is a direct relationship between inflammation and new bone formation. Like others, we have hypothesized that the molecular pathways underlying ankylosis recapitulate the process of endochondral bone formation and that bone morphogenetic proteins (BMPs) play a key role in this process in AS. Furthermore, we discuss the entheseal stress hypothesis, which proposes that inflammation and ankylosis are linked but largely independent processes, and consider observations from mouse models and other human diseases which also imply that biomechanical factors contribute to the pathogenesis of AS. As current therapeutics, such as tumour necrosis factor inhibitors do not impede disease progression and ankylosis in AS, it is the pathways discussed in this review that are the now the focus for the identification of future drug targets.
doi:10.1177/1759720X12444175
PMCID: PMC3403253  PMID: 22859928
ankylosing spondylitis; ankylosis; arthritis; bone morphogenetic proteins; spondyloarthritis
22.  Search for heavy neutrinos and right-handed W bosons in events with two leptons and jets in pp collisions at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\sqrt{s} = 7~\mathrm{TeV}$\end{document} with the ATLAS detector 
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This letter reports on a search for hypothetical heavy neutrinos, N, and right-handed gauge bosons, WR, in events with high transverse momentum objects which include two reconstructed leptons and at least one hadronic jet. The results were obtained from data corresponding to an integrated luminosity of 2.1 fb−1 collected in proton–proton collisions at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\sqrt{s}=7~\mathrm{TeV}$\end{document} with the ATLAS detector at the CERN Large Hadron Collider. No excess above the Standard Model background expectation is observed. Excluded mass regions for Majorana and Dirac neutrinos are presented using two approaches for interactions that violate lepton and lepton-flavor numbers. One approach uses an effective operator framework, the other approach is guided by the Left–Right Symmetric Model. The results described in this letter represent the most stringent limits to date on the masses of heavy neutrinos and WR bosons obtained in direct searches.
doi:10.1140/epjc/s10052-012-2056-4
PMCID: PMC4370896  PMID: 25814841
23.  Measurement of τ polarization in W→τν decays with the ATLAS detector in pp collisions at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\sqrt{s} =7~\mathrm{TeV}$\end{document} 
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In this paper, a measurement of τ polarization in W→τν decays is presented. It is measured from the energies of the decay products in hadronic τ decays with a single final state charged particle. The data, corresponding to an integrated luminosity of 24 pb−1, were collected by the ATLAS experiment at the Large Hadron Collider in 2010. The measured value of the τ polarization is \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}${P_{\tau}}= -1.06 \pm0.04\ (\mathrm{stat})\;^{+0.05}_{-0.07}\ (\mathrm{syst})$\end{document}, in agreement with the Standard Model prediction, and is consistent with a physically allowed 95 % CL interval [−1,−0.91]. Measurements of τ polarization have not previously been made at hadron colliders.
doi:10.1140/epjc/s10052-012-2062-6
PMCID: PMC4371045  PMID: 25814842
24.  Measurement of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$t\bar{t}$\end{document} production with a veto on additional central jet activity in pp collisions at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\sqrt{s}=7$\end{document} TeV using the ATLAS detector 
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A measurement of the jet activity in \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$t\bar{t}$\end{document} events produced in proton–proton collisions at a centre-of-mass energy of 7 TeV is presented, using 2.05 fb−1 of integrated luminosity collected by the ATLAS detector at the Large Hadron Collider. The \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$t\bar{t}$\end{document} events are selected in the dilepton decay channel with two identified b-jets from the top quark decays. Events are vetoed if they contain an additional jet with transverse momentum above a threshold in a central rapidity interval. The fraction of events surviving the jet veto is presented as a function of this threshold for four different central rapidity interval definitions. An alternate measurement is also performed, in which events are vetoed if the scalar transverse momentum sum of the additional jets in each rapidity interval is above a threshold. In both measurements, the data are corrected for detector effects and compared to the theoretical models implemented in MC@NLO, Powheg, Alpgen and Sherpa. The experimental uncertainties are often smaller than the spread of theoretical predictions, allowing deviations between data and theory to be observed in some regions of phase space.
doi:10.1140/epjc/s10052-012-2043-9
PMCID: PMC4370895  PMID: 25814839
25.  Measurement of the top quark mass with the template method in the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$t\bar{t} \to\mathrm{lepton}+\mathrm{jets}$\end{document} channel using ATLAS data 
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The top quark mass has been measured using the template method in the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$t\bar{t}\to\mathrm{lepton}+\mathrm{jets}$\end{document} channel based on data recorded in 2011 with the ATLAS detector at the LHC. The data were taken at a proton-proton centre-of-mass energy of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\sqrt{s}=7\ \mbox{TeV}$\end{document} and correspond to an integrated luminosity of 1.04 fb−1. The analyses in the e+jets and μ+jets decay channels yield consistent results. The top quark mass is measured to be mtop=174.5±0.6stat±2.3syst GeV.
doi:10.1140/epjc/s10052-012-2046-6
PMCID: PMC4371085  PMID: 25814840

Results 1-25 (35)