28 research outputs found
The Role of Expectancy Violation in Extinction Learning: A Two-Day Online Fear Conditioning Study
No full text[Background] Exposure therapy is at the core of the treatment of pathological anxiety. While the inhibitory learning model proposes a framework for the mechanisms underlying exposure therapy, in particular expectancy violation, causal evidence for its assumptions remains elusive. Therefore, the aim of the current study was to provide evidence for the influence of expectancy violation on extinction retention by manipulating the magnitude of expectancy violation during extinction learning. [Method] In total, 101 individuals completed a web-based fear conditioning protocol, consisting of a fear acquisition and extinction phase, as well as a spontaneous recovery and fear reinstatement test 24h later. To experimentally manipulate expectancy violation, participants were presented only with states of the conditioned stimulus that either weakly or strongly predicted the aversive outcome. Consequently, the absence of any aversive outcomes in the extinction phase resulted in low or high expectancy violation, respectively. [Results] We found successful fear acquisition and manipulation of expectancy violation, which was associated with reduced threat ratings for the high compared to the low expectancy violation group directly after extinction learning. On Day 2, inhibitory CS-noUS associations could be retrieved for expectancy ratings, whereas there were no substantial group differences for threat ratings. [Conclusion] These findings indicate that the magnitude of expectancy violation is related to the retrieval of conscious threat expectancies, but it is unclear how these changes translate to affective components (i.e., threat ratings) of the fear response and to symptoms of pathological anxiety
How Particle Deformability Influences the Surfactant Distribution in Colloidal Polymer Films
No full textThe distribution of surfactants in waterborne colloidal
polymer
films is of significant interest for scientific understanding and
defining surface properties in applications including pressure-sensitive
adhesives and coatings. Because of negative effects on appearance,
wetting, and adhesion, it is desirable to prevent surfactant accumulation
at film surfaces. The effect of particle deformation on surfactant
migration during film formation was previously investigated by Gromer
et al. through simulations, but experimental investigations are lacking.
Here, we study deuterium-labeled sodium dodecyl sulfate surfactant
in a poly(butyl acrylate) latex model system. The particle deformability
was varied via cross-linking of the intraparticle polymer chains by
differing extents. The cross-linker concentration varied from 0 to
35 mol % in the copolymer, leading to a transition from viscoelastic
to elastic. Ion beam analysis was used to probe the dry films and
provide information on the near-surface depth distribution of surfactant.
Films of nondeformable particles, containing the highest concentration
of cross-linker, show no surfactant accumulation at the top surface.
Films from particles partially deformed by capillary action show a
distinct surfactant surface layer (ca. 150 nm thick). Films of coalesced
particles, containing little or no cross-linker, show a very small
amount of surfactant on the surface (ca. 20 nm thick). The observed
results are explained by considering the effect of cross-linking on
rubber elasticity and applying the viscous particle deformation model
by Gromer et al. to elastically deformed particles. We find that partially
deformed particles allow surfactant transport to the surface during
film formation, whereas there is far less transport when skin formation
acts as a barrier. With elastic particles, the surfactant is carried
in the water phase as it falls beneath the surface of packed particles.
The ability to exert control over surfactant distribution in waterborne
colloidal films will aid in the design of new high-performance adhesives
and coatings
Interactions of Methylene Blue with Human Disulfide Reductases and Their Orthologues from Plasmodium falciparum
No full textMethylene blue (MB) has experienced a renaissance mainly as a component of drug combinations against Plasmodium falciparum malaria. Here, we report biochemically relevant pharmacological data on MB such as rate constants for the uncatalyzed reaction of MB at pH 7.4 with cellular reductants like NAD(P)H (k 4 M1 s1), thioredoxins (k 8.5 to 26 M1 s1), dihydrolipoamide (k 53 M1 s1), and slowly reacting glutathione. As the disulfide reductases are prominent targets of MB, optical tests for enzymes reducing MB at the expense of NAD(P)H under aerobic conditions were developed. The product leucomethylene blue (leucoMB) is auto-oxidized back to MB at pH 7 but can be stabilized by enzymes at pH 5.0, which makes this colorless compound an interesting drug candidate. MB was found to be an inhibitor and/or a redox-cycling substrate of mammalian and P. falciparum disulfide reductases, with the kcat values ranging from 0.03 s 1 to 10 s1 at 25°C. Kinetic spectroscopy of mutagenized glutathione reductase indicates that MB reduction is conducted by enzyme-bound reduced flavin rather than by the active-site dithiol Cys58/Cys63. The enzyme-catalyzed reduction of MB and subsequent auto-oxidation of the product leucoMB mean that MB is a redox-cycling agent which produces H2O2 at the expense of O2 and of NAD(P)H in each cycle, turning the antioxidant disulfide reductases into pro-oxidant enzymes. Thi
The bacterial redox signaller pyocyanin as an antiplasmodial agent: comparisons with its thioanalog methylene blue
No full textThe quorum sensor and signalling molecule pyocyanin (PYO) contributes significantly to the pathophysiology of Pseudomonas aeruginosa infections. Comparison to phenothiazine drugs suggests that the antimalarial compound methylene blue (MB) can be regarded as a sulfur analog of PYO. This working hypothesis would explain why the synthetic drug MB behaves as a compound shaped in biological evolution. Here we report on redox−associated biological and biochemical properties of PYO in direct comparison to its synthetic analog MB. We quantitatively describe the reactivity of both compounds toward cellular reductants, the reactivity of their reduced leuco−forms towards O2, and their interactions with FAD−containing disulfide reductases. Furthermore, the interaction of PYO with human glutathione reductase was studied in structural detail by x−ray crystallography, showing that a single PYO molecule binds to the intersubunit cavity of the enzyme. Like MB, also PYO was also found to be active against blood schizonts of the malaria parasite P. falciparum in vitro. Furthermore, both compounds were active against the disease transmitting gametocyte forms of the parasites, which was systematically studied in vitro. As shown for mice, PYO is too toxic to be used as a drug. It may, however, have antimalarial activity in numerous human patients with concomitant Pseudomonas infections. MB, in contrast to PYO, is well tolerated and represents a promising agent for MB−based combination therapies against malaria. Current and future clinical studies can be guided by the comparisons between MB and PYO reported here. Additionally, it is of interest to study if and to what extent the protection from malaria in patients with cystic fibrosis or with severe wound infections is based on PYO produced by Pseudomonas specie
Safety and efficacy of methylene blue combined with artesunate or amodiaquine for uncomplicated falciparum malaria
No full textBesides existing artemisinin-based combination therapies, alternative safe, effective and affordable drug combinations against falciparum malaria are needed. Methylene blue (MB) was the first synthetic antimalarial drug ever used, and recent studies have been promising with regard to its revival in malaria therapy. The objective of this study was to assess the safety and efficacy of two MB-based malaria combination therapies, MB-artesunate (AS) and MB-amodiaquine (AQ), compared to the local standard of care, AS-AQ, in Burkina Faso. Open-label randomised controlled phase II study in 180 children aged 6-10 years with uncomplicated falciparum malaria in Nouna, north-western Burkina Faso. Follow-up was for 28 days and analysis by intention-to-treat. The treatment groups were similar in baseline characteristics and there was only one loss to follow-up. No drug-related serious adverse events and no deaths occurred. MB-containing regimens were associated with mild vomiting and dysuria. No early treatment failures were observed. Parasite clearance time differed significantly among groups and was the shortest with MB-AS. By day 14, the rates of adequate clinical and parasitological response after PCR-based correction for recrudescence were 87% for MB-AS, 100% for MB-AQ (p = 0.004), and 100% for AS-AQ (p = 0.003). By day 28, the respective figure was lowest for MB-AS (62%), intermediate for the standard treatment AS-AQ (82%; p = 0.015), and highest for MB-AQ (95%; p<0.001; p = 0.03). MB-AQ is a promising alternative drug combination against malaria in Africa. Moreover, MB has the potential to further accelerate the rapid parasite clearance of artemisinin-based combination therapies. More than a century after the antimalarial properties of MB had been described, its role in malaria control deserves closer attention. ClinicalTrials.gov NCT00354380
The bacterial redox signaller pyocyanin as an antiplasmodial agent: comparisons with its thioanalog methylene blue
No full textThe quorum sensor and signalling molecule pyocyanin (PYO) contributes significantly to the pathophysiology of Pseudomonas aeruginosa infections. Comparison to phenothiazine drugs suggests that the antimalarial compound methylene blue (MB) can be regarded as a sulfur analog of PYO. This working hypothesis would explain why the synthetic drug MB behaves as a compound shaped in biological evolution. Here we report on redox−associated biological and biochemical properties of PYO in direct comparison to its synthetic analog MB. We quantitatively describe the reactivity of both compounds toward cellular reductants, the reactivity of their reduced leuco−forms towards O2, and their interactions with FAD−containing disulfide reductases. Furthermore, the interaction of PYO with human glutathione reductase was studied in structural detail by x−ray crystallography, showing that a single PYO molecule binds to the intersubunit cavity of the enzyme. Like MB, also PYO was also found to be active against blood schizonts of the malaria parasite P. falciparum in vitro. Furthermore, both compounds were active against the disease transmitting gametocyte forms of the parasites, which was systematically studied in vitro. As shown for mice, PYO is too toxic to be used as a drug. It may, however, have antimalarial activity in numerous human patients with concomitant Pseudomonas infections. MB, in contrast to PYO, is well tolerated and represents a promising agent for MB−based combination therapies against malaria. Current and future clinical studies can be guided by the comparisons between MB and PYO reported here. Additionally, it is of interest to study if and to what extent the protection from malaria in patients with cystic fibrosis or with severe wound infections is based on PYO produced by Pseudomonas specie
Selenocysteine, pyrrolysine and the unique energy metabolism of methanogenic archaea
No full textMethanogenic archaea are a group of strictly anaerobic microorganisms characterized by their strict dependence on the process of methanogenesis for energy conservation. Among the archaea, they are also the only known group synthesizing proteins containing selenocysteine or pyrrolysine. All but one of the known archaeal pyrrolysine-containing and all but two of the confirmed archaeal selenocysteine-containing protein are involved in methanogenesis. Synthesis of these proteins proceeds through suppression of translational stop codons but otherwise the two systems are fundamentally different. This paper highlights these differences and summarizes the recent developments in selenocysteine- and pyrrolysine-related research on archaea and aims to put this knowledge into the context of their unique energy metabolism
Antiprotozoal activity profiling of approved drugs : a starting point toward drug repositioning
No full textNeglected tropical diseases cause significant morbidity and mortality and are a source of poverty in endemic countries. Only a few drugs are available to treat diseases such as leishmaniasis, Chagas' disease, human African trypanosomiasis and malaria. Since drug development is lengthy and expensive, a drug repurposing strategy offers an attractive fast-track approach to speed up the process. A set of 100 registered drugs with drug repositioning potential for neglected diseases was assembled and tested in vitro against four protozoan parasites associated with the aforementioned diseases. Several drugs and drug classes showed in vitro activity in those screening assays. The results are critically reviewed and discussed in the perspective of a follow-up drug repositioning strategy where R&D has to be addressed with limited resources
