Antithrombin and Its Role in Host Defense and Inflammation

Antithrombin (AT) is a natural anticoagulant that interacts with activated proteases of the coagulation system and with heparan sulfate proteoglycans (HSPG) on the surface of cells. The protein, which is synthesized in the liver, is also essential to confer the effects of therapeutic heparin. However, AT levels drop in systemic inflammatory diseases. The reason for this decline is consumption by the coagulation system but also by immunological processes. Aside from the primarily known anticoagulant effects, AT elicits distinct anti-inflammatory signaling responses. It binds to structures of the glycocalyx (syndecan-4) and further modulates the inflammatory response of endothelial cells and leukocytes by interacting with surface receptors. Additionally, AT exerts direct antimicrobial effects: depending on AT glycosylation it can bind to and perforate bacterial cell walls. Peptide fragments derived from proteolytic degradation of AT exert antibacterial properties. Despite these promising characteristics, therapeutic supplementation in inflammatory conditions has not proven to be effective in randomized control trials. Nevertheless, new insights provided by subgroup analyses and retrospective trials suggest that a recommendation be made to identify the patient population that would benefit most from AT substitution. Recent experiment findings place the role of various AT isoforms in the spotlight. This review provides an overview of new insights into a supposedly well-known molecule.     

Nitroreductase-Mediated Release of Inhibitors of Lysine-Specific Demethylase 1 (LSD1) from Prodrugs in Transfected Acute Myeloid Leukaemia Cells

Lysine-specific demethylase 1 (LSD1) has evolved as a promising therapeutic target for cancer treatment, especially in acute myeloid leukaemia (AML). To approach the challenge of site-specific LSD1 inhibition, we developed an enzyme-prodrug system with the bacterial nitroreductase NfsB (NTR) that was expressed in the virally transfected AML cell line THP1-NTR⁺. The cellular activity of the NTR was proven with a new luminescent NTR probe. We synthesised a diverse set of nitroaromatic prodrugs that by design do not affect LSD1 and are reduced by the NTR to release an active LSD1 inhibitor. The emerging side products were differentially analysed using negative controls, thereby revealing cytotoxic effects. The 2-nitroimidazolyl prodrug of a potent LSD1 inhibitor emerged as one of the best prodrug candidates with a pronounced selectivity window between wild-type and transfected THP1 cells. Our prodrugs are selectively activated and release the LSD1 inhibitor locally, proving their suitability for future targeting approaches.     

A toy or a friend? Children's anthropomorphic beliefs about robots and how these relate to second-language word learning

This study investigates the degree to which children anthropomorphize a robot tutor and whether this anthropomorphism relates to their vocabulary learning in a second-language (L2) tutoring intervention. With this aim, an anthropomorphism questionnaire was administered to 5-year-old children (N = 104) twice: prior to and following a seven-session L2 vocabulary training with a humanoid robot. On average, children tended to anthropomorphize the robot prior to and after the lessons to a similar degree, but many children changed their attributed anthropomorphic features. Boys anthropomorphized the robot less after the lessons than girls. Moreover, there was a weak but significant positive correlation between anthropomorphism as measured before the lessons and scores on a word-knowledge post-test administered the day after the last lesson. There was also a weak but significant positive correlation between the change in anthropomorphism over time and scores on a word-knowledge post-test administered approximately 2 weeks after the last lesson. Our results underscore the need to manage children's expectations in robot-assisted education. Also, future research could explore adaptations to individual children's expectations in child-robot interactions.     

The impact of alkali elements on the degradation of CIGS solar cells

Unencapsulated CIGS solar cells with high and low contents of sodium (Na) and potassium (K) were simultaneously exposed to damp heat and illumination. The solar cells with a high alkali (Na, K) content exhibited higher initial conversion efficiencies, but degraded severely within 100 h, while the alkali poor samples kept relatively stable performance under damp heat and illumination. The degradation of the samples with a high alkali content resulted in the formation of sodium rich spots on the top ZnO:Al surface of the samples. This is likely caused by light‐induced Na⁺ migration via the grain boundaries in the absorber to the depletion region, where the Na⁺ accumulated. This allowed subsequent Na⁺ transport through the depletion region due to the lowering of the internal electric field caused both by the Na⁺ accumulation and illumination. The migration resulted in the formation of shunt paths, which reduced the shunt resistance and open circuit voltage. Furthermore, ingression of water into the ZnO:Al is expected to be responsible for a slow but steady increase in series resistance for both high and low alkali solar cells. Additionally, sodium migration led to a severe increase of the series resistance in case of alkali rich samples. Copyright © 2015 John Wiley & Sons, Ltd.     

Self-adaptive differential evolution algorithm using population size reduction and three strategies

Many real-world optimization problems are large-scale in nature. In order to solve these problems, an optimization algorithm is required that is able to apply a global search regardless of the problems’ particularities. This paper proposes a self-adaptive differential evolution algorithm, called jDElscop, for solving large-scale optimization problems with continuous variables. The proposed algorithm employs three strategies and a population size reduction mechanism. The performance of the jDElscop algorithm is evaluated on a set of benchmark problems provided for the Special Issue on the Scalability of Evolutionary Algorithms and other Metaheuristics for Large Scale Continuous Optimization Problems. Non-parametric statistical procedures were performed for multiple comparisons between the proposed algorithm and three well-known algorithms from literature. The results show that the jDElscop algorithm can deal with large-scale continuous optimization effectively. It also behaves significantly better than other three algorithms used in the comparison, in most cases.     

Type D personality and the development of PTSD symptoms: A prospective study.

Psychological trauma and prolonged stress may cause mental disorders such as posttraumatic stress disorder (PTSD). Pretrauma personality is an important determinant of posttraumatic adjustment. Specifically, trait neuroticism has been identified as a risk factor for PTSD. Additionally, the combination of high negative affectivity or neuroticism with marked social inhibition or introversion, also called Type D personality (Denollet, 2000), may compose a risk factor for PTSD. There is no research available that examined pretrauma Type D personality in relation to PTSD. The present study examined the predictive validity of the Type D personality construct in a sample of Dutch soldiers. Data were collected prior to and 6 months after military deployment to Afghanistan. Separate multiple regression analyses were performed to examine the predictive validity of Type D personality. First, Type D personality was defined as the interaction between negative affect and social inhibition (Na × Si). In a second analysis, Type D was defined following cutoff criteria recommended by Denollet (2000). Results showed that negative affectivity was a significant predictor of PTSD symptoms. Social inhibition and the interaction Na × Si did not add to the amount of explained variance in postdeployment PTSD scores over the effects of childhood abuse, negative affectivity, and prior psychological symptoms. A second analysis showed that Type D personality (dichotomous) did not add to the amount of explained variance in postdeployment PTSD scores over the effects of childhood abuse, and prior psychological symptoms. Therefore, Type D personality appears to be of limited value to explain development of combat-related PTSD symptoms. (PsycINFO Database Record (c) 2011 APA, all rights reserved)