Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine

Elevated activation of the autophagy pathway is currently thought to be one of the survival mechanisms allowing therapy-resistant cancer cells to escape elimination, including for cytarabine (AraC)-resistant acute myeloid leukemia (AML) patients. Consequently, the use of autophagy inhibitors such as chloroquine (CQ) is being explored for the re-sensitization of AraC-resistant cells. In our study, no difference in the activity of the autophagy pathway was detected when comparing AraC-Res AML cell lines to parental AraC-sensitive AML cell lines. Furthermore, treatment with autophagy inhibitors CQ, 3-Methyladenine (3-MA), and bafilomycin A1 (BafA1) did not re-sensitize AraC-Res AML cell lines to AraC treatment. However, in parental AraC-sensitive AML cells, treatment with AraC did activate autophagy and, correspondingly, combination of AraC with autophagy inhibitors strongly reduced cell viability. Notably, the combination of these drugs also yielded the highest level of cell death in a panel of patient-derived AML samples even though not being additive. Furthermore, there was no difference in the cytotoxic effect of autophagy inhibition during AraC treatment in matched de novo and relapse samples with differential sensitivity to AraC. Thus, inhibition of autophagy may improve AraC efficacy in AML patients, but does not seem warranted for the treatment of AML patients that have relapsed with AraC-resistant disease.     

Structural and kinetic studies on ligand binding in wild-type and active-site mutants of penicillin acylase

Penicillin acylase catalyses the condensation of Calpha-substituted phenylacetic acids with beta-lactam nucleophiles, producing semi-synthetic beta-lactam antibiotics. For efficient synthesis a low affinity for phenylacetic acid and a high affinity for Calpha-substituted phenylacetic acid derivatives is desirable. We made three active site mutants, alphaF146Y, betaF24A and alphaF146Y/betaF24A, which all had a 2- to 10-fold higher affinity for Calpha-substituted compounds than wild-type enzyme. In addition, betaF24A had a 20-fold reduced affinity for phenylacetic acid. The molecular basis of the improved properties was investigated by X-ray crystallography. These studies showed that the higher affinity of alphaF146Y for (R)-alpha-methylphenylacetic acid can be explained by van der Waals interactions between alphaY146:OH and the Calpha-substituent. The betaF24A mutation causes an opening of the phenylacetic acid binding site. Only (R)-alpha-methylphenylacetic acid, but not phenylacetic acid, induces a conformation with the ligand tightly bound, explaining the weak binding of phenylacetic acid. A comparison of the betaF24A structure with other open conformations of penicillin acylase showed that betaF24 has a fixed position, whereas alphaF146 acts as a flexible lid on the binding site and reorients its position to achieve optimal substrate binding.     

A new multi‐scale dispersive gradient elasticity model with micro‐inertia: Formulation and ‐finite element implementation

Motivated by nano‐scale experimental evidence on the dispersion characteristics of materials with a lattice structure, a new multi‐scale gradient elasticity model is developed. In the framework of gradient elasticity, the simultaneous presence of acceleration and strain gradients has been denoted as dynamic consistency. This model represents an extension of an earlier dynamically consistent model with an additional micro‐inertia contribution to improve the dispersion behaviour. The model can therefore be seen as an enhanced dynamic extension of the Aifantis' 1992 strain‐gradient theory for statics obtained by including two acceleration gradients in addition to the strain gradient. Compared with the previous dynamically consistent model, the additional micro‐inertia term is found to improve the prediction of wave dispersion significantly and, more importantly, requires no extra computational cost. The fourth‐order equations are rewritten in two sets of symmetric second‐order equations so that ‐continuity is sufficient in the finite element implementation. Two sets of unknowns are identified as the microstructural and macrostructural displacements, thus highlighting the multi‐scale nature of the present formulation. The associated energy functionals and variationally consistent boundary conditions are presented, after which the finite element equations are derived. Considerable improvements over previous gradient models are observed as confirmed by two numerical examples. Copyright © 2016 John Wiley & Sons, Ltd.     

Tendon layout optimisation through configurational forces equilibration in plane stress analysis of prestressed concrete structures

The focus of this work is a novel application of configurational forces to tendon layout optimisation problems in prestressed concrete beams. To this end, the application of the method of the configurational forces is extended to two-dimensional plane stress analysis. The optimum tendon position is obtained by iteratively arriving at vanishing configurational forces. The performance of the optimisation algorithm is illustrated by means of numerical examples.     

Tailoring real-time physical activity coaching systems: a literature survey and model

Technology mediated healthcare services designed to stimulate patients’ self-efficacy are widely regarded as a promising paradigm to reduce the burden on the healthcare system. The promotion of healthy, active living is a topic of growing interest in research and business. Recent advances in wireless sensor technology and the widespread availability of smartphones have made it possible to monitor and coach users continuously during daily life activities. Physical activity monitoring systems are frequently designed for use over long periods of time placing usability, acceptance and effectiveness in terms of compliance high on the list of design priorities to achieve sustainable behavioral change. Tailoring, or the process of adjusting the system’s behavior to individuals in a specific context, is an emerging topic of interest within the field. In this article we report a survey of tailoring techniques currently employed in state of the art real time physical activity coaching systems. We present a survey of state of the art activity coaching systems as well as a conceptual framework which identifies seven important tailoring concepts that are currently in use and how they relate to each other. A detailed analysis of current use of tailoring techniques in real time physical activity coaching applications is presented. According to the literature, tailoring is currently used only sparsely in this field. We underline the need to increase adoption of tailoring methods that are based on available theories, and call for innovative evaluation methods to demonstrate the effectiveness of individual tailoring approaches.     

Röntgendiagnostik plasma‐gestützt abgeschiedener dünner Schichten

X‐ray diagnostics of plasma deposited thin layers Grazing incidence x‐ray diffractometry (GIXD) and x‐ray reflectometry (XR) have been introduced as well suited tools for investigations of plasma deposited thin layers. They are non‐destructive techniques, therefore a sample can be reused and measured with other techniques. A combination of GIXD and XR can give a range of interesting information about chemical, physical and crystallographic properties of thin films. Conclusions can be drawn how plasma deposition techniques and plasma parameters influence the film growth. In three examples we present the analysis of phase and chemical composition, defect structure and measurements of kinetic process parameters.     

Selective reaching: Evidence for multiple frames of reference.

Students participated in 3 experiments investigating the use of environment- and action-centered reference frames in selective reaching. They pointed to a green target appearing either with or without a red distractor. Target-distractor distance was manipulated, and distractor interference (difference between distractor trials and no-distractor trials) was measured in reaction time, movement time, and movement endpoint. Target-distractor distance determined the dominant frame of reference. Small distances evoked an environment-centered framework that encoded targets within an external context. Large distances evoked an action-centered framework that encoded targets relative to the start position of the hand. Results support the hypothesis that the brain represents spatial information in multiple frames of reference, with the dominant frame of reference being dependent on the task demands. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Emergency nurses'' perceptions of critical incidents and stress debriefing

The efficacy of examining antinuclear antibody (ANA) was investigated as a screening test detecting subclinical immune disorders in infertility and sterility. ANA was measured in 116 unexplained infertile or sterile patients. The ANA positive rate was 43.5% in group A (habitual abortion, n = 23), 38.1% in group B (consecutive miscarriages, n = 21), 30.0% in group C (one miscarriage, n = 10), 16.7% in group D (one or more deliveries n = 12) 22.0% in group E (primary sterility, n = 50), and 22.4% in the control group (n = 54). The positive rate for all the infertile patients (group A+B) was 40.9% and significantly higher than that in for the control group (p < 0.05). Ten patients with positive ANA had 12 deliveries and 20 patients with negative ANA had 23 deliveries. The frequency of preeclampsia in the patients with positive ANA was higher than in those with negative ANA (41.7% versus 4.3%, p < 0.05). A higher incidence of premature deliveries was recognized in the patients with positive ANA than in those with negative ANA (41.7% versus 8.7%, p < 0.1). Average birth weight (> 35 week) for patients with and without positive ANA was 2,976g (n = 8) and 3,122g (n = 19) respectively. The former tends to be smaller than the latter (p < 0.1).