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.     

Regulatory RNAs: A Universal Language for Inter-Domain Communication

In eukaryotes, microRNAs (miRNAs) have roles in development, homeostasis, disease and the immune response. Recent work has shown that plant and mammalian miRNAs also mediate cross-kingdom and cross-domain communications. However, these studies remain controversial and are lacking critical mechanistic explanations. Bacteria do not produce miRNAs themselves, and therefore it is unclear how these eukaryotic RNA molecules could function in the bacterial recipient. In this review, we compare and contrast the biogenesis and functions of regulatory RNAs in eukaryotes and bacteria. As a result, we discovered several conserved features and homologous components in these distinct pathways. These findings enabled us to propose novel mechanisms to explain how eukaryotic miRNAs could function in bacteria. Further understanding in this area is necessary to validate the findings of existing studies and could facilitate the use of miRNAs as novel tools for the directed remodelling of the human microbiota.     

Computational Analysis of the Solid-State and Solvation Properties of Carbamazepine in Relation to its Polymorphism

The solvent-dependent polymorphism of the active pharmaceutical ingredient (API) carbamazepine is interpreted from calculations of the solid-state and API-solvent intermolecular interactions. These simulations suggested that apolar solute-solute interactions could be disrupted by apolar solvents. In contrast, the polar solute-solute interactions were found to be easily disrupted by polar and protic solvents. This is consistent with experimental observations that the crystallization of the metastable form II is more dominant in apolar solvents. The Mercury program remains the gold standard in terms of usability; however, further expansion into more complex simulation techniques could make this package of even greater use in pharmaceutical manufacturing workflows.     

Attentional Biases for Negative Interpersonal Stimuli in Clinical Depression.

An information-processing paradigm was used to examine attentional biases in clinically depressed participants, participants with generalized anxiety disorder (GAD), and nonpsychiatric control participants for faces expressing sadness, anger, and happiness. Faces were presented for 1,000 ms, at which point depressed participants had directed their attention selectively to depression-relevant (i.e., sad) faces. This attentional bias was specific to the emotion of sadness; the depressed participants did not exhibit attentional biases to the angry or happy faces. This bias was also specific to depression; at 1,000 ms, participants with GAD were not attending selectively to sad, happy, or anxiety-relevant (i.e., angry) faces. Implications of these findings for both the cognitive and the interpersonal functioning of depressed individuals are discussed and directions for future research are advanced. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Driver detection and recognition of lineside signals and signs at different approach speeds

A study was carried out using simulation to investigate driver responses to lineside signals and signs at various approach speeds. The objectives of the study were: (1) to find out whether train speed would significantly affect signal/sign reading; (2) to examine at which point certain types of signs or signals could be detected or recognised, and (3) to determine a speed cut-off level above which certain types of signs or signals are no longer recognisable or detectable. Fifty-seven train drivers from 12 Train Operating Companies in the UK participated in the trials. Twenty different types of lineside signs and ten types of signals were tested under six different approach speeds ranging from 100 to 350 km/h (62–218 mph). Driver performance measures were ‘time remaining to the signal/sign’ at the point of detection or recognition, and reading error rate. The results showed a significant influence of train speed on driver responses to lineside signals/signs and demonstrated a non-linear relationship between driver responses to signals/signs and approach speed. This has been used to estimate a maximum approach speed limit within which a specific signal or sign can be correctly detected or recognised. The findings and implications of the study are discussed in the paper.     

The validity of the Gammarus:Asellus ratio as an index of organic pollution: abiotic and biotic influences.

In freshwaters. Gammarus spp. are more sensitive to organic pollution than Asellus spp. and the relative abundance of the two taxa has been proposed as a pollution index. We tested the validity of this by examining the relationship between the Gammarus: Asellus (G : A) ratio and (1) a suite of physico-chemical variables. (2) established biotic (average score per taxon, ASPT) and richness (species richness (S) and Ephemeroptera, Plecoptera and Trichoptera families richness (EPT family richness)) indices generated from the macroinvertebrate community. In addition, we investigated a suspected biotic interaction, predation, between Gammarus and Asellus. Both univariate and multivariate analyses showed that the G: A ratio was sometimes responsive to changes in parameters linked to organic pollution, such as BOD5 and nitrate levels. However, the G : A ratio also appeared responsive to variables not directly linked to organic pollution, such as conductivity and distance from source. There were significant positive correlations among the G : A ratio and the ASPT, S and EPT, indicating that changes in the relative abundances of Gammarus and Asellus were reflected in changes in the pollution sensitivity and richness of the wider macroinvertebrate community. A laboratory experiment revealed significant predation of Asellus aquaticus juveniles by Gammarus duebeni celticus adults, but no reciprocal predation. We propose that the G: A ratio may be useful as a crude measure of organic pollution that could supplement more complex indices in a multimetric approach to pollution monitoring or be used for monitoring individual sites, where a simple technique is required for monitoring purposes over a period of time. Also, we urge recognition of the possible role of biotic interactions among taxa used in the generation of pollution indices.     

Fuzzy versus quantitative association rules: a fair data-driven comparison.

As opposed to quantitative association rule mining, fuzzy association rule mining is said to prevent the overestimation of boundary cases, as can be shown by small examples. Rule mining, however, becomes interesting in large databases, where the problem of boundary cases is less apparent and can be further suppressed by using sensible partitioning methods. A data-driven approach is used to investigate if there is a significant difference between quantitative and fuzzy association rules in large databases. The influence of the choice of a particular triangular norm in this respect is also examined.     

Multibody simulation tool for the calculation of lashing loads on RoRo ships

Approximately 80% of the international transport of goods is carried on by means of ships. A large portion of the transport capacity is represented by Roll-on-Roll-off (RoRo) ships. Especially in Europe this is a relevant potential for the RoRo segment. Consequently, the design and construction of RoRo ships plays an increasing role for German shipyards and their suppliers. In order to make the loading and unloading procedure of trailer economically more competitive, ship owners would like to improve the lashing of trailers on the ship. On the basis of a multibody system formalism, a software tool has been developed which allows for an optimization of the loading of trailers on RoRo ships. Commemorative Contribution.