Modulation of Induced Cytotoxicity of Doxorubicin by Using Apoferritin and Liposomal Cages

Doxorubicin is an effective chemotherapeutic drug, however, its toxicity is a significant limitation in therapy. Encapsulation of doxorubicin inside liposomes or ferritin cages decreases cardiotoxicity while maintaining anticancer potency. We synthesized novel apoferritin- and liposome-encapsulated forms of doxorubicin (“Apodox” and “lip-8-dox”) and compared its toxicity with doxorubicin and Myocet on prostate cell lines. Three different prostatic cell lines PNT1A, 22Rv1, and LNCaP were chosen. The toxicity of the modified doxorubicin forms was compared to conventional doxorubicin using the MTT assay, real-time cell impedance-based cell growth method (RTCA), and flow cytometry. The efficiency of doxorubicin entrapment was 56% in apoferritin cages and 42% in the liposome carrier. The accuracy of the RTCA system was verified by flow-cytometric analysis of cell viability. The doxorubicin half maximal inhibition concentrations (IC₅₀) were determined as 170.5, 234.0, and 169.0 nM for PNT1A, 22Rv1, and LNCaP, respectively by RTCA. Lip8-dox is less toxic on the non-tumor cell line PNT1A compared to doxorubicin, while still maintaining the toxicity to tumorous cell lines similar to doxorubicin or epirubicin (IC₅₀ = 2076.7 nM for PNT1A vs. 935.3 and 729.0 nM for 22Rv1 and LNCaP). Apodox IC₅₀ was determined as follows: 603.1, 1344.2, and 931.2 nM for PNT1A, 22Rv1, and LNCaP.     

Expanding Substrate Promiscuity by Engineering a Novel Adenylating‐Methylating NRPS Bifunctional Enzyme

Nonribosomal peptides synthetases (NRPSs), which are multifunctional mega‐enzymes producing many biologically active metabolites, are ideal targets for enzyme engineering. NRPS adenylation domains play a critical role in selecting/activating the amino acids to be transferred to downstream NRPS domains in the biosynthesis of natural products. Both monofunctional and bifunctional A domains interrupted with an auxiliary domain are found in nature. Here, we show that a bifunctional interrupted A domain can be uninterrupted by deleting its methyltransferase auxiliary domain portion to make an active monofunctional enzyme. We also demonstrate that a portion of an auxiliary domain with almost no sequence identity to the original auxiliary domain can be insert into naturally interrupted A domain to develop a new active bifunctional A domain with increased substrate profile. This work shows promise for the creation of new interrupted A domains in engineered NRPS enzymes.     

Identification of Ebsulfur Analogues with Broad‐Spectrum Antifungal Activity

Invasive fungal infections are on the rise due to an increased population of critically ill patients as a result of HIV infections, chemotherapies, and organ transplantations. Current antifungal drugs are helpful, but are insufficient in addressing the problem of drug‐resistant fungal infections. Thus, there is a growing need for novel antimycotics that are safe and effective. The ebselen scaffold has been evaluated in clinical trials and has been shown to be safe in humans. This makes ebselen an attractive scaffold for facile translation from bench to bedside. We recently reported a library of ebselen‐inspired ebsulfur analogues with antibacterial properties, but their antifungal activity has not been characterized. In this study, we repurposed ebselen, ebsulfur, and 32 additional ebsulfur analogues as antifungal agents by evaluating their antifungal activity against a panel of 13 clinically relevant fungal strains. The effect of induction of reactive oxygen species (ROS) by three of these compounds was evaluated. Their hemolytic and cytotoxicity activities were also determined using mouse erythrocytes and mammalian cells. The MIC values of these compounds were found to be in the range of 0.02–12.5 μg mL^?1 against the fungal strains tested. Notably, yeast cells treated with our compounds showed an accumulation of ROS, which may further contribute to the growth‐inhibitory effect against fungi. This study provides new lead compounds for the development of antimycotic agents.     

Effect of pressure and temperature on viscosity of a borosilicate glass

During industrial glass production processes, the actual distribution of stress components in the glass during scribing remains, to date, poorly quantified, and thus continues to be challenging to model numerically. In this work, we experimentally quantified the effect of pressure and temperature on the viscosity of SCHOTT N‐BK7^® glass, by performing in situ deformation experiments at temperatures between 550 and 595°C and confining pressures between 100 and 300 MPa. Experiments were performed at constant displacement rates to produce almost constant strain rates between 9.70 × 10^?6 and 4.98 × 10^?5 s^?1. The resulting net axial stresses range from 81 to 802 MPa, and the finite strains range from 1.4% to 8.9%. The mechanical results show that the SCHOTT N‐BK7^® glass is viscoelastic near the glass transition temperature at 300 MPa of confining pressure. To elucidate the data, we incorporated both 1‐element and 2‐element generalized Maxwell viscoelastic models in an inversion approach, for which we provide MATLAB scrips. Results show that the 2‐element Maxwell model fits the experimental data well. The stress decreases with increasing temperature at 300 MPa and the temperature dependence yields a similar activation energy (601 ± 10 kJ mol^?1 or ?H/R = 7.2 × 10⁴ K) to a previously reported value at 1‐atm (615 kJ mol^?1 or ?H/R = 7.4 × 10⁴ K). The SCHOTT N‐BK7^® glass shows a limited linear increase in viscosity with increasing pressure of ~0.1 log₁₀ (Pa·s)/100 MPa, which is in agreement with the most recent 2‐internal‐parameter relaxation model (based on experiments).     

Spark plasma sintering and mechanical properties of compounds in TiB2-SiC pseudo-diagram

The influence of spark plasma sintering (SPS) parameters (temperature, time, pressure) and the role of particle size on densification, microstructure and mechanical properties of commercial additive-free TiB₂, SiC and composites thereof were studied by X-ray diffraction, scanning electron microscopy, the ultrasonic method and indentation. Three particle sizes of SiC and 2 of TiB₂ were processed. An optimal cycle was found for TiB₂ and SiC: 2000?°C, 3?min dwell time, and 100?MPa applied at 600?°C. The relative density of pure SiC increases linearly from 70% to 90% when the initial particle size decreases from 1.75?µm to 0.5?µm. Pure TiB₂ was densified up to 87%. Using 2.5?wt% SiC in TiB₂, the relative density increases to 97%. Young's modulus and the hardness of all samples were measured, with results discussed. The higher properties were obtained for additive-free TiB₂–5%SiC with a relative density of 97% and with the Young's modulus and Vickers hardness values being close to 378?GPa and 23?GPa, respectively.     

A revisited approach to linear fuzzy regression using trapezoidal fuzzy intervals

Conventional Fuzzy regression using possibilistic concepts allows the identification of models from uncertain data sets. However, some limitations still exist. This paper deals with a revisited approach for possibilistic fuzzy regression methods. Indeed, a new modified fuzzy linear model form is introduced where the identified model output can envelop all the observed data and ensure a total inclusion property. Moreover, this model output can have any kind of spread tendency. In this framework, the identification problem is reformulated according to a new criterion that assesses the model fuzziness independently from the collected data distribution. The potential of the proposed method with regard to the conventional approach is illustrated by simulation examples.     

Detection of equipment aging and determination of the efficiency of a corrective measure

When too many failures occur on a given piece of equipment, the dependability engineer needs to decide whether these failures are attributable to poor initial design or if they are due to a phenomenon of aging. If aging is confirmed, the problem is then to determine the moment at which the process began and what corrective measure (generally, a modification in the design or in the preventive maintenance program) is the best suited to delay the occurrence of the failure. This measure will thus make it possible to extend the lifetime of the equipment.The method is based on the simple hypothesis of a model of step aging and on Bayesian techniques.The principal benefit of this method is the determination of the time at which aging begins (and the related uncertainties), the evolution in the failure rate of the component in its initial state and once modified, and the probability of success of the corrective measure. The IBTV software was developed to implement this methodology.     

Concept extraction from business documents for software engineering projects

Acquiring relevant business concepts is a crucial first step for any software project for which the software experts are not domain experts. The wealth of information buried within an organization’s written documentation is a precious source of concepts, relationships and attributes which can be used to model the enterprise’s domain. The lack of targeted extraction tools can make perusing through this type of resource a lengthy and costly process. We propose a domain model focused extraction process aimed at the rapid discovery of knowledge relevant to the software expert. To avoid undesirable noise from high-level linguistic tools, the process is mainly composed of positive and negative base filters that are less error prone and more robust. The extracted candidates are then reordered using a weight propagation algorithm based on structural hints from source documents. When tested on French text corpora from public organizations, our process performs 2.7 times better than a statistical baseline for relevant concept discovery. A new metric to assess the performance discovery speed of relevant concepts is introduced. The annotation of a gold standard definition of software engineering oriented concepts for knowledge extraction tasks is also presented.     

Context-based mobile GeoBI: enhancing business analysis with contextual metrics/statistics and context-based reasoning

Business professionals are increasingly mobile and should be supported by suitable mobile Decision Support Systems (DSS). In our previous work, we have established that such suitable mobile DSS should be (i) GeoBI(Geospatial Business Intelligence)-enabled and (ii) context-based, and have addressed issues regarding context characterization and context modeling. The present paper deals with mobile GeoBI context-based reasoning. Through realistic scenarios, it highlights (i) the requirement for context-based reasoning to enhance mobile GeoBI experience, (ii) the need for contextual metrics/statistics to help mobile business professionals discover their local context, (iii) the need for crossing business performance metrics with contextual metrics to help mobile business professionals in discovering the context hidden behind business performance figures, and proposes convenient solutions to tackle these needs.     

A Methodology for Spatial Consistency Improvement of Geographic Databases

In any information system the reliability of any results of queries, analysis or reasoning, depends on data quality (positional accuracy, consistency and so on). In some cases, answers cannot be obtained due to a lack of information, whereas in other cases answers are wrong or not complete because of inconsistent data. In geographical information systems (GIS), data quality management has to handle the spatial features of objects, which brings specific problems. The goal of this paper is to describe a methodology for spatial consistency improvement of geographical data sets in vector format. It is based on errors survey and classification. Three kinds of errors are identified which lead to three kinds of consistency, namely structural consistency, geometric consistency and topo-semantic consistency. Each of them needs specific checking and correcting processes. All these processes are integrated in a general framework that is presented in this paper. An application of this framework to the Lyon Urban Community GIS (the SUR) is currently conducted; first results are presented.