Evaluation of Floxuridine Oligonucleotide Conjugates Carrying Potential Enhancers of Cellular Uptake

Conjugation of small molecules such as lipids or receptor ligands to anti-cancer drugs has been used to improve their pharmacological properties. In this work, we studied the biological effects of several small-molecule enhancers into a short oligonucleotide made of five floxuridine units. Specifically, we studied adding cholesterol, palmitic acid, polyethyleneglycol (PEG 1000), folic acid and triantennary N-acetylgalactosamine (GalNAc) as potential enhancers of cellular uptake. As expected, all these molecules increased the internalization efficiency with different degrees depending on the cell line. The conjugates showed antiproliferative activity due to their metabolic activation by nuclease degradation generating floxuridine monophosphate. The cytotoxicity and apoptosis assays showed an increase in the anti-cancer activity of the conjugates related to the floxuridine oligomer, but this effect did not correlate with the internalization results. Palmitic and folic acid conjugates provide the highest antiproliferative activity without having the highest internalization results. On the contrary, cholesterol oligomers that were the best-internalized oligomers had poor antiproliferative activity, even worse than the unmodified floxuridine oligomer. Especially relevant is the effect induced by palmitic and folic acid derivatives generating the most active drugs. These results are of special interest for delivering other therapeutic oligonucleotides.     

A robot learning from demonstration framework to perform force-based manipulation tasks

This paper proposes an end-to-end learning from demonstration framework for teaching force-based manipulation tasks to robots. The strengths of this work are manyfold. First, we deal with the problem of learning through force perceptions exclusively. Second, we propose to exploit haptic feedback both as a means for improving teacher demonstrations and as a human–robot interaction tool, establishing a bidirectional communication channel between the teacher and the robot, in contrast to the works using kinesthetic teaching. Third, we address the well-known what to imitate? problem from a different point of view, based on the mutual information between perceptions and actions. Lastly, the teacher’s demonstrations are encoded using a Hidden Markov Model, and the robot execution phase is developed by implementing a modified version of Gaussian Mixture Regression that uses implicit temporal information from the probabilistic model, needed when tackling tasks with ambiguous perceptions. Experimental results show that the robot is able to learn and reproduce two different manipulation tasks, with a performance comparable to the teacher’s one.     

Agent mobility architecture based on IEEE-FIPA standards

Mobile agents are autonomous software entities driven by a set of goals and tasks. Reactivity, social ability, autonomy, the ability to move to different network locations, and the weak agent notion of proactiveness, allow for autonomous processing of distributed information according to their environment (context awareness).Although agent mobility has been devised for homogeneous environments, deployment of agent mobility in heterogeneous environments has been hindered by the absence of a common set of interoperation rules and ontologies for different agent middlewares.In this article, an agent migration model based on the communication standards of the IEEE-FIPA organisation is proposed. The approach described encompasses the definition of several specifications to achieve interoperability in the migration process in heterogeneous environments.The model provides a basic and extensible common migration process, which is flexible enough to support different kinds of migration methods and future upgrades. It is completely independent of any specific middleware implementation.     

Incremental Learning of Skills in a Task-Parameterized Gaussian Mixture Model

Programming by demonstration techniques facilitate the programming of robots. Some of them allow the generalization of tasks through parameters, although they require new training when trajectories different from the ones used to estimate the model need to be added. One of the ways to re-train a robot is by incremental learning, which supplies additional information of the task and does not require teaching the whole task again. The present study proposes three techniques to add trajectories to a previously estimated task-parameterized Gaussian mixture model. The first technique estimates a new model by accumulating the new trajectory and the set of trajectories generated using the previous model. The second technique permits adding to the parameters of the existent model those obtained for the new trajectories. The third one updates the model parameters by running a modified version of the Expectation-Maximization algorithm, with the information of the new trajectories. The techniques were evaluated in a simulated task and a real one, and they showed better performance than that of the existent model.     

Novel Monocyclam Derivatives as HIV Entry Inhibitors: Design,Synthesis, Anti‐HIV Evaluation,and Their Interaction with the CXCR4 Co‐receptor

The CXCR4 receptor has been shown to interact with the human immunodeficiency virus (HIV) envelope glycoprotein gp120, leading to fusion of viral and cell membranes. Therefore, ligands that can attach to this receptor represent an important class of therapeutic agents against HIV, thus inhibiting the first step in the cycle of viral infection: the virus–cell entry/fusion. Herein we describe the in silico design, synthesis, and biological evaluation of novel monocyclam derivatives as HIV entry inhibitors. In vitro activity testing of these compounds in cell cultures against HIV strains revealed EC₅₀ values in the low micromolar range without cytotoxicity at the concentrations tested. Docking and molecular dynamics simulations were performed to predict the binding interactions between CXCR4 and the novel monocyclam derivatives. A binding mode of these compounds is proposed which is consistent with the main existing site‐directed mutagenesis data on the CXCR4 co‐receptor. Moreover, molecular modeling comparisons were performed between these novel monocyclams, previously reported non‐cyclam compounds from which the monocyclams are derived, and the well‐known AMD3100 bicyclam CXCR4 inhibitors. Our results suggest that these three structurally diverse CXCR4 inhibitors bind to overlapping but not identical amino acid residues in the transmembrane regions of the receptor.     

High level communication functionalities for wireless sensor networks

In this paper we show how to establish a reliable and efficient high level communication system in a randomly deployed network of sensors equipped with directional antennas. This high level communication system enables the programming of the sensor network using high level communication functionalities without the burden of taking care of their physical capacities (low range, unidirectional links, single frequency, presence of collisions, etc.). The high level communication functionalities we offer include point-to-point communication, point-to-area communication, and one-to-all communication. The basic idea to implement this system is to simulate a virtual network that emerges from the ad-hoc network using self-organization, self-discovery and collaborative methods. We also analyse the efficiency, scalability and robustness of the proposed protocols.     

Concentrations and patterns of organochlorine pesticides and PCBs in Mediterranean monk seals (Monachus monachus) from Western Sahara and Greece

Blubber from Mediterranean monk seals (Monachus monachus) from the Western Sahara coast (Atlantic), sampled during 1996-1999, and from the Greek coast (Mediterranean), sampled during 1995-1999, was analyzed for organochlorine pollutants (OCs). In both populations, no significant difference was found between sexes. In the Atlantic population, mature females presented greater percentages of higher chlorinated PCB (polychlorinated biphenyl) congeners in relation to total PCBs (sum of 25 congeners) than pups, indicating a differential transfer of PCB congeners through lactation. In the Mediterranean, the reduced sample size of adult individuals precluded proper statistical investigation of age-related variation. Significant differences in concentrations and pollutant patterns were found between populations. Thus, Mediterranean individuals presented significantly higher levels of HCB (hexachlorobenzene), tPCB, and DDTs (dichlorodiphenyltrichloroethane) concentrations and DDE/tDDT and tDDT/tPCB ratios than their counterparts from the Atlantic. Moreover, the relative proportion of different congeners in relation to the total PCB load (congener/tPCB) was also different between the two areas. The 100*tDDT/tPCB ratio in Atlantic seals was 38.46, which indicates a predominance of industrial inputs over those associated with agriculture. Conversely, in the Mediterranean seal population, the 100*tDDT/tPCB ratio was 177.1, denoting a proportionally higher contribution of pollutants of agricultural origin.