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.     

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.     

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.     

In vitro drug sensitivity and clinical aspects of Plasmodium falciparum malaria in African children

OBJECTIVE: To compare body mass index (BMI), lipid, lipoprotein and apolipoprotein concentrations according to the Hind III and Pvu II restriction polymorphisms of the LPL gene in obese subjects. DESIGN: Cross sectional study of anthropometric and lipid variables in relation to genetic factors. SETTING: Nutrition Outpatient Clinic of Bichat Hospital in Paris, France. SUBJECTS: 236 unrelated patients (162 women and 74 men) were selected on the basis of 120% of ideal body weight. MAIN OUTCOME MEASURES: Anthropometry (body mass index, waist to hip ratio), blood lipids and lipoproteins, determination of LPL Hind III and Pvu II genotypes. RESULTS: Digestion with Hind III generated two alleles, H1 (absence of cutting site) and H2 (presence of cutting site), with frequencies of 0.30 and 0.70 respectively. Digestion with Pvu II generated two alleles P1 and P2 with frequencies of 0.49 and 0.51 respectively. The Hind III polymorphism was significantly associated with body mass index (BMI) (P < 0.05). The H2H2 genotype was associated with hypertriglyceridemia: 68% of the hypertriglyceridemic subjects have the H2H2 genotype vs 43% of the normotriglyceridemic group (P < 0.05). Plasma triglyceride levels varied significantly among the Hind III genotypes, H2H2 genotype having the highest total and VLDL-triglyceride levels; the Hind III polymorphism also showed a significant association with HDL2-cholesterol. These associations were only seen in women and were not explained by the variations in BMI and age. No significant associations were found between lipid traits and Pvu II genotype. CONCLUSION: These results suggest that genetic variation in the LPL gene in obese subjects is associated with hypertriglyceridemia and possibly with a predisposition to obesity.     

Social class, education, and smoking cessation: Long-term follow-up of patients treated at a smoking cessation unit.

Our objective was to examine social class and educational differences in long-term smoking cessation success among a cohort of smokers attending a specialized smoking clinic. We studied sustained abstinence after cessation among 1,516 smokers (895 men and 621 women) treated for smoking cessation between 1995 and 2001 at a university teaching hospital in the metropolitan area of Barcelona, Spain. We calculated 1-year and long-term (up to 8-year) abstinence probabilities by means of Kaplan-Meier curves and the hazard ratio of relapse by means of Cox regression, after adjusting for other predictors of relapse. Overall abstinence probability was .277 (95% CI = .254-.301). Men and women in social classes IV-V had significant hazard ratios of relapse after long-term follow-up (men: 1.36, 95% CI = 1.07-1.72; women: 1.60, 95% CI = 1.24-2.06), as compared with patients in social classes I-II. The same independent effect was observed for education: Men and women with primary or less than primary studies had higher hazard ratios of relapse (men: 1.75, 95% CI = 1.35-2.25; women: 1.92, 95% CI = 1.51-2.46), as compared with patients with a university degree. Similar estimates were obtained after adjustment for stage of change, Fagerstr?m score for nicotine dependence, and type of treatment. Patients of lower socioeconomic status are at higher risk of relapse, and this association is independent of other well-known predictors of relapse. Social differences have to be taken into account in the clinical setting when tailoring specific actions to treat smoking dependence.