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.     

Genetic Contribution of Endometriosis to the Risk of Developing Hormone-Related Cancers

Endometriosis is a common gynecological disorder that has been associated with endometrial, breast and epithelial ovarian cancers in epidemiological studies. Since complex diseases are a result of multiple environmental and genetic factors, we hypothesized that the biological mechanism underlying their comorbidity might be explained, at least in part, by shared genetics. To assess their potential genetic relationship, we performed a two-sample mendelian randomization (2SMR) analysis on results from public genome-wide association studies (GWAS). This analysis confirmed previously reported genetic pleiotropy between endometriosis and endometrial cancer. We present robust evidence supporting a causal genetic association between endometriosis and ovarian cancer, particularly with the clear cell and endometrioid subtypes. Our study also identified genetic variants that could explain those associations, opening the door to further functional experiments. Overall, this work demonstrates the value of genomic analyses to support epidemiological data, and to identify targets of relevance in multiple disorders.     

High efficiency and reusability of iridium complexes adsorbed in montmorillonite clay on catalytic hydrogenation of imines

Heterogenised homogeneous catalytic hydrogenation of aldimines by removable and reusable immobilised iridium complexes on montmorillonite clay. This revised version was published online in July 2006 with corrections to the Cover Date.     

Control and optimization of the divided wall column

The divided wall column (DWC) is, in terms of capital costs and energy savings, a promising alternative for separating ternary mixtures. Since its design was proposed, almost 50 years ago, many authors have addressed design considerations. Operation and control of the DWC have received much less attention. However, some works have been published recently. Preliminary results reported indicate that feedback diagonal control structures may be used to control the DWC. In this work, the study of feedback diagonal control strategies has been further extended to consider the DWC control design in detail. Different control structures have been systematically analyzed and compared under performance and robustness considerations. In order to study the effect of the energy optimization on the controllability of the DWC, a column at optimal nominal operating conditions is compared to a column under non-optimal operation. Finally, a complete control strategy is proposed. Linear analysis tools are used for the multiple input multiple output (MIMO) feedback control analysis, and simulations using a non-linear model are performed to study the non-linear behavior of the control systems.     

Effect of inoculum size, relative humidity, storage temperature, and ripening stage on the attachment of Salmonella Montevideo to tomatoes and tomatillos

The influence of inoculum populations and environmental factors on attachment of Salmonella Montevideo to the surface of tomatoes and tomatillos was evaluated. To study the effect of inoculum size, red, ripe tomatoes were spot-inoculated with bacterial suspensions (10(5) and 10(8) CFU/fruit) and stored at 22 degrees C under 100% relative humidity. The effects of temperature (12, 22, and 30 degrees C) and relative humidity (75, 85, and 97%) on attachment of the pathogen (10(7) CFU/fruit) to tomatoes (red and green) and ripe tomatillos were also evaluated. Inoculated fruits were stored for 90 min at all combinations of temperature and relative humidity, and after rinsing with water, the number of cells attached to the surface was determined. Salmonella Montevideo attached to the surface of tomatoes within 90 min. A direct correlation between the number of attached cells and the population in the inoculum was observed. The percentage of cells that attached immediately after inoculation was approximately 0.3% for the three test products. After storage for 90 min at various temperature and relative humidity conditions, the number of adhering cells ranged from 4.0 to 5.4 log CFU/fruit (1.2% of inoculum). Both the type of product and the temperature/relative humidity combination had a significant (P < 0.05) effect on attachment of Salmonella Montevideo to the surfaces of tomatoes and tomatillos. Scanning electron micrographs of the cuticles of inoculated washed tomatoes and tomatillos revealed typical skin cell patterns, and only a few randomly dispersed Salmonella Montevideo were observed. Deposition of Salmonella Montevideo on the surface of tomatoes and tomatillos could result in attachment and subsequent colonization under suitable conditions.     

Increased sensitivity for the diagnosis of Taenia saginata cysticercus infection by additional heart examination compared to the EU-approved routine meat inspection

In spite of the statutory meat inspection at abattoirs, Taenia saginata cysticercus infection in cattle remains an economically important parasitic disease for the livestock industry by affecting food safety. The routinely performed standard meat inspection protocol has a low diagnostic sensitivity for the detection of T. saginata cysticerci infections. Therefore, an abattoir trial aiming to increase the detection level was undertaken. In three EU-approved abattoirs, several additional heart incisions were performed in a total of 1088 slaughtered cattle originating from 832 farms throughout Switzerland. Cysticerci as putative parasitic lesions were classified by visual examination during meat inspection and confirmed microscopically and/or by molecular analyses. With the EU-approved routine meat inspection, bovine cysticercosis was diagnosed in 1.8% (20/1088) of the slaughtered animals. Additional incisions into the heart muscle revealed a further 29 cases, indicating that the prevalence was at least 4.5%. All infected animals originated from individual farms. This straightforward technique had a significantly higher sensitivity and is feasible for routine practice. It also confirms that the prevalence of this zoonotic parasite in the cattle population is underestimated based on the routine abattoir reports.     

Metal-Coated &lt;100&gt;-Cut GaAs Coupled to Tapered Parallel-Plate Waveguide for Cherenkov-Phase-Matched Terahertz Detection: Influence of Crystal Thickness

The influence of crystal thickness of metal-coated <100>-cut GaAs (M-G-M) on Cherenkov-phase-matched terahertz (THz) pulse detection was studied. The M-G-M detectors were utilized in conjunction with a metallic tapered parallel-plate waveguide (TPPWG). Polarization-sensitive measurements were carried out to exemplify the efficacy of GaAs in detecting transverse magnetic (TM)- and transverse electric (TE)-polarized THz waves. The reduction of GaAs’ thickness increased the THz amplitude spectra of the detected TM-polarized THz electro-optic (EO) signal due to enhanced electric field associated with a more tightly-focused and well-concentrated THz radiation on the thinner M-G-M. The higher-fluence THz beam coupled to the thinner M-G-M improved the integrated intensity of the detected THz amplitude spectrum. This trend was not observed for TE-polarized THz waves, wherein the integrated intensities were almost comparable. Nevertheless, good agreement of spectral line shapes of the superposed TM- and TE-polarized THz-EO signals with that of elliptically polarized THz-EO signal demonstrates excellent polarization-resolved detection capabilities of M-G-M via Cherenkov-phase-matched EO sampling technique.     

A practical approach to electrode-skin impedance unbalance measurement

Unbalance between electrode-skin impedances is a major problem in biopotential recordings, leading to increased power-line interference. This paper proposes a simple, direct method to measure that unbalance at power-line frequency (50-60 Hz), thus allowing the determination of actual recording conditions for biopotential amplifiers. The method is useful in research, amplifier testing, electrode design and teaching purposes. It has been experimentally validated by using both phantom impedances and real electrode-skin impedances.     

A case-based approach for coordinated action selection in robot soccer

Designing coordinated robot behaviors in uncertain, dynamic, real-time, adversarial environments, such as in robot soccer, is very challenging. In this work we present a case-based reasoning approach for cooperative action selection, which relies on the storage, retrieval, and adaptation of example cases. We focus on cases of coordinated attacking passes between robots in the presence of the defending opponent robots. We present the case representation explicitly distinguishing between controllable and uncontrollable indexing features, corresponding to the positions of the team members and opponent robots, respectively. We use the symmetric properties of the domain to automatically augment the case library. We introduce a retrieval technique that weights the similarity of a situation in terms of the continuous ball positional features, the uncontrollable features, and the cost of moving the robots from the current situation to match the case controllable features. The case adaptation includes a best match between the positions of the robots in the past case and in the new situation. The robots are assigned an adapted position to which they move to maximize the match to the retrieved case. Case retrieval and reuse are achieved within the distributed team of robots through communication and sharing of own internal states and actions. We evaluate our approach, both in simulation and with real robots, in laboratory scenarios with two attacking robots versus two defending robots as well as versus a defender and a goalie. We show that we achieve the desired coordinated passing behavior, and also outperform a reactive action selection approach.