α4-α5 Helices on Surface of KRAS Can Accommodate Small Compounds That Increase KRAS Signaling While Inducing CRC Cell Death

KRAS is the most frequently mutated oncogene associated with the genesis and progress of pancreatic, lung and colorectal (CRC) tumors. KRAS has always been considered as a therapeutic target in cancer but until now only two compounds that inhibit one specific KRAS mutation have been approved for clinical use. In this work, by molecular dynamics and a docking process, we describe a new compound (P14B) that stably binds to a druggable pocket near the α4-α5 helices of the allosteric domain of KRAS. This region had previously been identified as the binding site for calmodulin (CaM). Using surface plasmon resonance and pulldown analyses, we prove that P14B binds directly to oncogenic KRAS thus competing with CaM. Interestingly, P14B favors oncogenic KRAS interaction with BRAF and phosphorylated C-RAF, and increases downstream Ras signaling in CRC cells expressing oncogenic KRAS. The viability of these cells, but not that of the normal cells, is impaired by P14B treatment. These data support the significance of the α4-α5 helices region of KRAS in the regulation of oncogenic KRAS signaling, and demonstrate that drugs interacting with this site may destine CRC cells to death by increasing oncogenic KRAS downstream signaling.     

Self-assembled films of multi-wall carbon nanotubes used in gas sensors to increase the sensitivity limit for oxygen detection

We have developed a self-assembly method to obtain multi-wall carbon nanotube films applied in resistive gas sensor devices. This self-assembly method produces a homogeneous multi-wall carbon nanotube film with good adhesion to the substrate and an oxygen sensor device with a sensitivity 3.4 times higher than films made by regular casting deposition. A fast recovery time of 0.9 s was observed at 160 °C operation temperature.     

Room-temperature synthesis of three-dimensional porous ZnO@CuNi hybrid magnetic layers with photoluminescent and photocatalytic properties

A facile synthetic approach to prepare porous ZnO@CuNi hybrid films is presented. Initially, magnetic CuNi porous layers (consisting of phase separated CuNi alloys) are successfully grown by electrodeposition at different current densities using H₂ bubbles as a dynamic template to generate the porosity. The porous CuNi alloys serve as parent scaffolds to be subsequently filled with a solution containing ZnO nanoparticles previously synthesized by sol-gel. The dispersed nanoparticles are deposited dropwise onto the CuNi frameworks and the solvent is left to evaporate while the nanoparticles impregnate the interior of the pores, rendering ZnO-coated CuNi 3D porous structures. No thermal annealing is required to obtain the porous films. The synthesized hybrid porous layers exhibit an interesting combination of tunable ferromagnetic and photoluminescent properties. In addition, the aqueous photocatalytic activity of the composite is studied under UV?visible light irradiation for the degradation of Rhodamine B. The proposed method represents a fast and inexpensive approach towards the implementation of devices based on metal-semiconductor porous systems, avoiding the use of post-synthesis heat treatment steps which could cause deleterious oxidation of the metallic counterpart, as well as collapse of the porous structure and loss of the ferromagnetic properties.     

Contraceptive potential of a mifepristone-nomegestrol acetate sequential regimen in women

The effectiveness of a sequential regimen consisting of mifepristone, 10 mg/day for 15 days, followed by nomegestrol acetate (NOMA), 5 mg/day for the next 13 days, for inhibiting ovulation and maintaining regular bleeding cycles was assessed in 10 surgically sterilized volunteers who were followed for one pretreatment and three treated cycles. Hormonal determinations in blood and urine, ovarian ultrasonography, bleeding records in all cycles and an endometrial biopsy taken on day 22-25 of the third treatment cycle were used to monitor the effects of treatment. During treatment, 24 monophasic (no sustained progesterone rise above 12 nmol/l) and six biphasic cycles were recorded. Nine follicular ruptures were detected echographically in these 30 treated cycles, five of which occurred in monophasic cycles. All follicular ruptures occurred on days 1-7 of NOMA treatment. Echographic and endocrine features of ovulatory cycles were both present in only four treated cycles (13.3%). Development of a secretory endometrium was achieved in all cases, but it was always irregular. Regular withdrawal bleeding occurred in all subjects and no adverse reactions were recorded. The ovarian and endometrial effects of this regimen justify testing its contraceptive effectiveness in phase 2 clinical trials.     

Relationship between the acid and limonin content of Washington Navel orange juices

Juice samples of Washington Navel oranges from three groves were analysed for limonin, °Brix and acid during several seasons. A strong correlation between limonin and acid content has been found.     

A communication infrastructure to ease the development of mobile collaborative applications

Mobile workers doing loosely coupled activities typically perform on demand collaboration in the physical workplace. Communication services available in such work scenarios are uncertain, therefore mobile collaborative applications supporting those activities must provide ad hoc communication mechanisms in order to use each cooperation opportunity. Typically, the complexity of implementing such mobile ad hoc communication mechanisms becomes a challenge that jeopardizes the development of mobile collaborative solutions. This article presents a communication infrastructure named HLMP API dealing with that challenge. HLMP API intends to ease the development of such applications through the reuse of communication services. The infrastructure is an application programming interface that implements the HLMP routing protocol and also some awareness mechanisms that are required for mobile loosely coupled work. Developers using this infrastructure do not have to perform low-level programming.     

A connected-component-labeling-based approach to virtual porosimetry

Analyzing the pore-size distribution of porous materials, made up of an aggregation of interconnected pores, is a demanding task. Mercury intrusion porosimetry (MIP) is a physical method that intrudes mercury into a sample at increasing pressures to obtain a pore-size histogram. This method has been simulated in-silice with several approaches requiring prior computation of a skeleton.We present a new approach to simulate MIP that does not require skeleton computation. Our method is an iterative process that considers the diameters corresponding to pressures. At each iteration, geometric tests detect throats for the corresponding diameter and a CCL process collects the region invaded by the mercury. Additionally, a new decomposition model called CUDB, is used. This is suitable for computing the throats and performs better with the CCL algorithm than a voxel model. Our approach obtains the pore-size distribution of the porous medium, and the corresponding pore graph.     

Retro‐Enantio N‐Methylated Peptides as β‐Amyloid Aggregation Inhibitors

An emerging and attractive target for the treatment of Alzheimer's disease is to inhibit the aggregation of β‐amyloid protein (Aβ). We applied the retro‐enantio concept to design an N‐methylated peptidic inhibitor of the Aβ42 aggregation process. This inhibitor, inrD, as well as the corresponding all‐L (inL) and all‐D (inD) analogues were assayed for inhibition of Aβ42 aggregation. They were also screened in neuroblastoma cell cultures to assess their capacity to inhibit Aβ42 cytotoxicity and evaluated for proteolytic stability. The results reveal that inrD and inD inhibit Aβ42 aggregation more effectively than inL, that inrD decreases Aβ42 cytotoxicity to a greater extent than inL and inD, and that as expected, both inD and inrD are stable to proteases. Based on these results, we propose that the retro‐enantio approach should be considered in future designs of peptide inhibitors of protein aggregation.     

Operational strategy for a partial nitritation–sequencing batch reactor treating urban landfill leachate to achieve a stable influent for an anammox reactor

BACKGROUND: In recent years, new technologies have been developed to deal with streams with high nitrogen loads, most of them based on the anammox process. As a first step in this process, ammonium has to be partially oxidized to nitrite. This partial nitritation is usually carried out through the SHARON process. However, it can also be achieved using other configurations (sequencing batch reactor or biofilm airlift, among others). The aim of this paper is to compare two different feeding strategies (fed‐batch and step‐feed) for the operation of a partial nitritation–sequencing batch reactor (PN‐SBR) treating raw urban landfill leachate. RESULTS: A PN‐SBR treating urban landfill leachate was started up and operated using two different feeding strategies: fed‐batch and step‐feed. When the experimental results were compared, it could be seen that during the step‐feed strategy the system was more stable and presented a better performance. In addition, a cycle profile evolution of the reactor in each strategy was carried out to study the dynamics of the main chemical compounds, as well as different physical parameters. The profiles were similar for the nitrogen compounds, but with a difference in behaviour of pH, inorganic carbon and oxygen uptake ratio, which could explain the better performance and stability of the step‐feed strategy. CONCLUSIONS: This study has demonstrated that the step‐feed strategy is more suitable than the fed‐batch because it performs better overall, there is less fluctuation in its operation and it has higher effluent quality stabilization. Copyright © 2008 Society of Chemical Industry     

Effect of the type of fat on the physicochemical,instrumental and sensory characteristics of reduced fat non-acid fermented sausages

Four batches of reduced fat non-acid fermented sausages were manufactured with pork-ham lean, and the addition of no fat (Lean), 5% pork backfat (BF), 5% sunflower oil (SO) and 5% diacylglycerols (DAGs). The effect of the type of fat as pork-fat substitute on some physicochemical parameters, instrumental color and texture and sensory attributes of the sausages was studied. Results showed that reduced fat non-acid fermented sausages containing less than 12.5% of fat (BF, SO and DAGs) had a good overall sensory quality. This means a fat reduction of more than 70% compared with the average fat content of standard fermented sausages of similar characteristics. Sausages with SO showed higher sensory ratings in desirable ripened odor and flavor attributes and improved texture defined by lower hardness and chewiness (both sensory and instrumental) and higher crumbliness. Sausages with DAGs showed a similar behavior to that of BF, so they could be a good alternative to produce healthier reduced fat non-acid fermented sausages.