γ-Tocopheryl quinone stimulates apoptosis in drug-sensitive and multidrug-resistant cancer cells

Chemotherapy-induced cell death is linked to apoptosis, and there is increasing evidence that multidrug-resistance in cancer cells may be the result of a decrease in the ability of a cell to initiate apoptosis in response to cytotoxic agents. In previous studies, we synthesized two classes of electrophilic tocopheryl quinones (TQ), nonarylating α-TQ and arylating γ-and δ-TQ, and found that γ-and δ-TQ, but not α-TQ, were highly cytotoxic in human acute lymphoblastic leukemia cells (CEM) and multidrug-resistant (MDR) CEM/VLB₁₀₀. We have now extended these studies on tumor biology with CFM, HL60 and MDR HL60/MX2 human promyelocytic leukemia, U937 human monocytic leukemia, and ZR-75-1 breast adenocarcinoma cells. γ-TQ, but not α-TQ or tocopherols, showed concentration and incubation time-dependent effects on loss of plasma membrane integrity, diminished viable cell number, and stimulation of apoptosis. Its cytotoxicity exceeded that of doxorubicin in HL60/MX2 cells, which express MRP, an MDR-associated protein. Apoptosis was confirmed by TEM, TUNEL, and DNA gel electrophoresis. Kinetic studies showed that an induction period was required to initiate an irreversible multiphase process. γ-TQ released mitochondrial cytochrome c to the cytosol, induced the cleavage of poly(ADP-ribose)polymerase, and depleted intracellular glutathione. Unlike xenobiotic electrophiles, γ-TQ is a highly cytotoxic arylating electrophile that stimulates apoptosis in several cancer cell lines including cells that express MDR through both P-glycoprotein and MRP-associated proteins. The biological properties of arylating TQ electrophiles are closely associated with cytotoxicity and may contribute to other biological effects of these highly active agents.     

Is There a Specific Executive Capacity for Dual Task Coordination? Evidence From Alzheimer's Disease.

Three experiments compared groups of Alzheimer's disease (AD) patients and healthy older and younger participants on visuospatial tracking and digit sequence recall, as single tasks and performed concurrently. In Experiment 1, tasks were performed concurrently with very low demand relative to span. Only the AD patients showed a dual task deficit. In Experiment 2, single task demand was manipulated on each task from below span to above span for each individual. All groups showed the same performance reductions with increasing demand. In Experiment 3, demand on 1 task was constant, whereas demand on the concurrent task was varied. AD patients showed a clear dual task deficit but were no more sensitive than control groups to varying demand. Results suggest an identifiable cognitive resource for dual task coordination within a multiple component working memory system. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Drug Repurposing in Rare Diseases: An Integrative Study of Drug Screening and Transcriptomic Analysis in Nephropathic Cystinosis

Diagnosis and cure for rare diseases represent a great challenge for the scientific community who often comes up against the complexity and heterogeneity of clinical picture associated to a high cost and time-consuming drug development processes. Here we show a drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases. This approach consists in combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels. Then, we identified potential drugs and metabolic pathways relevant for the pathophysiology of nephropathic cystinosis by comparing gene-expression signature of drugs that share common mechanisms of action or that involve similar pathways with the disease gene-expression signature achieved with RNA-seq.     

Oxidized Substrates of APEH as a Tool to Study the Endoprotease Activity of the Enzyme

APEH is a ubiquitous and cytosolic serine protease belonging to the prolyl oligopeptidase (POP) family, playing a critical role in the processes of degradation of proteins through both exo- and endopeptidase events. Endopeptidase activity has been associated with protein oxidation; however, the actual mechanisms have yet to be elucidated. We show that a synthetic fragment of GDF11 spanning the region 48–64 acquires sensitivity to the endopeptidase activity of APEH only when the methionines are transformed into the corresponding sulphoxide derivatives. The data suggest that the presence of sulphoxide-modified methionines is an important prerequisite for the substrates to be processed by APEH and that the residue is crucial for switching the enzyme activity from exo- to endoprotease. The cleavage occurs on residues placed on the C-terminal side of Met(O), with an efficiency depending on the methionine adjacent residues, which thereby may play a crucial role in driving and modulating APEH endoprotease activity.     

Plasma Levels of Homocysteine and Cysteine Increased in Pediatric NAFLD and Strongly Correlated with Severity of Liver Damage

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of metabolic abnormalities ranging from simple triglyceride accumulation in the hepatocytes to hepatic steatosis with inflammation, ballooning and fibrosis. It has been demonstrated that the pathogenesis of NAFLD involves increased oxidative stress, with consumption of the major cellular antioxidant, glutathione (GSH). Liver has a fundamental role in sulfur compound metabolism, although the data reported on plasma thiols status in NAFLD are conflicting. We recruited 63 NAFLD patients, and we analyzed all plasma thiols, such as homocysteine (Hcy), cysteine (Cys), cysteinylglycine (CysGly) and GSH, by high-performance liquid chromatography (HPLC) with fluorescence detection. Hcy, Cys and CysGly plasma levels increased in NAFLD patients (p < 0.0001); whereas GSH levels were decreased in NAFLD patients when compared to controls (p < 0.0001). On the contrary, patients with steatohepatitis exhibited lower levels of Hcy and Cys than subjects without. Furthermore, a positive correlation was found between Hcy and Cys and the presence of fibrosis in children with NAFLD. Taken together, these data demonstrated a defective hepatic sulfur metabolism in children with NAFLD, and that high levels of Hcy and Cys probably correlates with a pattern of more severe histological liver damage, due to mechanisms that require further studies.     

Airflow modelling in a computer room

This study concerns the numerical simulation of airflow and the prediction of comfort properties in a visualisation room of a research centre. Because simulation accuracy depends on the modelling level, special care has been given to fine details. Particular interest has been concentrated on the four-way ceiling air supply diffuser, on the furniture and on the thermal conditions given on computers and on mannequins.

The geometric model was created using the parametric features of the pre-processor Gambit, in combination with elements created with the Rhinoceros NURBS modelling tool.

Mass, momentum, energy, turbulence, species and radiation conservation equations were solved using Fluent commercial flow solver. Computed airflow and heat transfer parameters were used for numerical prediction of indoor air quality quantities based on ISO 7730. Basic parameters included air temperature, relative humidity and air velocity. These were combined with clothing insulation and metabolic activity measures to obtain standard IAQ indices such as the mean age of air, the predicted mean vote and the predicted percentage of dissatisfied room occupants.

Post-processing was carried out with standard Fluent elements and also using Vu, a multi-platform tool which also allows data to be displayed in the Cave immersive environment.     

The development of a sustainable development model framework

The emergence of the “sustainable development” concept as a response to the mining of natural resources for the benefit of multinational corporations has advanced the cause of long-term environmental management. A sustainable development model (SDM) framework that is inclusive of the “whole” natural environment is presented to illustrate the integration of the sustainable development of the “whole” ecosystem. The ecosystem approach is an inclusive framework that covers the natural environment relevant futures and constraints. These are dynamically interconnected and constitute the determinates of resources development component of the SDM. The second component of the SDM framework is the resources development patterns, i.e., the use of land, water, and atmospheric resources. All of these patterns include practices that utilize environmental resources to achieve a predefined outcome producing waste and by-products that require disposal into the environment. The water quality management practices represent the third component of the framework. These practices are governed by standards, limitations and available disposal means subject to quantity and quality permits. These interconnected standards, practices and permits shape the resulting environmental quality of the ecosystem under consideration. A fourth component, environmental indicators, of the SDM framework provides a measure of the ecosystem productivity and status that may differ based on societal values and culture. The four components of the SDM are interwoven into an outcome assessment process to form the management and feedback models. The concept of Sustainable Development is expressed in the management model as an objective function subject to desired constraints imposing the required bounds for achieving ecosystem sustainability. The development of the objective function and constrains requires monetary values for ecosystem functions, resources development activities and environmental cost. The feedback model ensures policy and resources use changes required for sustainability. An iterative process would be required to define the optimum ecosystem development plan that satisfies sustainable outcome.     

Prediction of fire and smoke propagation in an underwater tunnel

Different models and solvers are used to calculate the spread of fire and smoke in a tunnel. The methodology for obtaining the numerical solution of this fire dynamics problem involves commercial software and a research program. Both can handle geometries described in three dimensions. Particular emphasis was placed on road tunnels in which vehicles are present. The specific application of this work is a study of a fire scenario in the Louis-Hippolyte-Lafontaine Tunnel which runs under a river in the Montreal area. Besides standard representation, visualization is also used, with elements which consider the optical properties of the phenomenon for a realistic rendering of smoke and fire.     

Cell proliferation’ differentiation’ and apoptosis are modified by n−3 polyunsaturated fatty acids in normal colonic mucosa

Supplementation with low doses of eicosapentaenoic (EPA) or docosahexaenoic (DHA) acid was used here to investigate changes in epithelial proliferation’ differentiation’ and apoptosis in normal rat colonic mucosa. ACI/T rats received by oral administration low doses of purified EPA or DHA ethyl esters (1g/kg body weight) and colonic mucosa was analyzed for cell proliferation’ differentiation’ and apoptosis. n−3 Polyunsaturated fatty acid incorporation into membrane phospholipids was investigated as reflections of fatty acid metabolism. Both EPA and DHA suppressed colonocyle proliferation and increased the numbers of differentiating and apoptotic cells without modification of the crypt morphology and the number of cells per crypt columns. A significant incorporation of the supplemented fatty acids into total phospholipids was observed. This enrichment was accompanied by a decreased content in arachidonic acid. The observation that EPA and DHA do not alter crypt morphology although they modify cell turnover in normal colonic mucosa suggests a possible use of these fatty acids as dietary chemopreventive agents.