Analytic philosophy for biomedical research: the imperative of applying yesterday's timeless messages to today's impasses

The mantra that "the best way to predict the future is to invent it" (attributed to the computer scientist Alan Kay) exemplifies some of the expectations from the technical and innovative sides of biomedical research at present. However, for technical advancements to make real impacts both on patient health and genuine scientific understanding, quite a number of lingering challenges facing the entire spectrum from protein biology all the way to randomized controlled trials should start to be overcome. The proposal in this chapter is that philosophy is essential in this process. By reviewing select examples from the history of science and philosophy, disciplines which were indistinguishable until the mid-nineteenth century, I argue that progress toward the many impasses in biomedicine can be achieved by emphasizing theoretical work (in the true sense of the word 'theory') as a vital foundation for experimental biology. Furthermore, a philosophical biology program that could provide a framework for theoretical investigations is outlined

Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias

<p>Abstract</p> <p>Background</p> <p>Gene mutation is an important mechanism of myeloid leukemogenesis. However, the number and combination of gene mutated in myeloid malignancies is still a matter of investigation.</p> <p>Methods</p> <p>We searched for mutations in the <it>ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 </it>and <it>WT1 </it>genes in 65 myelodysplastic syndromes (MDSs) and 64 acute myeloid leukemias (AMLs) without balanced translocation or complex karyotype.</p> <p>Results</p> <p>Mutations in <it>ASXL1 </it>and <it>CBL </it>were frequent in refractory anemia with excess of blasts. Mutations in <it>TET2 </it>occurred with similar frequency in MDSs and AMLs and associated equally with either <it>ASXL1 </it>or <it>NPM1 </it>mutations. Mutations of <it>RUNX1 </it>were mutually exclusive with <it>TET2 </it>and combined with <it>ASXL1 </it>but not with <it>NPM1</it>. Mutations in <it>FLT3 (</it>mutation and internal tandem duplication), <it>IDH1</it>, <it>IDH2</it>, <it>NPM1 </it>and <it>WT1 </it>occurred primarily in AMLs.</p> <p>Conclusion</p> <p>Only 14% MDSs but half AMLs had at least two mutations in the genes studied. Based on the observed combinations and exclusions we classified the 12 genes into four classes and propose a highly speculative model that at least a mutation in one of each class is necessary for developing AML with simple or normal karyotype.</p

Trypacidin, a Spore-Borne Toxin from Aspergillus fumigatus, Is Cytotoxic to Lung Cells

Inhalation of Aspergillus fumigatus conidia can cause severe aspergillosis in immunosuppressed people. A. fumigatus produces a large number of secondary metabolites, some of which are airborne by conidia and whose toxicity to the respiratory tract has not been investigated. We found that spores of A. fumigatus contain five main compounds, tryptoquivaline F, fumiquinazoline C, questin, monomethylsulochrin and trypacidin. Fractionation of culture extracts using RP-HPLC and LC-MS showed that samples containing questin, monomethylsulochrin and trypacidin were toxic to the human A549 lung cell line. These compounds were purified and their structure verified using NMR in order to compare their toxicity against A549 cells. Trypacidin was the most toxic, decreasing cell viability and triggering cell lysis, both effects occurring at an IC50 close to 7 µM. Trypacidin toxicity was also observed in the same concentration range on human bronchial epithelial cells. In the first hour of exposure, trypacidin initiates the intracellular formation of nitric oxide (NO) and hydrogen peroxide (H2O2). This oxidative stress triggers necrotic cell death in the following 24 h. The apoptosis pathway, moreover, was not involved in the cell death process as trypacidin did not induce apoptotic bodies or a decrease in mitochondrial membrane potential. This is the first time that the toxicity of trypacidin to lung cells has been reported

3D micro-macro fluid-structure model of pressure relief valve leak tightness

Controlling and assessing the leak tightness of a Pressure Relief Valve (PRV) has been a challenge since the original design of the product. With more stringent demands from the nu- clear power industry for leakproof PRV’s, closer to the set point, there has been a drive by both industry and academia for a better design method for many known metal-to-metal contacting seal/surface problems. This paper outlines a numerical modelling strategy drawn from industry experience and metrology measurements and investigates the effects of lapping and surface finish on leakage rate. Key influencing parameters of surface form, waviness and roughness are incorporated in the analysis. The numerical approach requires efficient coupling of a non-linear structural Finite Element Analysis (FEA) with a Computational Fluid Dynamic (CFD) solver. This allows the examination of the relationship between deformation of the contacting surfaces, based on the applied spring force, and the resulting micro-flow of gas through any available gaps and the overall leakage to be found. The API527 Seat Tightness methodology is followed to allow leakage rates to be measured and the computational model to be preliminarily validated. Using this model, engineers can adjust and optimise the design of pressure relief valves to find the minimal leakage condition for a given configuration. In addition, the numerical approach can potentially be applied to other metal-to-metal contacting surface components, such as flanges with metal gaskets, and help eliminate leakage

Impact de l'érosion sur l'envasement des barrages, la recharge des nappes phréatiques côtières et les intrusions marines dans la zone semi-aride méditerranéenne : cas du barrage de Boukourdane (Algérie)

Impact of erosion on the silting of dams, on the recharging groundwater and on coastal marine intrusion in the Mediterranean semi-arid area: Case of Boukourdane dam (Algeria). Description of the subject. Water erosion is a particularly important issue, especially in the Mediterranean and semi-arid zone. This zone is characterized by irregular rainfall patterns, which have a considerable influence on soil loss. In mountainous areas, water erosion phenomena are accentuated by steep slopes and low ground cover. The dams draining these areas undergo siltation linked to significant erosion. The silting of the dams drastically limits their capacity and thus their operating life. When used for recharging aquifers, the resuspension of fine particles may accumulate in the recharge areas and reduce infiltration capacity by clogging soil porosity. This leads to a significant reduction of groundwater levels. Additionally, groundwater situated in the coastal zone is submitted to intensive pumping. These two phenomena make groundwater particularly sensitive to marine intrusions. Objectives. This article aims, on the one hand to quantify the rate of siltation in the case of the Boukourdane dam (northern Algeria), which is used to recharge groundwater. On the other hand, the article also shows the reduction in permeability in the capturing field with the current management of releases. Method. Solid rates were set in relation to the liquid flow and sediment concentration occasionally taken from the wadi. The relation established made it possible to evaluate the solid contributions to the dam of Boukourdane. The impact of the releases on recharging the well field was evaluated by grouping wells and the well field mushrooms using heuristic k-means. Regressions were applied to the piezometric variations of each group. Results. This dam is fed by a catchment area of 156 km². Sediment transport was estimated from empirical formulas. The specific degradation rate was estimated at 366 t·km-2·year-1 during the 1993 to 2005 period. The increase in the frequency of extreme rainfall resulted in an increase in the soil erosion rate to 446 t·km-2·year-1 during the 1993 to 2013 period. The volume of sediments accumulated in the dam reached 8·104 m³·year-1 and 11·104 m³·year-1 respectively during these two periods. Conclusions. A change in the management of current releases has a positive impact on the partial restoration of the hydraulic conductivity and de facto, on the fight against marine intrusion

Effect of PR toxin on THP1 and Caco-2 cells: an in vitro study

International audiencePenicillium roqueforti produces mycotoxins including PR toxin, which is a food and feed contaminant. In this study, PR toxin was purified from culture material of the Penicillium roqueforti F43-1 strain. Toxic effects were evaluated in undifferentiated human Caco-2 intestinal epithelial cells and THP-1 monocytic immune cells. To understand the mechanisms involved in PR-toxin toxicity, cell death and pro-inflammatory gene expression were studied. In addition, PR toxin degradation was assessed. Cytotoxicity studies showed a dose-dependent effect of PR toxin and the calculated mean cytotoxic concentration (IC50) concentrations were for Caco-2 and THP-1 cells >12.5 and 0.83 mu M, respectively. Gene expression studies showed that tumour necrosis factor-a expression was significantly increased after 24 h exposure to 312 mu M PR toxin. PR toxin induced necrosis on THP-1 cells after 3 h exposure. In the cell culture system, the PR toxin showed a 10-fold reduction in PR toxin concentration within 48 h, indicating that PR toxin was degraded by THP-1. To conclude, PR toxin appears to be one of the most cytotoxic P. roqueforti mycotoxins on Caco-2 and/or THP-1 cells and induces in THP-1 cells both necrosis and an inflammatory response