Selection of Evolutionary Multicriteria Strategies: Application in Designing a Regional Water Restoration Management Plan

Sustainability of water resources has become a challenging problem worldwide, as the pollution levels of natural water resources (particularly of rivers) have increased drastically in the last decades. Nowadays, there are many Waste Water Treatment Plant (WWTP) technologies that provide different levels of efficiency in the removal of water pollutants, leading to a great number of combinations of different measures (PoM) or strategies. The management problem, then, involves finding which of these combinations are efficient, regarding the desired objectives (cost and quality). Therefore, decisions affecting water resources require the application of multi-objective optimization techniques which will lead to a set of tradeoff solutions, none of which is better or worse than the others, but, rather, the final decision must be one particular PoM including representative features of the whole set of solutions. Besides, there is not a universally accepted standard way to assess the water quality of a river. In order to consider simultaneously all these issues, we present in this work a hydroinformatics management tool, designed to help decision makers with the selection of a PoM that satisfies the WFD objectives. Our approach combines: 1) a Water Quality Model (WQM), devised to simulate the effects of each PoM used to reduce pollution pressures on the hydrologic network; 2) a Multi-Objective Evolutionary Algorithm (MOEA), used to identify efficient tradeoffs between PoMs’ costs and water quality; and 3) visualization of the Pareto optimal set, in order to extract knowledge from optimal decisions in a usable form. We have applied our methodology in a real scenario, the inner Catalan watersheds with promising results

An Analysis by Synthesis Approach for Automatic Vertebral Shape Identification in Clinical QCT

Quantitative computed tomography (QCT) is a widely used tool for osteoporosis diagnosis and monitoring. The assessment of cortical markers like cortical bone mineral density (BMD) and thickness is a demanding task, mainly because of the limited spatial resolution of QCT. We propose a direct model based method to automatically identify the surface through the center of the cortex of human vertebra. We develop a statistical bone model and analyze its probability distribution after the imaging process. Using an as-rigid-as-possible deformation we find the cortical surface that maximizes the likelihood of our model given the input volume. Using the European Spine Phantom (ESP) and a high resolution \mu CT scan of a cadaveric vertebra, we show that the proposed method is able to accurately identify the real center of cortex ex-vivo. To demonstrate the in-vivo applicability of our method we use manually obtained surfaces for comparison.Comment: Presented on German Conference on Pattern Recognition (GCPR) 2018 in Stuttgar

Δ40 Isoform of p53 Controls β-Cell Proliferation and Glucose Homeostasis in Mice

Objective: Investigating the dynamics of pancreatic $\beta$-cell mass is critical for developing strategies to treat both type 1 and type 2 diabetes. p53, a key regulator of the cell cycle and apoptosis, has mostly been a focus of investigation as a tumor suppressor. Although p53 alternative transcripts can modulate p53 activity, their functions are not fully understood. We hypothesized that $\beta$-cell proliferation and glucose homeostasis were controlled by $\Delta$40p53, a p53 isoform lacking the transactivation domain of the full-length protein that modulates total p53 activity and regulates organ size and life span in mice. Research Design and Methods: We phenotyped metabolic parameters in $\Delta$40p53 transgenic (p44tg) mice and used quantitative RT-PCR, Western blotting, and immunohistochemistry to examine $\beta$-cell proliferation. Results: Transgenic mice with an ectopic p53 gene encoding $\Delta$40p53 developed hypoinsulinemia and glucose intolerance by 3 months of age, which worsened in older mice and led to overt diabetes and premature death from $\sim$14 months of age. Consistent with a dramatic decrease in $\beta$-cell mass and reduced $\beta$-cell proliferation, lower expression of cyclin D2 and pancreatic duodenal homeobox-1, two key regulators of proliferation, was observed, whereas expression of the cell cycle inhibitor p21, a p53 target gene, was increased. Conclusions: These data indicate a significant and novel role for $\Delta$40p53 in $\beta$-cell proliferation with implications for the development of age-dependent diabetes

The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia

Cytarabine (ara-C) is the most effective agent for the treatment of acute myeloid leukaemia (AML). Aberrant expression of enzymes involved in the transport/metabolism of ara-C could explain drug resistance. We determined mRNA expression of these factors using quantitative-real-time-PCR in leukemic blasts from children diagnosed with de novo AML. Expression of the inactivating enzyme pyrimidine nucleotidase-I (PN-I) was 1.8-fold lower in FAB-M5 as compared to FAB-M1/2 (P=0.007). In vitro sensitivity to deoxynucleoside analogues was determined using the MTT-assay. Human equilibrative nucleoside transporter-1 (hENT1) mRNA expression and ara-C sensitivity were significantly correlated (rp=−0.46; P=0.001), with three-fold lower hENT1 mRNA levels in resistant patients (P=0.003). hENT1 mRNA expression also seemed to correlate inversely with the LC50 values of cladribine (rp=−0.30; P=0.04), decitabine (rp=−0.29; P=0.04) and gemcitabine (rp=−0.33; P=0.02). Deoxycytidine kinase (dCK) and cytidine deaminase (CDA) mRNA expression seemed to correlate with in vitro sensitivity to gemcitabine (rp=−0.31; P=0.03) and decitabine (rp=0.33; P=0.03), respectively. The dCK/PN-I ratio correlated inversely with LC50 values for gemcitabine (rp=−0.45, P=0.001) and the dCK/CDA ratio seemed to correlate with LC50 values for decitabine (rp=−0.29; 0.04). In conclusion, decreased expression of hENT1, which transports ara-C across the cell membrane, appears to be a major factor in ara-C resistance in childhood AML

Comparative molecular biological analysis of membrane transport genes in organisms

Comparative analyses of membrane transport genes revealed many differences in the features of transport homeostasis in eight diverse organisms, ranging from bacteria to animals and plants. In bacteria, membrane-transport systems depend mainly on single genes encoding proteins involved in an ATP-dependent pump and secondary transport proteins that use H+ as a co-transport molecule. Animals are especially divergent in their channel genes, and plants have larger numbers of P-type ATPase and secondary active transporters than do other organisms. The secondary transporter genes have diverged evolutionarily in both animals and plants for different co-transporter molecules. Animals use Na+ ions for the formation of concentration gradients across plasma membranes, dependent on secondary active transporters and on membrane voltages that in turn are dependent on ion transport regulation systems. Plants use H+ ions pooled in vacuoles and the apoplast to transport various substances; these proton gradients are also dependent on secondary active transporters. We also compared the numbers of membrane transporter genes in Arabidopsis and rice. Although many transporter genes are similar in these plants, Arabidopsis has a more diverse array of genes for multi-efflux transport and for response to stress signals, and rice has more secondary transporter genes for carbohydrate and nutrient transport

Gpr124 is essential for blood-brain barrier integrity in central nervous system disease

Although blood-brain barrier (BBB) compromise is central to the etiology of diverse central nervous system (CNS) disorders, endothelial receptor proteins that control BBB function are poorly defined. The endothelial G-protein-coupled receptor (GPCR) Gpr124 has been reported to be required for normal forebrain angiogenesis and BBB function in mouse embryos, but the role of this receptor in adult animals is unknown. Here Gpr124 conditional knockout (CKO) in the endothelia of adult mice did not affect homeostatic BBB integrity, but resulted in BBB disruption and microvascular hemorrhage in mouse models of both ischemic stroke and glioblastoma, accompanied by reduced cerebrovascular canonical Wnt-β-catenin signaling. Constitutive activation of Wnt-β-catenin signaling fully corrected the BBB disruption and hemorrhage defects of Gpr124-CKO mice, with rescue of the endothelial gene tight junction, pericyte coverage and extracellular-matrix deficits. We thus identify Gpr124 as an endothelial GPCR specifically required for endothelial Wnt signaling and BBB integrity under pathological conditions in adult mice. This finding implicates Gpr124 as a potential therapeutic target for human CNS disorders characterized by BBB disruption

Early Treatment with Basal Insulin Glargine in People with Type 2 Diabetes: Lessons from ORIGIN and Other Cardiovascular Trials

Dysglycemia results from a deficit in first-phase insulin secretion compounded by increased insulin insensitivity, exposing beta cells to chronic hyperglycemia and excessive glycemic variability. Initiation of intensive insulin therapy at diagnosis of type 2 diabetes mellitus (T2DM) to achieve normoglycemia has been shown to reverse glucotoxicity, resulting in recovery of residual beta-cell function. The United Kingdom Prospective Diabetes Study (UKPDS) 10-year post-trial follow-up reported reductions in cardiovascular outcomes and all-cause mortality in persons with T2DM who initially received intensive glucose control compared with standard therapy. In the cardiovascular outcome trial, outcome reduction with an initial glargine intervention (ORIGIN), a neutral effect on cardiovascular disease was observed in the population comprising prediabetes and T2DM. Worsening of glycemic control was prevented over the 6.7 year treatment period, with few serious hypoglycemic episodes and only moderate weight gain, with a lesser need for dual or triple oral treatment versus standard care. Several other studies have also highlighted the benefits of early insulin initiation as first-line or add-on therapy to metformin. The decision to introduce basal insulin to metformin must, however be individualized based on a risk-benefit analysis. The landmark ORIGIN trial provides many lessons relating to the concept and application of early insulin therapy for the prevention and safe and effective induction and maintenance of glycemic control in type 2 diabetes