Motor neurons degenerate in amyotrophic lateral sclerosis (ALS). The mechanisms for this neuronal... more Motor neurons degenerate in amyotrophic lateral sclerosis (ALS). The mechanisms for this neuronal cell death are not known, although apoptosis has been implicated. Oxidative damage to DNA and activation of p53 has been identified directly in motor neurons in cases of ALS. We evaluated whether motor neuron degeneration in ALS is associated with changes in the levels and function of the multifunctional protein apurinic/apyrimidinic enodnuclease (APE/Ref-1). APE/Ref-1 functions as an enzyme in the DNA base-excision repair pathway and as a redox-regulation protein for transcription factors. The protein level and localization of APE/Ref-1 are changed in ALS. Immunoblotting showed that APE/Ref-1 protein levels are increased in selectively vulnerable central nervous system (CNS) regions in individuals with ALS compared to age-matched controls. Plasmid DNA repair assay demonstrated that APE from individuals with ALS is competent in repairing apurinic (AP) sites. DNA repair function in nuclear fractions is increased significantly in ALS motor cortex and spinal cord. Immunocytochemistry and single-cell densitometry revealed that APE/Ref-1 is expressed at lower levels in control motor neurons than in ALS motor neurons, which are decreased in number by 42% in motor cortex. APE/Ref-1 is increased in the nucleus of remaining upper motor neurons in ALS, which show a 38% loss of nuclear area. APE-Ref-1 is also upregulated in astrocytes in spinal cord white matter pathways in familial ALS. We conclude that mechanisms for DNA repair are activated in ALS, supporting the possibility that DNA damage is an upstream mechanism for motor neuron degeneration in this disease.
When a developer is building different construction projects simultaneously, cash flow management... more When a developer is building different construction projects simultaneously, cash flow management is very important. If the actual cash flow has been reduced than expected, the developer may need to decide which of the projects need to proceed and which need to be either suspended or terminated. This paper builds a financial model that evaluates the various construction projects based on the status of the project technically and financially to determine the decision path that needs to be undertaken for each project, based on a multivariate approach from the expected cash inflow, priority, likelihood, and time of construction. The model builds a chain of possible outcomes, where a project may be temporarily put on hold for a while and then resumed by cash inflow expected from previous projects.
Finding the optimal portfolio (that is the portfolio with the highest utility) for an investor me... more Finding the optimal portfolio (that is the portfolio with the highest utility) for an investor means finding the best combination of the risk-free asset and the market portfolio. This is because we have seen that each portfolio on the CML (Which is the efficient frontier) is a combination of the market portfolio and the risk-free asset. The red point on the figure shows the maximal utility. The red point is denoted with "θ" where optimal asset is allocated. This point dominates all the individual assets below itself. Above this point, investors invest in risky assets borrowing from risk free assets.
Motor neurons degenerate in amyotrophic lateral sclerosis (ALS). The mechanisms for this neuronal... more Motor neurons degenerate in amyotrophic lateral sclerosis (ALS). The mechanisms for this neuronal cell death are not known, although apoptosis has been implicated. Oxidative damage to DNA and activation of p53 has been identified directly in motor neurons in cases of ALS. We evaluated whether motor neuron degeneration in ALS is associated with changes in the levels and function of the multifunctional protein apurinic/apyrimidinic enodnuclease (APE/Ref-1). APE/Ref-1 functions as an enzyme in the DNA base-excision repair pathway and as a redox-regulation protein for transcription factors. The protein level and localization of APE/Ref-1 are changed in ALS. Immunoblotting showed that APE/Ref-1 protein levels are increased in selectively vulnerable central nervous system (CNS) regions in individuals with ALS compared to age-matched controls. Plasmid DNA repair assay demonstrated that APE from individuals with ALS is competent in repairing apurinic (AP) sites. DNA repair function in nuclear fractions is increased significantly in ALS motor cortex and spinal cord. Immunocytochemistry and single-cell densitometry revealed that APE/Ref-1 is expressed at lower levels in control motor neurons than in ALS motor neurons, which are decreased in number by 42% in motor cortex. APE/Ref-1 is increased in the nucleus of remaining upper motor neurons in ALS, which show a 38% loss of nuclear area. APE-Ref-1 is also upregulated in astrocytes in spinal cord white matter pathways in familial ALS. We conclude that mechanisms for DNA repair are activated in ALS, supporting the possibility that DNA damage is an upstream mechanism for motor neuron degeneration in this disease.
When a developer is building different construction projects simultaneously, cash flow management... more When a developer is building different construction projects simultaneously, cash flow management is very important. If the actual cash flow has been reduced than expected, the developer may need to decide which of the projects need to proceed and which need to be either suspended or terminated. This paper builds a financial model that evaluates the various construction projects based on the status of the project technically and financially to determine the decision path that needs to be undertaken for each project, based on a multivariate approach from the expected cash inflow, priority, likelihood, and time of construction. The model builds a chain of possible outcomes, where a project may be temporarily put on hold for a while and then resumed by cash inflow expected from previous projects.
Finding the optimal portfolio (that is the portfolio with the highest utility) for an investor me... more Finding the optimal portfolio (that is the portfolio with the highest utility) for an investor means finding the best combination of the risk-free asset and the market portfolio. This is because we have seen that each portfolio on the CML (Which is the efficient frontier) is a combination of the market portfolio and the risk-free asset. The red point on the figure shows the maximal utility. The red point is denoted with "θ" where optimal asset is allocated. This point dominates all the individual assets below itself. Above this point, investors invest in risky assets borrowing from risk free assets.
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