Pseudospectral Knotting Methods for Solving Optimal Control Problems

The article of record as published may be found at https://doi.org/10.2514/1.3426A class of computational methods for solving a wide variety of optimal control problems is presented; these problems include nonsmooth, nonlinear, switched optimal control problems, as well as standard multiphase prob lems. Methods are based on pseudospectral approximations of the differential constraints that are assumed to be given in the form of controlled differential inclusions including the usual vector field and differential-algebraic forms. Discontinuities and switches in states, controls, cost functional, dynamic constraints, and various other mappings associated with the generalized Bolza problem are allowed by the concept of pseudospectral (PS) knots. Information across switches and corners is passed in the form of discrete event conditions localized at the PS knots. The optimal control problem is approximated to a structured sparse mathematical programming problem. The discretized problem is solved using off-the-shelf solvers that include sequential quadratic programming and interior point methods. Two examples that demonstrate the concept of hard and soft knots are presented.Charles Stark Draper Laboratory, Inc. (Draper)Jet Propulsion Laboratory (JPL)Naval Postgraduate SchoolSecretary of the U.S. Air Forc

Convergence of Pseudospectral Discretization of Optimal Control Problems, IEEE (40th; 2001; Orlando, Florida)

The article of record as published may be located at http://ieeexplore.ieee.orgProceedings of the 40th IEEE Conference on Decision and Control ; Orlando, Florida USA, December 2001A generic nonlinear optimal control problem with a Bolza cost functional is discretized by a Legendre pseudospectral method. According to the covector mapping theorem, the Karush-Kuhn-Tucker multipliers of the discrete problem map linearly to the spectrally discretized covectors of the Bolza problem. Using this result, it is shown that the nonlinear programming problem converges to the continuous Bolza problem at a spectral rate assuming regularity of appropriate functions.Approved for public release; distribution is unlimited

On the Pseudospectral Convector Mapping Theorem for Nonlinear Optimal Control, IEEE (45th; 2006)

The article of record as published may be located at http://ieeexplore.ieee.orgProceedings of 45th IEEE Conference on Decision and Control Page(s): 2679 - 2686, Dec.13-15, 2006In recent years, a large number of nonlinear optimal control problems have been solved by pseudospectral (PS) methods. In an effort to better understand the PS approach to solving control problems, we present convergence results for problems with mixed state and control constraints. A set of sufficient conditions are proved under which the solution of the discretized optimal control problem converges to the continuous solution. Conditions for the convergence of the duals are described and illustrated. This leads to a clarification of covector mapping theorem and its connections to constraint qualifications.Approved for public release; distribution is unlimited

Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth

The tumor microenvironment is composed of a complex mixture of different cell types interacting under conditions of nutrient deprivation, but the metabolism therein is not fully understood due to difficulties in measuring metabolic fluxes and exchange of metabolites between different cell types in vivo. Genome-scale metabolic modeling enables estimation of such exchange fluxes as well as an opportunity to gain insight into the metabolic behavior of individual cell types. Here, we estimated the availability of nutrients and oxygen within the tumor microenvironment using concentration measurements from blood together with a metabolite diffusion model. In addition, we developed an approach to efficiently apply enzyme usage constraints in a comprehensive metabolic model of human cells. The combined modeling reproduced severe hypoxic conditions and the Warburg effect, and we found that limitations in enzymatic capacity contribute to cancer cells’ preferential use of glutamine as a substrate to the citric acid cycle. Furthermore, we investigated the common hypothesis that some stromal cells are exploited by cancer cells to produce metabolites useful for the cancer cells. We identified over 200 potential metabolites that could support collaboration between cancer cells and cancer-associated fibroblasts, but when limiting to metabolites previously identified to participate in such collaboration, no growth advantage was observed. Our work highlights the importance of enzymatic capacity limitations for cell behaviors and exemplifies the utility of enzyme-constrained models for accurate prediction of metabolism in cells and tumor microenvironments

Pediatric patient with systemic lupus erythematosus & congenital acquired immunodeficiency syndrome: An unusual case and a review of the literature

The coexistence of systemic lupus erythematosus (SLE) in patients with congenital human immunodeficiency virus (HIV) infection is rare. This is a case report of a child diagnosed with SLE at nine years of age. She initially did well on non-steroidal anti-inflammatory agents, hydroxychloroquine, and steroids. She then discontinued her anti-lupus medications and was lost to follow-up. At 13 years of age, her lupus symptoms had resolved and she presented with intermittent fevers, cachexia, myalgias, arthralgias, and respiratory symptoms. Through subsequent investigations, the patient was ultimately diagnosed with congenitally acquired immunodeficiency syndrome (AIDS)

Improvement in symptoms and pulmonary function of asthmatic patients due to their treatment according to the Global Strategy for Asthma Management (GINA)

<p>Abstract</p> <p>Background</p> <p>Global Initiative Strategy for Asthma Management (GINA) is poorly applied in undeveloped and developing countries. The current study examined the effects of applying GINA guidelines on treatment efficacy in asthmatic patients in Iran.</p> <p>Methods</p> <p>Twenty four asthmatic patients (usual care group) were treated as usual and 26 patients (intervention group) according to the GINA for 2 months. Asthma symptom score, asthma severity, frequency of symptoms/week and wheezing were recorded at the beginning (first visit), one month after treatment (second visit), and at the end of the study (third visit). Pulmonary function tests (PFTs) were performed by spirometry, and the patients' use of asthma drugs and their symptoms were evaluated, at each visit.</p> <p>Results</p> <p>Asthma symptoms, frequency of symptoms/week, chest wheezing, and PFT values were significantly improved in the intervention group at the second and third visits compared to first visit (p < 0.001 for all measures). In addition, exercise induced cough and wheeze were significant improved in the third visit compared to the second visit in this group (p < 0.01 for both measures). In the second and third visits all symptoms were significantly lower, and PFT values higher, in the intervention group compared to the usual care group (p < 0.005 to p < 0.001). In the usual care group, there were only small improvements in some parameters in just the second visit (p < 0.01 for all measures). The use of asthma drugs was unchanged in the usual care group and significantly reduced in the intervention group (p < 0.01) by the end of the study.</p> <p>Conclusion</p> <p>Adoption of GINA guidelines improves asthma symptoms and pulmonary function in asthmatic patients in Iran.</p

Plasma Metabolomics Identifies Markers of Impaired Renal Function: A Meta-analysis of 3089 Persons with Type 2 Diabetes

CONTEXT: There is a need for novel biomarkers and better understanding of the pathophysiology of diabetic kidney disease. OBJECTIVE: To investigate associations between plasma metabolites and kidney function in people with type 2 diabetes (T2D). DESIGN: 3089 samples from individuals with T2D, collected between 1999 and 2015, from 5 independent Dutch cohort studies were included. Up to 7 years follow-up was available in 1100 individuals from 2 of the cohorts. MAIN OUTCOME MEASURES: Plasma metabolites (n = 149) were measured by nuclear magnetic resonance spectroscopy. Associations between metabolites and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and eGFR slopes were investigated in each study followed by random effect meta-analysis. Adjustments included traditional cardiovascular risk factors and correction for multiple testing. RESULTS: In total, 125 metabolites were significantly associated (PFDR = 1.5×10-32 - 0.046; β = -11.98-2.17) with eGFR. Inverse associations with eGFR were demonstrated for branched-chain and aromatic amino acids (AAAs), glycoprotein acetyls, triglycerides (TGs), lipids in very low-density lipoproteins (VLDL) subclasses, and fatty acids (PFDR < 0.03). We observed positive associations with cholesterol and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1 (PFDR < 0.05). Albeit some metabolites were associated with UACR levels (P < 0.05), significance was lost after correction for multiple testing. Tyrosine and HDL-related metabolites were positively associated with eGFR slopes before adjustment for multiple testing (PTyr = 0.003; PHDLrelated < 0.05), but not after. CONCLUSIONS: This study identified metabolites associated with impaired kidney function in T2D, implying involvement of lipid and amino acid metabolism in the pathogenesis. Whether these processes precede or are consequences of renal impairment needs further investigation

Peroxiredoxin 6 in human brain: molecular forms, cellular distribution and association with Alzheimer’s disease pathology

Peroxiredoxin 6 is an antioxidant enzyme and is the 1-cys member of the peroxiredoxin family. Using two-dimensional electrophoresis and Western blotting, we have shown for the first time that, in human control and brain tissue of patient’s with Alzheimer’s disease (AD), this enzyme exists as three major and five minor forms with pIs from 5.3 to 6.1. Using specific cellular markers, we have shown that peroxiredoxin 6 is present in astrocytes with very low levels in neurons, but not detectable in microglia or oligodendrocytes. In control brains, there was a very low level of peroxiredoxin 6 staining in astrocytes that was confined to a “halo” around the nucleus. In AD, there were marked increases in the number and staining intensity of peroxiredoxin 6 positive astrocytes in both gray and white matter in the midfrontal cortex, cingulate, hippocampus and amygdala. Confocal microscopy using antibodies to Aβ peptide, tau and peroxiredoxin 6 showed that peroxiredoxin 6 positive astrocytes are closely involved with diffuse plaques and to a lesser extent with neuritic plaques, suggesting that plaques are producing reactive oxygen species. There appeared to be little astrocytic response to tau containing neurons. Although peroxiredoxin 6 positive astrocytes were seen to make multiple contacts with tau positive neurons, there was no intraneuronal colocalization. In brain tissue of patients with AD, many blood vessels exhibited peroxiredoxin 6 staining that appeared to be due to the astrocytic foot processes. These results suggest that oxidative stress conditions exist in AD and that peroxiredoxin 6 is an important antioxidant enzyme in human brain defenses

Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol

OBJECTIVE LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown. RESEARCH DESIGN AND METHODS We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses. RESULTS A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (b 5 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P 5 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P 5 0.04). CONCLUSIONS These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications