Reduced-order modeling using Dynamic Mode Decomposition and Least Angle Regression

Dynamic Mode Decomposition (DMD) yields a linear, approximate model of a system's dynamics that is built from data. We seek to reduce the order of this model by identifying a reduced set of modes that best fit the output. We adopt a model selection algorithm from statistics and machine learning known as Least Angle Regression (LARS). We modify LARS to be complex-valued and utilize LARS to select DMD modes. We refer to the resulting algorithm as Least Angle Regression for Dynamic Mode Decomposition (LARS4DMD). Sparsity-Promoting Dynamic Mode Decomposition (DMDSP), a popular mode-selection algorithm, serves as a benchmark for comparison. Numerical results from a Poiseuille flow test problem show that LARS4DMD yields reduced-order models that have comparable performance to DMDSP. LARS4DMD has the added benefit that the regularization weighting parameter required for DMDSP is not needed.Comment: 14 pages, 2 Figures, Submitted to AIAA Aviation Conference 201

Comparison of Measurement Accuracy Between Caliper and iPhone Apps

Measurements of bone artifacts can give insight into the influence of ecological resources on the survival and health of area inhabitants. Calipers are traditionally used for accurate measurements for shell and bone artifacts. Measurement apps may present an accurate alternative to calipers. In this experiment shell and bone artifacts were measured with calipers, the Ruler iPhone App, and the ARuler iPhone app. The results of this experiment show no statistical difference in the measurements taken using a caliper vs measurements taken on an iPhone apps. Though they were not statistically significant, there were differences in measurements between the various methods

The Relationship Between Magmatism and Deformation During the Acadian Orogeny: A Case Study from Eastern-Central Vermont

The Silurian-Devonian metasedimentary rocks of the Connecticut Valley-Gaspé trough (CVGT) were subjected to multiple deformational and metamorphic events during the Acadian orogeny in the Middle-Late Devonian. Plutons intruding the Devonian Waits River and Gile Mountain Formations have been considered post-tectonic, but microstructural studies of the intrusions and their metamorphic aureoles indicate some of these plutons intruded syntectonically. This study investigates the relationship between Acadian deformation and intrusion of the Knox Mountain pluton (KMP) of central Vermont. Structural and geochronological data were collected along a c. 15 km transect from the western limit of the CVGT, where the unconformable Richardson Memorial Contact coincides with the Dog River Fault Zone, into the margin of the KMP in the east. Field and microstructural observations indicate the KMP intruded syntectonically. Evidence for Acadian deformation post-dating intrusion includes folded and boudinaged granitic dikes at the margin of the KMP, and microstructures such as flame perthite, myrmekite, deformation twins, and textures associated with grain-boundary migration recrystallization in the granite. In the metamorphic aureole, biotite porphyroblasts overgrow S3, the earliest Acadian secondary foliation, and were deformed during S4 crenulation cleavage development. The KMP intruded at 377±5.2 Ma based on a U-Th-total Pb monazite crystallization age, which is concordant with the published age of the nearby Barre granite. The timing of S4 foliation development in the CVGT is constrained locally by 40Ar/39Ar geochronology at ~365 Ma, consistent with the microstructurally-inferred relative-age relationships. Plateau/weighted mean 40Ar/39Ar ages from across the transect and minimum ages from argon-loss profiles show a general trend of younging towards the east, suggesting these rocks have been affected by Alleghanian and Mesozoic deformation and exhumation

Path planning, flow estimation, and dynamic control for underwater vehicles

Underwater vehicles such as robotic fish and long-endurance ocean-sampling platforms operate in challenging fluid environments. This dissertation incorporates models of the fluid environment in the vehicles' guidance, navigation, and control strategies while addressing uncertainties associated with estimates of the environment's state. Coherent flow structures may be on the same spatial scale as the vehicle or substantially larger than the vehicle. This dissertation argues that estimation and control tasks across widely varying spatial scales, from vehicle-scale to long-range, may be addressed using common tools of empirical observability analysis, nonlinear/non-Gaussian estimation, and output-feedback control. As an application in vehicle-scale flow estimation and control, this dissertation details the design, fabrication, and testing of a robotic fish with an artificial lateral-line inspired by the lateral-line flow-sensing organ present in fish. The robotic fish is capable of estimating the flow speed and relative angle of the oncoming flow. Using symmetric and asymmetric sensor configurations, the robot achieves the primitive fish behavior called rheotaxis, which describes a fish's tendency to orient upstream. For long-range flow estimation and control, path planning may be accomplished using observability-based path planning, which evaluates a finite set of candidate control inputs using a measure related to flow-field observability and selects an optimizer over the set. To incorporate prior information, this dissertation derives an augmented observability Gramian using an optimal estimation strategy known as Incremental 4D-Var. Examination of the minimum eigenvalue of an empirical version of this Gramian yields a novel measure for path planning, called the empirical augmented unobservability index. Numerical experiments show that this measure correctly selects the most informative paths given the prior information. As an application in long-range flow estimation and control, this dissertation considers estimation of an idealized pair of ocean eddies by an adaptive Lagrangian sensor (i.e., a platform that uses its position data as measurements of the fluid transport, after accounting for its own control action). The adaptive sampling is accomplished using the empirical augmented unobservability index, which is extended to non-Gaussian posterior densities using an approximate expected-cost calculation. Output feedback recursively improves estimates of the vehicle position and flow-field states

In vivo editing of the pan-endothelium by immunity evading simian adenoviral vector

Biological applications deriving from the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 site-specific nuclease system continue to impact and accelerate gene therapy strategies. Safe and effective in vivo co-delivery of the CRISPR/Cas9 system to target somatic cells is essential in the clinical therapeutic context. Both non-viral and viral vector systems have been applied for this delivery matter. Despite elegant proof-of-principle studies, available vector technologies still face challenges that restrict the application of CRISPR/Cas9-facilitated gene therapy. Of note, the mandated co-delivery of the gene-editing components must be accomplished in the potential presence of pre-formed anti-vector immunity. Additionally, methods must be sought to limit the potential of off-target editing. To this end, we have exploited the molecular promiscuities of adenovirus (Ad) to address the key requirements of CRISPR/Cas9-facilitated gene therapy. In this regard, we have endeavored capsid engineering of a simian (chimpanzee) adenovirus isolate 36 (SAd36) to achieve targeted modifications of vector tropism. The SAd36 vector with the myeloid cell-binding peptide (MBP) incorporated in the capsid has allowed selective in vivo modifications of the vascular endothelium. Importantly, vascular endothelium can serve as an effective non-hepatic cellular source of deficient serum factors relevant to several inherited genetic disorders. In addition to allowing for re-directed tropism, capsid engineering of nonhuman primate Ads provide the means to circumvent pre-formed vector immunity. Herein we have generated a SAd36. MBP vector that can serve as a single intravenously administered agent allowing effective and selective in vivo editing for endothelial target cells of the mouse spleen, brain and kidney. DATA AVAILABILITY: The data that support the findings of this study are available from the corresponding author upon reasonable request

Somatic genome editing with CRISPR/Cas9 generates and corrects a metabolic disease

Germline manipulation using CRISPR/Cas9 genome editing has dramatically accelerated the generation of new mouse models. Nonetheless, many metabolic disease models still depend upon laborious germline targeting, and are further complicated by the need to avoid developmental phenotypes. We sought to address these experimental limitations by generating somatic mutations in the adult liver using CRISPR/Cas9, as a new strategy to model metabolic disorders. As proof-of-principle, we targeted the low-density lipoprotein receptor (Ldlr), which when deleted, leads to severe hypercholesterolemia and atherosclerosis. Here we show that hepatic disruption of Ldlr with AAV-CRISPR results in severe hypercholesterolemia and atherosclerosis. We further demonstrate that co-disruption of Apob, whose germline loss is embryonically lethal, completely prevented disease through compensatory inhibition of hepatic LDL production. This new concept of metabolic disease modeling by somatic genome editing could be applied to many other systemic as well as liver-restricted disorders which are difficult to study by germline manipulation

The Effects of Apolipoprotein F Deficiency on High Density Lipoprotein Cholesterol Metabolism in Mice

Apolipoprotein F (apoF) is 29 kilodalton secreted sialoglycoprotein that resides on the HDL and LDL fractions of human plasma. Human ApoF is also known as Lipid Transfer Inhibitor protein (LTIP) based on its ability to inhibit cholesteryl ester transfer protein (CETP)-mediated transfer events between lipoproteins. In contrast to other apolipoproteins, ApoF is predicted to lack strong amphipathic alpha helices and its true physiological function remains unknown. We previously showed that overexpression of Apolipoprotein F in mice reduced HDL cholesterol levels by 20–25% by accelerating clearance from the circulation. In order to investigate the effect of physiological levels of ApoF expression on HDL cholesterol metabolism, we generated ApoF deficient mice. Unexpectedly, deletion of ApoF had no substantial impact on plasma lipid concentrations, HDL size, lipid or protein composition. Sex-specific differences were observed in hepatic cholesterol content as well as serum cholesterol efflux capacity. Female ApoF KO mice had increased liver cholesteryl ester content relative to wild type controls on a chow diet (KO: 3.4+/−0.9 mg/dl vs. WT: 1.2+/−0.3 mg/dl, p<0.05). No differences were observed in ABCG1-mediated cholesterol efflux capacity in either sex. Interestingly, ApoB-depleted serum from male KO mice was less effective at promoting ABCA1-mediated cholesterol efflux from J774 macrophages relative to WT controls

Beyond the genetics of HDL:why is HDL cholesterol inversely related to cardiovascular disease?

There is unequivocal evidence that high-density lipoprotein (HDL) cholesterol levels in plasma are inversely associated with the risk of cardiovascular disease (CVD). Studies of families with inherited HDL disorders and genetic association studies in general (and patient) population samples have identified a large number of factors that control HDL cholesterol levels. However, they have not resolved why HDL cholesterol and CVD are inversely related. A growing body of evidence from nongenetic studies shows that HDL in patients at increased risk of CVD has lost its protective properties and that increasing the cholesterol content of HDL does not result in the desired effects. Hopefully, these insights can help improve strategies to successfully intervene in HDL metabolism. It is clear that there is a need to revisit the HDL hypothesis in an unbiased manner. True insights into the molecular mechanisms that regulate plasma HDL cholesterol and triglycerides or control HDL function could provide the handholds that are needed to develop treatment for, e.g., type 2 diabetes and the metabolic syndrome. Especially genome-wide association studies have provided many candidate genes for such studies. In this review we have tried to cover the main molecular studies that have been produced over the past few years. It is clear that we are only at the very start of understanding how the newly identified factors may control HDL metabolism. In addition, the most recent findings underscore the intricate relations between HDL, triglyceride, and glucose metabolism indicating that these parameters need to be studied simultaneously

Discovery of Novel Biomarker Candidates for Liver Fibrosis in Hepatitis C Patients: A Preliminary Study

Background: Liver biopsy is the reference standard for assessing liver fibrosis and no reliable non-invasive diagnostic approach is available to discriminate between the intermediate stages of fibrosis. Therefore suitable serological biomarkers of liver fibrosis are urgently needed. We used proteomics to identify novel fibrosis biomarkers in hepatitis C patients with different degrees of liver fibrosis.Methodology/Principal Findings: Proteins in plasma samples from healthy control individuals and patients with hepatitis C virus (HCV) induced cirrhosis were analysed using a proteomics technique: two dimensional gel electrophoresis (2-DE). This technique separated the proteins in plasma samples of control and cirrhotic patients and by visualizing the separated proteins we were able to identify proteins which were increasing or decreasing in hepatic cirrhosis. Identified markers were validated across all Ishak fibrosis stages and compared to the markers used in FibroTest, Enhanced Liver Fibrosis (ELF) test, Hepascore and FIBROSpect by Western blotting. Forty four candidate biomarkers for hepatic fibrosis were identified of which 20 were novel biomarkers of liver fibrosis. Western blot validation of all candidate markers using plasma samples from patients across all Ishak fibrosis scores showed that the markers which changed with increasing fibrosis most consistently included lipid transfer inhibitor protein, complement C3d, corticosteroid-binding globulin, apolipoprotein J and apolipoprotein L1. These five novel fibrosis markers which are secreted in blood showed a promising consistent change with increasing fibrosis stage when compared to the markers used for the FibroTest, ELF test, Hepascore and FIBROSpect. These markers will be further validated using a large clinical cohort.Conclusions/Significance: This study identifies 20 novel fibrosis biomarker candidates. The proteins identified may help to assess hepatic fibrosis and eliminate the need for invasive liver biopsies.</br