Morten Hartvig Hansen

The effect of short-chain fatty acids on human monocyte-derived dendritic cells

The gut microbiota is essential for human health and plays an important role in the pathogenesis of several diseases. Short-chain fatty acids (SCFA), such as acetate, butyrate and propionate, are end-products of microbial fermentation of macronutrients that distribute systemically via the blood. The aim of this study was to investigate the transcriptional response of immature and LPS-matured human monocyte-derived DC to SCFA. Our data revealed distinct effects exerted by each individual SCFA on gene expression in human monocyte-derived DC, especially in the mature ones. Acetate only exerted negligible effects, while both butyrate and propionate strongly modulated gene expression in both immature and mature human monocyte-derived DC. An Ingenuity pathway analysis based on the differentially expressed genes suggested that propionate and butyrate modulate leukocyte trafficking, as SCFA strongly reduced the release of several pro-inflammatory chemokines including CCL3, CCL4, CCL5, CXCL9, CXCL10, and CXCL11. Additionally, butyrate and propionate inhibited the expression of lipopolysaccharide (LPS)-induced cytokines such as IL-6 and IL-12p40 showing a strong anti-inflammatory effect. This work illustrates that bacterial metabolites far from the site of their production can differentially modulate the inflammatory response and generally provides new insights into host-microbiome interactions.

Output-Only Modal Analysis of Linear Time Periodic Systems with Application to Wind Turbine Simulation Data

Many important systems, such as wind turbines, helicopters and turbomachinery, must be modeled with linear time-periodic equations of motion to correctly predict resonance phenomena. Time periodic effects in wind turbines might arise due to blade-to-blade manufacturing variations, stratification in the velocity of the wind with height and changes in the aerodynamics of the blades as they pass the tower. These effects may cause parametric resonance or other unexpected phenomena, so it is important to properly characterize them so that these machines can be designed to achieve high reliability, safety, and to produce economical power. This work presents a system identification methodology that can be used to identify models for linear, periodically time-varying systems when the input forces are unmeasured, broadband and random. The methodology is demonstrated for the well-known Mathieu oscillator and then used to interrogate simulated measurements from a rotating wind turbine. The measurements were simulated for a 5 MW turbine modeled in the HAWC2 simulation code, which includes both structural dynamic and aerodynamic effects. This simulated system identification provides insights into the test and measurement requirements and the potential pitfalls, and simulated experiments such as this may be useful to obtain a set of time-periodic equations of motion from a numerical model, since a closed form model is not readily available by other means due to the way in which the aeroelastic effects are treated in the simulation code.

Applicability Limits of Operational Modal Analysis to Operational Wind Turbines

Operational Modal Analysis (OMA) is one of the branches of experimental modal analysis which allows extracting modal parameters based on measuring only the responses of a structure under ambient or operational excitation which is not needed to be measured. This makes OMA extremely attractive to modal analysis of big structures such as wind turbines where providing measured excitation force is an extremely difficult task. One of the main OMA assumption concerning the excitation is that it is distributed randomly both temporally and spatially. Obviously, closer the real excitation is to the assumed one, better modal parameter estimation one can expect. Traditionally, wind excitation is considered as a perfect excitation obeying the OMA assumptions. However, the present study shows that the aeroelastic phenomena due to rotor rotation dramatically changes the character of aerodynamic excitation and sets limitations on the applicability of OMA to operational wind turbines. The main purpose of the study is to warn the experimentalists about these limitations and discuss possible ways of dealing with them.

Injection molded chips with integrated conducting polymer electrodes for electroporation of cells

We present the design-concept for an all polymer injection molded single use microfluidic device. The fabricated devices comprise integrated conducting polymer electrodes and Luer fitting ports to allow for liquid and electrical access. A case study of low voltage electroporation of biological cells in suspension is presented. The working principle of the electroporation device is based on a focusing of the electric field by means of a constriction in the flow channel for the cells. We demonstrate the use of AC voltage for electroporation by applying a 1 kHz, ±50 V square pulse train to the electrodes and show delivery of polynucleotide fluorescent dye in 46% of human acute monocytic leukemia cells passing the constriction.

Measurements of Brownian relaxation of magnetic nanobeads using planar Hall effect bridge sensors.

We compare measurements of the Brownian relaxation response of magnetic nanobeads in suspension using planar Hall effect sensors of cross geometry and a newly proposed bridge geometry. We find that the bridge sensor yields six times as large signals as the cross sensor, which results in a more accurate determination of the hydrodynamic size of the magnetic nanobeads. Finally, the bridge sensor has successfully been used to measure the change in dynamic magnetic response when rolling circle amplified DNA molecules are bound to the magnetic nanobeads. The change is validated by measurements performed in a commercial AC susceptometer. The presented bridge sensor is, thus, a promising component in future lab-on-a-chip biosensors for detection of clinically relevant analytes, including bacterial genomic DNA and proteins.

Aeroelastic properties of backward swept blades

It is investigated how the nonlinear geometric coupling between torsion and flapwise bending of backward swept blades affects their static and dynamic aeroelastic properties. A geometrically nonlinear co-rotational finite beam element formulation coupled with the Blade Element Momentum method is used to compute the steady state blade deflection and aerodynamic power and thrust (assuming uniform wind and neglecting tower shadow and gravity effects) of a blade with different backward sweep shapes. A linearization of this aeroelastic model with the addition of an unsteady aerodynamic model is used to compute frequencies, damping and mode shapes of the aeroelastic blade modes from eigenvalue analysis, and to compute the transfer function from mean wind speed variations to variations in the blade root bending moments. Using the blade of the 5 MW NREL reference turbine as a baseline, it is shown that the backward sweep creates torsion towards feathering for downwind flapwise defl ection in thefirst flapwise bending mode. This torsional component is shown to cause the frequency of the first aeroelastic flapwise bending mode to increase compared to the frequency of the corresponding structural mode, and this increase becomes larger for larger sweep. The frequency response of the flapwise blade root moment from wind excitation is shown to decrease below the increased first flapwise frequency which explains the reduced flapwise loads found in previous studies of backward swept blades. Computations of the classical flutter speed show that it decreases with the backward sweep.

Expansion of circulating CD56bright natural killer cells in patients with JAK2-positive chronic myeloproliferative neoplasms during treatment with interferon-α.

In recent years, major molecular remissions have been observed in patients with JAK2‐positive chronic myeloproliferative neoplasms (MPNs) after therapy with IFN‐α. IFN‐α is known to have altering effects on immune cells involved in immune surveillance and might consequently enhance anti‐tumor immune response against the JAK2‐mutated clone. The objective of this study was to investigate circulating levels and phenotype of natural killer cells in 29 JAK2‐positive MPN patients during IFN‐α treatment. Furthermore, functional studies of NK cells upon target‐cell recognition and cytokine stimulation were performed. The CD56bright and CD56dim NK cell subtypes display different properties in terms of cytokine production and cytotoxicity, respectively. Our results show a significant increase in the proportion of CD56bright NK cells and a decreasing CD56dim population during treatment with IFN‐α compared to patients that are untreated, treated with hydroxyurea and healthy controls, P < 0.0001. Furthermore, an overall increase in cytokine‐dependent (IL‐12 and IL‐15) IFN‐γ expression by CD56dim NK cells during IFN‐α treatment was observed. In contrast, our data indicate a compromised NK cell response to target‐cell recognition during treatment with IFN‐α in four patients. We also report low levels of circulating NK cells in untreated patients compared to healthy donors, patients treated with hydroxyurea and IFN‐α, P = 0.02. Based on our findings, one might speculate whether treatment with IFN‐α skews the human NK population toward a helper type that may assist in CD8+ T cell priming in lymphoid tissues at the expense of their immediate cytotoxic functions in peripheral blood and tissues.

Bile Acid Sequestrants: Glucose-Lowering Mechanisms and Efficacy in Type 2 Diabetes

Bile acids are synthesized in the liver from cholesterol and have traditionally been recognized for their role in absorption of lipids and in cholesterol homeostasis. In recent years, however, bile acids have emerged as metabolic signaling molecules that are involved in the regulation of lipid and glucose metabolism, and possibly energy homeostasis, through activation of the bile acid receptors farnesoid X receptor (FXR) and TGR5. Bile acid sequestrants (BASs) constitute a class of drugs that bind bile acids in the intestine to form a nonabsorbable complex resulting in interruption of the enterohepatic circulation. This increases bile acid synthesis and consequently reduces serum low-density lipoprotein cholesterol. Also, BASs improve glycemic control in patients with type 2 diabetes. Despite a growing understanding of the impact of BASs on glucose metabolism, the mechanisms behind their glucose-lowering effect in patients with type 2 diabetes remain unclear. This article offers a review of the mechanisms behind the glucose-lowering effect of BASs, and the efficacy of BASs in the treatment of type 2 diabetes.

Genome-wide gene expression analysis of mucosal colonic biopsies and isolated colonocytes suggests a continuous inflammatory state in the lamina propria of patients with quiescent ulcerative colitis

Background: Genome‐wide gene expression (GWGE) profiles of mucosal colonic biopsies have suggested the existence of a continuous inflammatory state in quiescent ulcerative colitis (UC). The aim of this study was to use DNA microarray‐based GWGE profiling of mucosal colonic biopsies and isolated colonocytes from UC patients and controls in order to identify the cell types responsible for the continuous inflammatory state. Methods: Adjacent mucosal colonic biopsies were obtained endoscopically from the descending colon in patients with active UC (n = 8), quiescent UC (n = 9), and with irritable bowel syndrome (controls, n = 10). After isolation of colonocytes and subsequent extraction of total RNA, GWGE data were acquired using Human Genome U133 Plus 2.0 GeneChip Array (Affymetrix, Santa Clara, CA). Data analysis was carried out by principal component analysis and projection to latent structure‐discriminant analysis using the SIMCA‐P 11 software (Umetrics, Umeå, Sweden). Results: A clear separation between active UC, quiescent UC, and control biopsies were found, whereas the model for the colonocytes was unable to distinguish between quiescent UC and controls. The differentiation between quiescent UC and control biopsies was governed by unique profiles containing gene expressions with significant fold changes. These primarily belonged to the family of homeostatic chemokines, revealing a plausible explanation for the abnormal regulated innate immune response seen in patients with UC. Conclusions: This study has demonstrated the presence of a continuous inflammatory state in quiescent UC, which seems to reflect an altered gene expression profile of lamina propria cells. Inflamm Bowel Dis 2009

Effect of chenodeoxycholic acid and the bile acid sequestrant colesevelam on glucagon-like peptide-1 secretion.

To evaluate the effects of the primary human bile acid, chenodeoxycholic acid (CDCA), and the bile acid sequestrant (BAS) colesevelam, instilled into the stomach, on plasma levels of glucagon‐like peptide‐1 (GLP‐1), glucose‐dependent insulinotropic polypeptide, glucose, insulin, C‐peptide, glucagon, cholecystokinin and gastrin, as well as on gastric emptying, gallbladder volume, appetite and food intake.