12-lipoxygenase (12-LOX) is one of several enzyme isoforms responsible for the metabolism of arachidonic acid and other poly-unsaturated fatty acids to both pro- and anti-inflammatory lipid ...mediators. Mounting evidence has shown that 12-LOX plays a critical role in the modulation of inflammation at multiple checkpoints during diabetes development. Due to this, interventions to limit pro-inflammatory 12-LOX metabolites either by isoform-specific 12-LOX inhibition, or by providing specific fatty acid substrates via dietary intervention, has the potential to significantly and positively impact health outcomes of patients living with both type 1 and type 2 diabetes. To date, the development of truly specific and efficacious inhibitors has been hampered by homology of LOX family members; however, improvements in high throughput screening have improved the inhibitor landscape. Here, we describe the function and role of human 12-LOX, and mouse 12-LOX and 12/15-LOX, in the development of diabetes and diabetes-related complications, and describe promise in the development of strategies to limit pro-inflammatory metabolites, primarily via new small molecule 12-LOX inhibitors.
Abstract Red blood cells migrate to the center of the blood vessel in a process called axial migration, while other blood cells, such as white blood cells and platelets, are disproportionately found ...near the blood vessel wall. However, much is still unknown concerning the lateral migration of cells in the blood; the specific effect of hydrodynamic factors such as a wall or a shear gradient is still unclear. In this study, we investigate the lateral migration of a capsule using the boundary integral method, in order to compute exactly an infinite computational domain for an unbounded parabolic flow and a semi-infinite computational domain for a near-wall parabolic flow in the limit of Stokes flow. We show that the capsule lift velocity in an unbounded parabolic flow is linear with respect to the shear gradient, while the lift velocity in a near-wall parabolic flow is dependent on the distance to the wall. Then, using these relations, we give an estimation of the relative effect of the shear gradient as a function of channel width and distance between the capsule and the wall. This estimation can be used to determine cases in which the effect of the shear gradient or wall can be neglected; for example, the formation of the cell-free layer in blood vessels is determined to be unaffected by the magnitude of the shear gradient.
We present a numerical analysis of the rheology of a dense suspension of spherical capsules in simple shear flow in the Stokes flow regime. The behaviour of neo-Hookean capsules is simulated for a ...volume fraction up to
${\it\phi}=0.4$
by graphics processing unit computing based on the boundary element method with a multipole expansion. To describe the specific viscosity using a polynomial equation of the volume fraction, the coefficients of the equation are calculated by least-squares fitting. The results suggest that the effect of higher-order terms is much smaller for capsule suspensions than rigid sphere suspensions; for example,
$O({\it\phi}^{3})$
terms account for only 8 % of the specific viscosity even at
${\it\phi}=0.4$
for capillary numbers
$Ca\geqslant 0.1$
. We also investigate the relationship between the deformation and orientation of the capsules and the suspension rheology. When the volume fraction increases, the deformation of the capsules increases while the orientation angle of the capsules with respect to the flow direction decreases. Therefore, both the specific viscosity and the normal stress difference increase with volume fraction due to the increased deformation, whereas the decreased orientation angle suppresses the specific viscosity, but amplifies the normal stress difference.
Psoriasis is a chronic inflammatory skin disease characterized by the infiltration of T cell and other immune cells to the skin in response to injury or autoantigens. Conventional, as well as ...unconventional, γδ T cells are recruited to the dermis and epidermis by CCL20 and other chemokines. Together with its receptor CCR6, CCL20 plays a critical role in the development of psoriasiform dermatitis in mouse models. We screened a panel of CCL20 variants designed to form dimers stabilized by intermolecular disulfide bonds. A single-atom substitution yielded a CCL20 variant (CCL20 S64C) that acted as a partial agonist for the chemokine receptor CCR6. CCL20 S64C bound CCR6 and induced intracellular calcium release, consistent with G-protein activation, but exhibited minimal chemotactic activity. Instead, CCL20 S64C inhibited CCR6-mediated T cell migration with nominal impact on other chemokine receptor signaling. When given in an IL-23–dependent mouse model for psoriasis, CCL20 S64C prevented psoriatic inflammation and the up-regulation of IL-17A and IL-22. Our results validate CCR6 as a tractable therapeutic target for psoriasis and demonstrate the value of CCL20 S64C as a lead compound.
This study aimed to compare the reliability and magnitude of conditioned pain modulation (CPM) by applying different test stimuli (TS) and conditioning stimuli (CS). Twenty-six healthy male ...participants were recruited in the study of two identical sessions. In each session, four TS (electrical, heat, handheld, and cuff pressure algometry) were applied before and during CS (cold pressor test (CPT) or cuff algometry). The same procedure was repeated with 45-min intervals, but with the other CS. Five thresholds were measured including four pain detection thresholds from four TS and pain tolerance threshold from cuff TS (cuff PTT). Intraclass correlation coefficient (ICC (3,1)) and coefficient of variation (CV) were calculated as measures of reliability. The reliability of TS before and during CS was good for all combinations (ICC: 0.60-0.96, CV: 2.2-22.9%), but the reliability of the CPM effect varied (ICC: 0.04-0.53, CV: 63.6-503.9%). The most reliable combinations were considered to be the handheld pressure pain threshold with CPT (ICC: 0.49, CV: 63.6%) and the cuff pressure pain threshold with CPT (ICC: 0.44, CV: 107.6%). Significant CPM effects were found for all combinations, except the combinations of electrical and heat pain thresholds with cuff CS, which indicates the novel classification of the CPM mechanism. The combinations of handheld pressure and heat pain threshold with CPT would provide the minimum sample size to detect the significant CPM changes in further studies. It is beneficial to provide and compare both ICC and CV to design further clinical trials.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Cilia-driven nodal flow is important in the determination of left-right asymmetry in the body. Several theoretical and computational models have been proposed to explain the mechanics of ciliary ...motion, although the full mechanism remains unknown. Here, we developed a three-dimensional nodal cilia axoneme model using a finite element-boundary element coupling method, and investigated the mechanics of nodal ciliary motion. We found that the rotational orbit was strongly dependent on the dynein activation frequency. We also investigated flow field generated by the ciliary rotation, and the flow strength decayed as r-3 at the far field from the cilium. Our numerical results also suggest that experimentally observed tilt angle θ=2π/9 is sufficiently large to make a leftward flow. These findings are helpful in better understanding ciliary motion and nodal flow.
Strongly enhanced quantum fluctuations often lead to a rich variety of quantum-disordered states. Developing approaches to enhance quantum fluctuations may open paths to realize even more fascinating ...quantum states. Here, we demonstrate that a coupling of localized spins with the zero-point motion of hydrogen atoms, that is, proton fluctuations in a hydrogen-bonded organic Mott insulator provides a different class of quantum spin liquids (QSLs). We find that divergent dielectric behavior associated with the approach to hydrogen-bond order is suppressed by the quantum proton fluctuations, resulting in a quantum paraelectric (QPE) state. Furthermore, our thermal-transport measurements reveal that a QSL state with gapless spin excitations rapidly emerges upon entering the QPE state. These findings indicate that the quantum proton fluctuations give rise to a QSL-a quantum-disordered state of magnetic and electric dipoles-through the coupling between the electron and proton degrees of freedom.
► Hydrous ethanol with high water contents up to 40% by volume can be used in a small SI engine for generator. ► Increasing the water content of ethanol decreased the overall efficiency and NOx ...emission, while other emissions increased. ► A catalytic converter is required to reduce the regulated emissions to meet EPA limit.
This study focused on the effects of the use of hydrous ethanol with high water contents up to 40% on the performance and emissions of a small spark ignition engine for a generator. The effects of loads and ethanol water contents on engine performance and emissions were investigated. The results show that for ethanol with 5% water content (Eh95) at constant engine speed of 3600rpm and at stoichiometric air–fuel ratio, CO and HC+NOx emissions after the catalytic converter were lower than the EPA limit model year 2011 tested under same load conditions of California exhaust emission standards and test procedures for 2005 and later small off-road engines. However for emissions before the catalytic converter, only CO is lower than the EPA limit model year 2011, while HC+NOx is higher. Increasing loads increased the overall efficiency, while BSFC, HC, formaldehyde and acetaldehyde emissions decreased. Increasing water content at constant load decreased overall efficiency and NOx emission, while BSFC, HC, CO, formaldehyde and acetaldehyde emissions were increased. A catalytic converter is required to reduce the regulated and unregulated emissions when hydrous ethanol is used for a small SI engine generator set.
Abstract
An oscillating water column-type wave energy extractor is composed of an air chamber, an air turbine and a generator. The energy conversion process is compounded of the primary conversion in ...an air chamber and the secondary conversion of an air turbine. The oscillating water column-type wave energy extractor is considered to be safe even under dirty weather conditions. For societal implementation, there is a need to make a design method which can consider the water surface motion, the pressure fluctuation in an air chamber, the rotations of an air turbine and a generator. At here, the authors carried out the 2-dimensional wave tank tests using the model oscillating water column equipped with the impulse turbine and a generator to obtain the experimental data needed to make this design method. In the experiments, the effects of the air chamber and curtain wall geometries on energy conversion performance in regular wave conditions were investigated. As the results, it is noticed that the geometry of the curtain wall and the vortex shedding from the corners of curtain wall affect the primary conversion efficiency.
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