Impaired Inflammatory Responses in Murine Lrrk2-Knockdown Brain Microglia

LRRK2, a Parkinson's disease associated gene, is highly expressed in microglia in addition to neurons; however, its function in microglia has not been evaluated. Using Lrrk2 knockdown (Lrrk2-KD) murine microglia prepared by lentiviral-mediated transfer of Lrrk2-specific small inhibitory hairpin RNA (shRNA), we found that Lrrk2 deficiency attenuated lipopolysaccharide (LPS)-induced mRNA and/or protein expression of inducible nitric oxide synthase, TNF-α, IL-1β and IL-6. LPS-induced phosphorylation of p38 mitogen-activated protein kinase and stimulation of NF-κB-responsive luciferase reporter activity was also decreased in Lrrk2-KD cells. Interestingly, the decrease in NF-κB transcriptional activity measured by luciferase assays appeared to reflect increased binding of the inhibitory NF-κB homodimer, p50/p50, to DNA. In LPS-responsive HEK293T cells, overexpression of the human LRRK2 pathologic, kinase-active mutant G2019S increased basal and LPS-induced levels of phosphorylated p38 and JNK, whereas wild-type and other pathologic (R1441C and G2385R) or artificial kinase-dead (D1994A) LRRK2 mutants either enhanced or did not change basal and LPS-induced p38 and JNK phosphorylation levels. However, wild-type LRRK2 and all LRRK2 mutant variants equally enhanced NF-κB transcriptional activity. Taken together, these results suggest that LRRK2 is a positive regulator of inflammation in murine microglia, and LRRK2 mutations may alter the microenvironment of the brain to favor neuroinflammation

Attenuation of ultrasonic shear waves in copper

The attenuation of circularly polarized shear waves propagating in the [001] direction in copper was calculated for external magnetic fields up to 32 kG. The attenuation by electrons on different regions of the Fermi surface was identified. This study used the Fermi surface calculated from the studies of M. R. Haise by L. T. Wood.Physics, Department o

Upgrading arc median shortest path problem for an urban transportation network

In this paper, we propose an algorithm for an upgrading arc median shortest path problem for a transportation network. The problem is to identify a set of nondominated paths that minimizes both upgrading cost and overall travel time of the entire network. These two objectives are realistic for transportation network problems, but of a conflicting and noncompensatory nature. In addition, unlike upgrading cost which is the sum of the arc costs on the path, overall travel time of the entire network cannot be expressed as a sum of arc travel times on the path. The proposed solution approach to the problem is based on heuristic labeling and exhaustive search techniques, in criteria space and solution space, respectively. The first approach labels each node in terms of upgrading cost, and deletes cyclic and infeasible paths in criteria space. The latter calculates the overall travel time of the entire network for each feasible path, deletes dominated paths on the basis of the objective vector and identifies a set of Pareto optimal paths in the solution space. The computational study, using two small-scale transportation networks, has demonstrated that the algorithm proposed herein is able to efficiently identify a set of nondominated median shortest paths, based on two conflicting and noncompensatory objectives.<br /

Pharmacokinetics of Jaspine B and Enhancement of Intestinal Absorption of Jaspine B in the Presence of Bile Acid in Rats

We aimed to investigate the pharmacokinetics and the underlying mechanisms of the intestinal absorption, distribution, metabolism, and excretion of Jaspine B in rats. The oral bioavailability of Jaspine B was 6.2%, but it decreased to 1.6% in bile-depleted rats and increased to 41.2% (normal) and 23.5% (bile-depleted) with taurocholate supplementation (60 mg/kg). Consistent with the increased absorption in the presence of bile salts, rat intestinal permeability of Jaspine B also increased in the presence of 10 mM taurocholate or 20% bile. Further studies demonstrated that the enhanced intestinal permeability with bile salts was due to increased lipophilicity and decreased membrane integrity. Jaspine B was designated as a highly tissue-distributed compound, because it showed large tissue to plasma ratios in the brain, kidney, heart, and spleen. Moreover, the recovery of Jaspine B from the feces and urine after an intravenous administration was about 6.3%, suggesting a substantial metabolism of Jaspine B. Consistent with this observation, 80% of the administered Jaspine B was degraded after 1 h incubation with rat liver microsomes. In conclusion, the facilitated intestinal permeability in the presence of bile salts could significantly increase the bioavailability of Jaspine B and could lead to the development of oral formulations of Jaspine B with bile salts. Moreover, the highly distributed features of Jaspine B in the brain, kidney, heart, and spleen should be carefully considered in the therapeutic effect and toxicity of this compound

A 1.22 TOPS and 1.52mW/MHz Augmented Reality Multi-Core Processor with Neural Network NoC for HMD Applications

Augmented reality (AR) is being investigated in advanced displays for the augmentation of images in a real-world environment. Wearable systems, such as head-mounted display (HMD) systems, have attempted to support real-time AR as a next generation UI/UX [1-2], but have failed, due to their limited computing power. In a prior work, a chip with limited AR functionality was reported that could perform AR with the help of markers placed in the environment (usually 1D or 2D bar codes) [3]. However, for a seamless visual experience, 3D objects should be rendered directly on the natural video image without any markers. Unlike marker-based AR, markerless AR requires natural feature extraction, general object recognition, 3D reconstruction, and camera-pose estimation to be performed in parallel. For instance, markerless AR for a VGA input-test video consumes ~1.3W power at 0.2fps throughput, with TI&apos;s OMAP4430, which exceeds power limits for wearable devices. Consequently, there is a need for a high-performance energy-efficient markerless AR processor to realize a real-time AR system, especially for HMD applications

Stereoselective Synthesis of d‑5-Homo-4-selenoribose as a Versatile Intermediate for 4′-Selenonucleosides

Stereoselective synthesis of d-5-homo-4-selenoribose, serving as a versatile intermediate for the synthesis of 4′-selenonucleosides <b>12a</b>–<b>c</b>, was accomplished using Sharpless asymmetric epoxidation, regioselective cleavage of the α,β-epoxide, and stereoselective reduction of the ketone as the key steps

LPS-induced p38 phosphorylation is specifically inhibited in Lrrk2-KD cells.

<p>(<b>A, C, D</b>) Cells were incubated with LPS (100 ng/mL) for the indicated times (A, C) or 30 min (D), and the levels of phosphorylated p38 (p-p38), JNK (p-JNK), ERK (p-ERK), and total p38 (A) or total and phosphorylated MKK3/6 (C, D) were determined by Western blotting. α-tubulin was used as an internal control. (<b>B, E</b>) Band intensities of p-p38 (B) and p-MKK3/6 (D) were quantified using a densitometer. Values are means ± SEMs of three independent experiments (*<i>p</i><0.05, **, <i>p</i><0.01 vs. control). Data are representative of three independent experiments.</p