Cbl-b regulates macrophage activation

Aging and overnutrition cause obesity in rodents and humans. It is well-known that obesity causes various diseases by producing insulin resistance (IR). Macrophages infiltrate the adipose tissue (AT) of obese individuals and cause chronic low-level inflammation associated with IR. Macrophage infiltration is regulated by the chemokines that are released from hypertrophied adipocytes and the immune cells in AT. Saturated fatty acids are recognized by toll-like receptor 4 (TLR4) and induce inflammatory responses in AT macrophages (ATMs). The inflammatory cytokines that are released from activated ATMs promote IR in peripheral organs, such as the liver, skeletal muscle and AT. Therefore, ATM activation is a therapeutic target for IR in obesity. The ubiquitin ligase Casitas b-lineage lymphoma-b (Cbl-b) appears to potently suppress macrophage migration and activation. Cbl-b is highly expressed in leukocytes and negatively regulates signals associated with migration and activation. Cbl-b deficiency enhances ATM accumulation and IR in aging- and diet-induced obese mice. Cbl-b inhibits migration-related signals and SFA-induced TLR4 signaling in ATMs. Thus, targeting Cbl-b may be a potential therapeutic strategy to reduce the IR induced by ATM activation. In this review, we summarize the regulatory functions of Cbl-b in ATMs

Deep Recurrent Factor Model: Interpretable Non-Linear and Time-Varying Multi-Factor Model

A linear multi-factor model is one of the most important tools in equity portfolio management. The linear multi-factor models are widely used because they can be easily interpreted. However, financial markets are not linear and their accuracy is limited. Recently, deep learning methods were proposed to predict stock return in terms of the multi-factor model. Although these methods perform quite well, they have significant disadvantages such as a lack of transparency and limitations in the interpretability of the prediction. It is thus difficult for institutional investors to use black-box-type machine learning techniques in actual investment practice because they should show accountability to their customers. Consequently, the solution we propose is based on LSTM with LRP. Specifically, we extend the linear multi-factor model to be non-linear and time-varying with LSTM. Then, we approximate and linearize the learned LSTM models by LRP. We call this LSTM+LRP model a deep recurrent factor model. Finally, we perform an empirical analysis of the Japanese stock market and show that our recurrent model has better predictive capability than the traditional linear model and fully-connected deep learning methods.Comment: In AAAI-19 Workshop on Network Interpretability for Deep Learnin

Ketogenic diet induces skeletal muscle atrophy via reducing muscle protein synthesis and possibly activating proteolysis in mice

Ketogenic diets (KD) that are very high in fat and low in carbohydrates are thought to simulate the metabolic effects of starvation. We fed mice with a KD for seven days to assess the underlying mechanisms of muscle wasting induced by chronic starvation. This diet decreased the weight of the gastrocnemius (Ga), tibialis anterior (TA) and soleus (Sol) muscles by 23%, 11% and 16%, respectively. The size of Ga, TA, Sol muscle fibers and the grip strength of four limbs also significantly declined by 20%, 28%, 16% and 22%, respectively. The muscle atrophy-related genes Mafbx, Murf1, Foxo3, Lc3b and Klf15 were upregulated in the skeletal muscles of mice fed with the KD. In accordance with the reduced expression of anabolic genes such as Igf1, surface sensing of translation (SUnSET) analyses of fast-twitch Ga, TA and Sol muscles revealed that the KD suppressed muscle protein synthesis. The mRNA expression of oxidative stress-responsive genes such as Sod1 was significantly increased in all muscles examined. In addition to hypercorticosteronemia, hypoinsulinemia and reduced IGF-1, oxidative stress might also be involved in KD-induced muscle atrophy. Feeding mice with a KD is a novel experimental animal model of muscle-wasting induced by chronic starvation

ZnSTe coherently grown onto GaP substrates by molecular beam epitaxy using ZnS buffer layers

ZnS1-xTex epitaxial layers with x ~ 0.06, nearly lattice-matched to GaP substrates, have been grown by molecular beam epitaxy. Direct growth of the layers onto the substrates results in poor crystal quality, showing no sign of coherent growth. This seems to be due to alloy composition deviation at the initial stage of the growth. To avoid the problem, a thin coherent ZnS buffer layer has been inserted at the ZnSTe/GaP interface. With the buffer layers, coherent growth of ZnSTe layers is achieved and the crystal quality has been improved

Building primary care in Japan: Literature review.

Japan's health system is well known for achieving one of the world's highest life expectancy with universal health coverage. However, the country now faces challenges of a rapidly aging population and changes in patterns and burden of disease. Primary care is an important component of a well-functioning health system. In Japan, primary care services are provided in both the community and hospital settings. The distinction between primary and secondary care may not always be clear. This review is based on the framework from the 2015 WHO publication on primary care systems in Europe. Our aim is to describe the journey of primary care in Japan, with its past, present, and future as a valuable addition to the academic English literature. We also hope that this article would inspire readers outside of Japan who might face similar issues in their respective countries

Uncoupling protein 3 attenuates generation of reactive oxygen species by interacting with thioredoxin 2 in the mitochondrial intermembrane space

Katsuya Hirasaka1*, Edward M Mills2, Shohei Kohno1, Tomoki Abe1, Chika Ikeda1, Tasuku Maeda1, Shigetada Kondo1, Ayako Maita1, Yuushi Okumura1 and Takeshi Nikawa1 Author Affiliations 1 Department of Nutritional Physiology, Institute of Health Biosciences, University of Tokushima, Tokushima, 770-8503, Japan 2 Division of Pharmacology/Toxicology, University of Texas at Austin, Austin, TX 78712, USAPoster presentation Uncoupling protein 3 (UCP3) is primarily expressed in the inner membrane of skeletal muscle mitochondria. It has been proposed that UCP3 reduces production of reactive oxygen species (ROS) and oxidative damage. However, the mechanisms by which UCP3 attenuates ROS production are not well understood. Here we report that UCP3 interacts with the non-processed form of thioredoxin 2 (Trx2), a redox protein that is localized in mitochondria, but not processed Trx2, which is involved in cellular responses to ROS. The hydrophilic sequences within the N-terminal tail of UCP3, which faces the intermembrane space, are necessary for binding to Trx2. In addition, Trx2 directly associated with UCP3 through a mitochondrial targeting signaling sequence, was processed in the intermembrane space, and thereby allowing redox reactions. A bimolecular fluorescence complementation analysis demonstrated that the interaction of these proteins occurs in the mitochondrial intermembrane space. Furthermore, increased UCP3 expression significantly attenuated ROS production in isolated mitochondrial without effects on membrane potential, however this effect is lost by Trx2 knock down. These results suggest that UCP3 binds to Trx2 in the mitochondrial intermembrane space and attenuates ROS production.Pharmac