Stem Cell-Derived Regulatory T Cells for Therapeutic Use

CD4+ regulatory T cells (Tregs) are essential for normal immune surveillance, and their dysfunction can lead the development of autoimmune diseases. Pluripotent stem cells (PSCs) can be utilized to obtain a renewable source of healthy Tregs to treat autoimmune disorders as they have the ability to produce almost all cell types in the body, including Tregs. However, the right conditions for the development of antigen (Ag)-specific Tregs from PSCs (i.e., PSC-Tregs) have not been fully defined, especially the signaling mechanisms that the direct differentiation of such Tregs. Ag-specific PSC-Tregs can be tissue-associated and infiltrate to local inflamed tissue to suppress autoimmune responses after adoptive transfer, thereby avoiding potential overall immunosuppression from non-specific Tregs. Development of cell-based therapies using Ag-specific PSC-Tregs will provide an important step toward personalized therapies for autoimmune disorders

Effect of Electrolytic Compositions in Kinetics Mechanism of High-Purity Titanium Electrochemical Extraction Process

High pure titanium, which is a critical material used for integrated circuit (IC) manufacturing, can be extracted by molten salt-electrolysis process. It will be widely used in the future for the process, is simple and easy, to achieve continuous production. However, some scientific questions need to be clarified at present. (1) Current efficiency needs to be enhanced by way of electrolyte designing and selection; (2) Product quality needs to be improved by means of electrolyte purification; (3) Electrolytic parameters need to be optimized for obtaining a better morphology. Above on, this chapter aims to explore the behaviors of titanium ions in various molten salts by means of chemical analysis and electrochemical testing. The complexes will be discussed for clarifying the influence of electrolytic compositions on kinetics mechanisms of the electrolysis process and the properties of the molten salt. A quantitative method for estimating oxygen content will be also discussed for the purpose of optimizing the composition of electrolytes. The chapter will provide a better understanding mechanism of kinetics of high pure titanium electrolysis, and the basic theory and experimental data can be used for reference in the industrialization process

BestConfig: Tapping the Performance Potential of Systems via Automatic Configuration Tuning

An ever increasing number of configuration parameters are provided to system users. But many users have used one configuration setting across different workloads, leaving untapped the performance potential of systems. A good configuration setting can greatly improve the performance of a deployed system under certain workloads. But with tens or hundreds of parameters, it becomes a highly costly task to decide which configuration setting leads to the best performance. While such task requires the strong expertise in both the system and the application, users commonly lack such expertise. To help users tap the performance potential of systems, we present BestConfig, a system for automatically finding a best configuration setting within a resource limit for a deployed system under a given application workload. BestConfig is designed with an extensible architecture to automate the configuration tuning for general systems. To tune system configurations within a resource limit, we propose the divide-and-diverge sampling method and the recursive bound-and-search algorithm. BestConfig can improve the throughput of Tomcat by 75%, that of Cassandra by 63%, that of MySQL by 430%, and reduce the running time of Hive join job by about 50% and that of Spark join job by about 80%, solely by configuration adjustment

Miniaturized-Element Frequency-Selective Rasorber Design Using Characteristic Modes Analysis

A dual-polarization frequency-selective rasorber with two absorptive bands at both sides of a passband is presented. Based on the characteristic mode analysis, a circuit analog absorber is designed using a lossy FSS that consists of miniaturized meander lines and lumped resistors. The positions and values of resistors are determined according to the analysis of modal significances and modal current. After that, the presented rasorber is designed by cascading of the lossy FSS and a lossless bandpass FSS. Equivalent circuits of the frequency-selective rasorber are modelled, and surface current distributions of both FSSs are illustrated to explain the operation mechanism. Measurement results show that, under the normal incidence, a minimum insertion loss of 0.27 dB is achieved at a passband around 6 GHz, and the absorption bands with an absorption rate higher than 80% are 2.5 to 4.6 GHz in the lower band and 7.7 to 12 GHz in the higher band, respectively. Our results exhibit good agreements between measurements and simulations

An Open Receptor-Binding Cavity of Hemagglutinin-Esterase-Fusion Glycoprotein from Newly-Identified Influenza D Virus: Basis for Its Broad Cell Tropism.

Influenza viruses cause seasonal flu each year and pandemics or epidemic sporadically, posing a major threat to public health. Recently, a new influenza D virus (IDV) was isolated from pigs and cattle. Here, we reveal that the IDV utilizes 9-O-acetylated sialic acids as its receptor for virus entry. Then, we determined the crystal structures of hemagglutinin-esterase-fusion glycoprotein (HEF) of IDV both in its free form and in complex with the receptor and enzymatic substrate analogs. The IDV HEF shows an extremely similar structural fold as the human-infecting influenza C virus (ICV) HEF. However, IDV HEF has an open receptor-binding cavity to accommodate diverse extended glycan moieties. This structural difference provides an explanation for the phenomenon that the IDV has a broad cell tropism. As IDV HEF is structurally and functionally similar to ICV HEF, our findings highlight the potential threat of the virus to public health

Immunotherapy in Autoimmune Diabetes

Autoimmune diabetes is a chronic autoimmune disease caused by the loss or selective destruction of the insulin-producing cells, called pancreatic beta cells. Damage to beta cells results in an absence or insufficient production of insulin produced by the body. Most cases of autoimmune diabetes have an autoimmune basis, and the immune system mistakenly attacks and destroys beta cells. The immune system plays a critical role in controlling the development of autoimmune diabetes. Over the past years there have been significant progress and an accumulation of scientific evidence for the concept of immunotherapy. Immunotherapy for the prevention and treatment of autoimmune diabetes has become the main focus of the research community. Three regimens of immunotherapy have been investigated: (1) Antigen-specific vaccines: Insulin-related molecules have attracted great interest in vaccine development, including the whole recombinant human GAD65 (rhGAD65) and the DiaPep277 peptide of HSP60. (2) Systemic immunomodulators: A large number of non–antigen-specific immunomodulators have been studied, including monoclonal anti-CD3 antibody, anti–CTLA-4 Ig, TNF-a, IFN-a, IL-1R antagonist, regulatory T cells, and dendritic cells. (3) Combination treatments: Combination therapies have the ability to enhance efficacy and will become the standard of care for autoimmune diabetes. Development of safe and efficient prevention of autoimmune diabetes is a general public health object in modern countries now. Although large numbers of preventive modalities including immunotherapy have been accomplished in animal models of autoimmune diabetes, prevention of human autoimmune diabetes remains indefinable. Genetic and environmental factors that control the relapsing-remitting course of β-cell destruction, terminating in complete insulin addiction are being determined. In the long run, initial prevention of islet autoimmunity will likely be the optimal approach to the prevention of autoimmune diabetes. However, environmental causes of islet autoimmunity need to be well stated. Modest predictive assessment of the existing genetic screening tools also means that the number of children requiring intervention will stay great, concerning the number of autoimmune diabetes cases prohibited. Nevertheless, combination treatments are more likely to be used for autoimmune diabetes. Primary systemic immunosuppression followed by antigen-specific induction of tolerance or islet regeneration is a sound approach

Deficiency of the Cyclin Kinase Inhibitor p21(WAF-1/CIP-1) Promotes Apoptosis of Activated/Memory T Cells and Inhibits Spontaneous Systemic Autoimmunity

A characteristic feature of systemic lupus erythematosus is the accumulation of activated/memory T and B cells. These G0/G1-arrested cells express high levels of cyclin-dependent kinase inhibitors such as p21, are resistant to proliferation and apoptosis, and produce large amounts of proinflammatory cytokines. Herein, we show that ablation of p21 in lupus-prone mice allows these cells to reenter the cell cycle and undergo apoptosis, leading to autoimmune disease reduction. Absence of p21 resulted in enhanced Fas/FasL-mediated activation-induced T cell death, increased activation of procaspases 8 and 3, and loss of mitochondrial transmembrane potential. Increased apoptosis was also associated with p53 up-regulation and a modest shift in the ratio of Bax/Bcl-2 toward the proapoptotic Bax. Proliferation and apoptosis of B cells were also increased in p21−/− lupus mice. Thus, modulation of the cell cycle pathway may be a novel approach to reduce apoptosis-resistant pathogenic lymphocytes and to ameliorate systemic autoimmunity

OX40 (CD134) Controls Memory T Helper 2 Cells that Drive Lung Inflammation

Asthma is caused by memory Th2 cells that often arise early in life and persist after repeated encounters with allergen. Although much is known regarding how Th2 cells develop, there is little information about the molecules that regulate memory Th2 cells after they have formed. Here we show that the costimulatory molecule OX40 is expressed on memory CD4 cells. In already sensitized animals, blocking OX40–OX40L interactions at the time of inhalation of aerosolized antigen suppressed memory effector accumulation in lung draining lymph nodes and lung, and prevented eosinophilia, airway hyperreactivity, mucus secretion, and Th2 cyto-kine production. Demonstrating that OX40 signals directly regulate memory T cells, antigen-experienced OX40-deficient T cells were found to divide initially but could not survive and accumulate in large numbers after antigen rechallenge. Thus, OX40–OX40L interactions are pivotal to the efficiency of recall responses regulated by memory Th2 cells