基于免疫遗传算法的工艺设计与调度集成

为实现工艺设计与调度的并行分布式集成，建立了工艺规程调度仿真优化的数学模型，确定了模型的决策空间、目标函数及约束条件。提出了一种协同进化免疫遗传算法，用以同时优化零件的备选工艺规程组合和调度方案，通过工艺种群及调度种群的相互促进，实现协同进化，依据抗体的亲和力及抗体浓度来保持群体的多样性，根据抗体的激励度来进行免疫选择，采用最优解保持策略，确保算法的收敛性，考虑编码特点，工艺抗体采用均匀交叉及随机扰动变异，而调度抗体采用均匀顺序交叉及倒位变异。通过对10台设备10种零件的实例仿真，验证了算法的有效性。     

Application of new fuzzy-weighted average (NFWA) method to engineering design evaluation

Engineering design evaluation is characterized by imprecise (vague) importance and satisfaction levels of criteria, which are better treated as fuzzy variables rather than as subjective crisp variables. Nevertheless, operations on fuzzy numbers tend to increase unnecessarily the imprecision when they are combined for some applications, particularly, when a fuzzy-weighted average (FWA) is calculated. This paper proposes a novel method of operating on fuzzy numbers to obtain a fuzzy-weighted average of desirability levels during design evaluation. The method produces overall desirability levels less imprecise and more realistic than those of the conventional FWA. Furthermore, the balance points of these fuzzy numbers seem to be more credible than those of the FWA. An example is presented, which demonstrates the advantages of the method developed.     

Modified Low Density Lipoprotein and Lipoprotein-Containing Circulating Immune Complexes as Diagnostic and Prognostic Biomarkers of Atherosclerosis and Type 1 Diabetes Macrovascular Disease

In atherosclerosis; blood low-density lipoproteins (LDL) are subjected to multiple enzymatic and non-enzymatic modifications that increase their atherogenicity and induce immunogenicity. Modified LDL are capable of inducing vascular inflammation through activation of innate immunity; thus, contributing to the progression of atherogenesis. The immunogenicity of modified LDL results in induction of self-antibodies specific to a certain type of modified LDL. The antibodies react with modified LDL forming circulating immune complexes. Circulating immune complexes exhibit prominent immunomodulatory properties that influence atherosclerotic inflammation. Compared to freely circulating modified LDL; modified LDL associated with the immune complexes have a more robust atherogenic and proinflammatory potential. Various lipid components of the immune complexes may serve not only as diagnostic but also as essential predictive markers of cardiovascular events in atherosclerosis. Accumulating evidence indicates that LDL-containing immune complexes can also serve as biomarker for macrovascular disease in type 1 diabetes.     

Monitoring applications: An immune inspired algorithm for software-fault detection

Large-scale software systems are in general difficult to manage and monitor. In many cases, these systems display unexpected behavior, especially after being updated or when changes occur in their environment (operating system upgrades or hardware migrations, to name a few). Therefore, to handle a changing environment, it is desirable to base fault detection and performance monitoring on self-adaptive techniques.Several studies have been carried out in the past which, inspired on the immune system, aim at solving complex technological problems. Among them, anomaly detection, pattern recognition, system security and data mining are problems that have been addressed in this framework.There are similarities between the software fault detection problem and the identification of the pathogens that are found in natural immune systems. Being inspired by vaccination and negative and clonal selection observed in these systems, we developed an effective self-adaptive model to monitor software applications analyzing the metrics of system resources.     

Modification by Ubiquitin-Like Proteins: Significance in Apoptosis and Autophagy Pathways

Ubiquitin-like proteins (Ubls) confer diverse functions on their target proteins. The modified proteins are involved in various biological processes, including DNA replication, signal transduction, cell cycle control, embryogenesis, cytoskeletal regulation, metabolism, stress response, homeostasis and mRNA processing. Modifiers such as SUMO, ATG12, ISG15, FAT10, URM1, and UFM have been shown to modify proteins thus conferring functions related to programmed cell death, autophagy and regulation of the immune system. Putative modifiers such as Domain With No Name (DWNN) have been identified in recent times but not fully characterized. In this review, we focus on cellular processes involving human Ubls and their targets. We review current progress in targeting these modifiers for drug design strategies.     

An antigen space density based real-value negative selection algorithm

The negative selection algorithm (NSA) is an important detector generation algorithm for artificial immune systems. In high-dimensional space, antigens (data samples) distribute sparsely and unevenly, and most of them reside in low-dimensional subspaces. Therefore, traditional NSAs, which randomly generate detectors without considering the distribution of the antigens, cannot effectively distinguish them. To overcome this limitation, the antigen space density based real-value NSA (ASD-RNSA) is proposed in this paper. The ASD-RNSA contains two new processes. First, in order to improve detection efficiency, ASD-RNSA utilizes the antigen space density to calculate the low-dimensional subspaces where antigens are densely gathered and directly generate detectors in these subspaces. Second, to eliminate redundant detectors and prevent the algorithm from prematurely converging in high-dimensional space, ASD-RNSA suppresses candidate detectors that are recognized by other mature detectors and adopts an “antibody suppression rate” to replace the “expected coverage” as the termination condition. Experimental results show that ASD-RNSA achieves a better detection rate and has better generation quality than classical real-value NSAs.     

Effects of feeding bentonite clay upon ochratoxin A–induced immunosuppression in broiler chicks

A presence of mycotoxins in feed is one of the most alarming issues in the poultry feed industry. Ochratoxins, produced by several Aspergillus and Penicillium species, are important mycotoxin regarding the health status of poultry birds. Ochratoxins are further classified into to several subtypes (A, B, C, etc) depending on their chemical structures, but ochratoxin A (OTA) is considered the most important and toxic. Bentonite clay, belonging to phyllosilicates and formed from weathering of volcanic ashes, has adsorbent ability for several mycotoxins. The present study was designed to study the effects of bentonite clay upon OTA-induced immunosuppression in broiler chicks. For this, 480 day-old broiler chicks were procured from a local hatchery and then different combinations of OTA (0.15, 0.3, or 1.0 mg/kg) and bentonite clay (5, 10, and 20 g/kg) were incorporated into their feed. At 13, 30, and 42 days of age, parameters such as antibody responses to sheep red blood cells, in situ lymphoproliferative responses to mitogen (PHA-P), and in situ phagocytic activity (i.e., via carbon clearance) were determined respectively. The results indicated there was a significant reduction of total antibody and immunoglobulin titres, lymphoproliferative responses, and phagocytic potential in OTA-treated birds, suggesting clear immunosuppression by OTA in birds in a dose-dependent manner. These results were also significantly lower in all combination groups (OTA with bentonite clay), suggesting few to no effects of feeding bentonite clay upon OTA- induced alterations in different immune parameters.     

Idiosyncratic Drug-Induced Liver Injury: Mechanistic and Clinical Challenges

Idiosyncratic drug-induced liver injury (IDILI) remains a significant problem for patients and drug development. The idiosyncratic nature of IDILI makes mechanistic studies difficult, and little is known of its pathogenesis for certain. Circumstantial evidence suggests that most, but not all, IDILI is caused by reactive metabolites of drugs that are bioactivated by cytochromes P450 and other enzymes in the liver. Additionally, there is overwhelming evidence that most IDILI is mediated by the adaptive immune system; one example being the association of IDILI caused by specific drugs with specific human leukocyte antigen (HLA) haplotypes, and this may in part explain the idiosyncratic nature of these reactions. The T cell receptor repertoire likely also contributes to the idiosyncratic nature. Although most of the liver injury is likely mediated by the adaptive immune system, specifically cytotoxic CD8+ T cells, adaptive immune activation first requires an innate immune response to activate antigen presenting cells and produce cytokines required for T cell proliferation. This innate response is likely caused by either a reactive metabolite or some form of cell stress that is clinically silent but not idiosyncratic. If this is true it would make it possible to study the early steps in the immune response that in some patients can lead to IDILI. Other hypotheses have been proposed, such as mitochondrial injury, inhibition of the bile salt export pump, unfolded protein response, and oxidative stress although, in most cases, it is likely that they are also involved in the initiation of an immune response rather than representing a completely separate mechanism. Using the clinical manifestations of liver injury from a number of examples of IDILI-associated drugs, this review aims to summarize and illustrate these mechanistic hypotheses.     

The Role of Extracellular Vesicles in the Progression of Human Neuroblastoma

The long-underestimated role of extracellular vesicles in cancer is now reconsidered worldwide by basic and clinical scientists, who recently highlighted novel and crucial activities of these moieties. Extracellular vesicles are now considered as king transporters of specific cargoes, including molecular components of parent cells, thus mediating a wide variety of cellular activities both in normal and neoplastic tissues. Here, we discuss the multifunctional activities and underlying mechanisms of extracellular vesicles in neuroblastoma, the most frequent common extra-cranial tumor in childhood. The ability of extracellular vesicles to cross-talk with different cells in the tumor microenvironment and to modulate an anti-tumor immune response, tumorigenesis, tumor growth, metastasis and drug resistance will be pinpointed in detail. The results obtained on the role of extracellular vesicles may represent a panel of suggestions potentially useful in practice, due to their involvement in the response to chemotherapy, and, moreover, their ability to predict resistance to standard therapies—all issues of clinical relevance.     

Emerging Immunotherapy for Acute Myeloid Leukemia

Several immune checkpoint molecules and immune targets in leukemic cells have been investigated. Recent studies have suggested the potential clinical benefits of immuno-oncology (IO) therapy against acute myeloid leukemia (AML), especially targeting CD33, CD123, and CLL-1, as well as immune checkpoint inhibitors (e.g., anti-PD (programmed cell death)-1 and anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) antibodies) with or without conventional chemotherapy. Early-phase clinical trials of chimeric antigen receptor (CAR)-T or natural killer (NK) cells for relapsed/refractory AML showed complete remission (CR) or marked reduction of marrow blasts in a few enrolled patients. Bi-/tri-specific antibodies (e.g., bispecific T-cell engager (BiTE) and dual-affinity retargeting (DART)) exhibited 11–67% CR rates with 13–78% risk of cytokine-releasing syndrome (CRS). Conventional chemotherapy in combination with anti-PD-1/anti-CTLA4 antibody for relapsed/refractory AML showed 10–36% CR rates with 7–24 month-long median survival. The current advantages of IO therapy in the field of AML are summarized herein. However, although cancer vaccination should be included in the concept of IO therapy, it is not mentioned in this review because of the paucity of relevant evidence.