Ionomic Approaches for Discovery of Novel Stress-Resilient Genes in Plants

Plants, being sessile, face an array of biotic and abiotic stresses in their lifespan that endanger their survival. Hence, optimized uptake of mineral nutrients creates potential new routes for enhancing plant health and stress resilience. Recently, minerals (both essential and non-essential) have been identified as key players in plant stress biology, owing to their multifaceted functions. However, a realistic understanding of the relationship between different ions and stresses is lacking. In this context, ionomics will provide new platforms for not only understanding the function of the plant ionome during stresses but also identifying the genes and regulatory pathways related to mineral accumulation, transportation, and involvement in different molecular mechanisms under normal or stress conditions. This article provides a general overview of ionomics and the integration of high-throughput ionomic approaches with other “omics” tools. Integrated omics analysis is highly suitable for identification of the genes for various traits that confer biotic and abiotic stress tolerance. Moreover, ionomics advances being used to identify loci using qualitative trait loci and genome-wide association analysis of element uptake and transport within plant tissues, as well as genetic variation within species, are discussed. Furthermore, recent developments in ionomics for the discovery of stress-tolerant genes in plants have also been addressed; these can be used to produce more robust crops with a high nutritional value for sustainable agriculture.     

Different Reactive Oxygen Species Lead to Distinct Changes of Cellular Metal Ions in the Eukaryotic Model Organism Saccharomyces cerevisiae

Elemental uptake and export of the cell are tightly regulated thereby maintaining the ionomic homeostasis. This equilibrium can be disrupted upon exposure to exogenous reactive oxygen species (ROS), leading to reduction or elevation of the intracellular metal ions. In this study, the ionomic composition in the eukaryotic model organism Saccharomyces cerevisiae was profiled using the inductively-coupled plasma optical emission spectrometer (ICP-OES) following the treatment with individual ROS, including hydrogen peroxide, cumen hydroperoxide, linoleic acid hydroperoxide (LAH), the superoxide-generating agent menadione, the thiol-oxidising agent diamide [diazine-dicarboxylic acid-bis(dimethylamide)], dimedone and peroxynitrite. The findings demonstrated that different ROS resulted in distinct changes in cellular metal ions. Aluminium (Al(3+)) level rose up to 50-fold after the diamide treatment. Cellular potassium (K(+)) in LAH-treated cells was 26-fold less compared to the non-treated controls. The diamide-induced Al(3+) accumulation was further validated by the enhanced Al(3+) uptake along the time course and diamide doses. Pre-incubation of yeast with individual elements including iron, copper, manganese and magnesium failed to block diamide-induced Al(3+) uptake, suggesting Al(3+)-specific transporters could be involved in Al(3+) uptake. Furthermore, LAH-induced potassium depletion was validated by a rescue experiment in which addition of potassium increased yeast growth in LAH-containing media by 26% compared to LAH alone. Taken together, the data, for the first time, demonstrated the linkage between ionomic profiles and individual oxidative conditions.     

Modeling Neuronal Pathology in Yeast: Insights into the Molecular Basis of Parkinson’s Disease

The budding yeast Saccharomyces cerevisiae has been extensively studied as a model organism for biochemical and genetic research for almost a century. In recent years, yeast has been successfully used to model many aspects of human diseases. These “humanized” yeast models have had a profound influence on our understanding of the molecular events underlying neurodegenerative disorders. Yeast models can recapitulate important molecular events that occur in neurodegeneration, and provide clues about the underpinnings of toxicity in animal models of disease. Moreover, yeast models have also served as a powerful tool for drug discovery. In this mini-review, we describe yeast models that have been used to study the molecular aspects of Parkinson’s disease pathology and recent advances in the field based on these models.     

Ferroptosis: A Double-Edged Sword in Gastrointestinal Disease

Ferroptosis is a novel form of regulated cell death (RCD) that is typically accompanied by iron accumulation and lipid peroxidation. In contrast to apoptosis, autophagy, and necroptosis, ferroptosis has unique biological processes and pathophysiological characteristics. Since it was first proposed in 2012, ferroptosis has attracted attention worldwide. Ferroptosis is involved in the progression of multiple diseases and could be a novel therapeutic target in the future. Recently, tremendous progress has been made regarding ferroptosis and gastrointestinal diseases, including intestinal ischemia/reperfusion (I/R) injury, inflammatory bowel disease (IBD), gastric cancer (GC), and colorectal cancer (CRC). In this review, we summarize the recent progress on ferroptosis and its interaction with gastrointestinal diseases. Understanding the role of ferroptosis in gastrointestinal disease pathogenesis could provide novel therapeutic targets for clinical treatment.     

Role of Branched-Chain Amino Acid Metabolism in Type 2 Diabetes,Obesity, Cardiovascular Disease and Non-Alcoholic Fatty Liver Disease

Branched-chain amino acids (BCAAs) include leucine, isoleucine, and valine. Mammalians cannot synthesize these amino acids de novo and must acquire them through their diet. High levels of BCAAs are associated with insulin resistance; type 2 diabetes; obesity; and non-metabolic diseases, including several forms of cancer. BCAAs—in particular leucine—activate the rapamycin complex1 mTORC1, which regulates cell growth and metabolism, glucose metabolism and several more essential physiological processes. Diets rich in BCAAs are associated with metabolic diseases (listed above), while diets low in BCAAs are generally reported to promote metabolic health. As for the dysregulation of the metabolism caused by high levels of BCAAs, recent studies propose that the accumulation of acyl-carnitine and diacyl-CoA in muscles alters lipid metabolism. However, this suggestion is not broadly accepted. On clinical grounds, pre- and post-operative metabolic profiles of candidate patients for bariatric surgery are being used to select the optimal procedure for each individual patient.     

Disease surveillance and data collection issues in epidemic modelling

This paper is founded on a tutorial session given to the School on Modern Statistical Methods in Medical Research which was held at the International Centre for Theoretical Physics, Trieste in September 1999. We review the aims, scope and purposes of infectious disease surveillance including determining transmission information to underpin model structure and parameterization in epidemic modelling. The practical problems inherent in collecting surveillance data are illustrated by a study of HIV/AIDS in Cambodia. We also review the basic elements of mathematical models developed to represent the transmission dynamics of infectious diseases, and discuss reasons for the gap between mathematical epidemic models and available data.     

Assessing Plasmin Generation in Health and Disease

Fibrinolysis is an important process in hemostasis responsible for dissolving the clot during wound healing. Plasmin is a central enzyme in this process via its capacity to cleave fibrin. The kinetics of plasmin generation (PG) and inhibition during fibrinolysis have been poorly understood until the recent development of assays to quantify these metrics. The assessment of plasmin kinetics allows for the identification of fibrinolytic dysfunction and better understanding of the relationships between abnormal fibrin dissolution and disease pathogenesis. Additionally, direct measurement of the inhibition of PG by antifibrinolytic medications, such as tranexamic acid, can be a useful tool to assess the risks and effectiveness of antifibrinolytic therapy in hemorrhagic diseases. This review provides an overview of available PG assays to directly measure the kinetics of plasmin formation and inhibition in human and mouse plasmas and focuses on their applications in defining the role of plasmin in diseases, including angioedema, hemophilia, rare bleeding disorders, COVID-19, or diet-induced obesity. Moreover, this review introduces the PG assay as a promising clinical and research method to monitor antifibrinolytic medications and screen for genetic or acquired fibrinolytic disorders.     

The Role of HECT-Type E3 Ligase in the Development of Cardiac Disease

Despite advances in medicine, cardiac disease remains an increasing health problem associated with a high mortality rate. Maladaptive cardiac remodeling, such as cardiac hypertrophy and fibrosis, is a risk factor for heart failure; therefore, it is critical to identify new therapeutic targets. Failing heart is reported to be associated with hyper-ubiquitylation and impairment of the ubiquitin–proteasome system, indicating an importance of ubiquitylation in the development of cardiac disease. Ubiquitylation is a post-translational modification that plays a pivotal role in protein function and degradation. In 1995, homologous to E6AP C-terminus (HECT) type E3 ligases were discovered. E3 ligases are key enzymes in ubiquitylation and are classified into three families: really interesting new genes (RING), HECT, and RING-between-RINGs (RBRs). Moreover, 28 HECT-type E3 ligases have been identified in human beings. It is well conserved in evolution and is characterized by the direct attachment of ubiquitin to substrates. HECT-type E3 ligase is reported to be involved in a wide range of human diseases and health. The role of HECT-type E3 ligases in the development of cardiac diseases has been uncovered in the last decade. There are only a few review articles summarizing recent advancements regarding HECT-type E3 ligase in the field of cardiac disease. This study focused on cardiac remodeling and described the role of HECT-type E3 ligases in the development of cardiac disease. Moreover, this study revealed that the current knowledge could be exploited for the development of new clinical therapies.     

Epileptic Mechanisms Shared by Alzheimer’s Disease: Viewed via the Unique Lens of Genetic Epilepsy

Our recent work on genetic epilepsy (GE) has identified common mechanisms between GE and neurodegenerative diseases including Alzheimer’s disease (AD). Although both disorders are seemingly unrelated and occur at opposite ends of the age spectrum, it is likely there are shared mechanisms and studies on GE could provide unique insights into AD pathogenesis. Neurodegenerative diseases are typically late-onset disorders, but the underlying pathology may have already occurred long before the clinical symptoms emerge. Pathophysiology in the early phase of these diseases is understudied but critical for developing mechanism-based treatment. In AD, increased seizure susceptibility and silent epileptiform activity due to disrupted excitatory/inhibitory (E/I) balance has been identified much earlier than cognition deficit. Increased epileptiform activity is likely a main pathology in the early phase that directly contributes to impaired cognition. It is an enormous challenge to model the early phase of pathology with conventional AD mouse models due to the chronic disease course, let alone the complex interplay between subclinical nonconvulsive epileptiform activity, AD pathology, and cognition deficit. We have extensively studied GE, especially with gene mutations that affect the GABA pathway such as mutations in GABA_A receptors and GABA transporter 1. We believe that some mouse models developed for studying GE and insights gained from GE could provide unique opportunity to understand AD. These include the pathology in early phase of AD, endoplasmic reticulum (ER) stress, and E/I imbalance as well as the contribution to cognitive deficit. In this review, we will focus on the overlapping mechanisms between GE and AD, the insights from mutations affecting GABA_A receptors, and GABA transporter 1. We will detail mechanisms of E/I imbalance and the toxic epileptiform generation in AD, and the complex interplay between ER stress, impaired membrane protein trafficking, and synaptic physiology in both GE and AD.     

AAS法快速测定头发中的微量元素

近年来,随着人们对健康的关心,人体内微量元素含量普遍受到人们的关注,头发与微量元素的关系受到营养学、职业医学和环境科学工作者的关注。通过动物实验、流行病学调查及临床观察治疗现已证实很多疾病与微量元素有关。为此笔者利用火焰原子吸收分光光度计,对江苏地区大学生头发进行了预处理,采用标准曲线法,对江苏地区大学生头发中铜、锌、铁、钙、铅五种元素的含量进行了测定。     

Relevance of a Novel Circuit-Level Model of Episodic Memories to Alzheimer’s Disease

The medial temporal lobe memory system has long been identified as the brain region showing the first histopathological changes in early Alzheimer’s disease (AD), and the functional decline observed in patients also points to a loss of function in this brain area. Nonetheless, the exact identity of the neurons and networks that undergo deterioration has not been determined so far. A recent study has identified the entorhinal and hippocampal neural circuits responsible for encoding new episodic memories. Using this novel model we describe the elements of the episodic memory network that are especially vulnerable in early AD. We provide a hypothesis of how reduced reelin signaling within such a network can promote AD-related changes. Establishing novel associations and creating a temporal structure for new episodic memories are both affected in AD. Here, we furnish a reasonable explanation for both of these previous observations.     

Second Cancer Onset in Myeloproliferative Neoplasms: What,When, Why?

The risk of developing a solid cancer is a major issue arising in the disease course of a myeloproliferative neoplasm (MPN). Although the connection between the two diseases has been widely described, the backstage of this complex scenario has still to be explored. Several cellular and molecular mechanisms have been suggested to link the two tumors. Sometimes the MPN is considered to trigger a second cancer but at other times both diseases seem to depend on the same source. Increasing knowledge in recent years has revealed emerging pathways, supporting older, more consolidated theories, but there are still many unresolved issues. Our work aims to present the biological face of the complex clinical scenario in MPN patients developing a second cancer, focusing on the main cellular and molecular pathways linking the two diseases.     

The Role of H2S Regulating NLRP3 Inflammasome in Diabetes

Nucleotide-binding oligomeric domain (NOD)-like receptor protein 3 (NLRP3) is a recently discovered cytoplasmic multiprotein complex involved in inflammation. The NLRP3 inflammasome contains NLRP3, apoptosis-related specific protein (ASC) and precursor caspase-1. The NLRP3 inflammasome is involved in many diseases, including diabetes. H₂S is a harmful gas with a rotten egg smell. Recently, it has been identified as the third gas signal molecule after nitric oxide and carbon monoxide. It has many biological functions and plays an important role in many diseases, including diabetes. In recent years, it has been reported that H₂S regulation of the NLRP3 inflammasome contributes to a variety of diseases. However, the mechanism has not been fully understood. In this review, we summarized the recent role and mechanism of H₂S in regulating the NLRP3 inflammasome in diabetes, in order to provide a theoretical basis for future research.     

Recent Progress in Enhancing Fungal Disease Resistance in Ornamental Plants

Fungal diseases pose a major threat to ornamental plants, with an increasing percentage of pathogen-driven host losses. In ornamental plants, management of the majority of fungal diseases primarily depends upon chemical control methods that are often non-specific. Host basal resistance, which is deficient in many ornamental plants, plays a key role in combating diseases. Despite their economic importance, conventional and molecular breeding approaches in ornamental plants to facilitate disease resistance are lagging, and this is predominantly due to their complex genomes, limited availability of gene pools, and degree of heterozygosity. Although genetic engineering in ornamental plants offers feasible methods to overcome the intrinsic barriers of classical breeding, achievements have mainly been reported only in regard to the modification of floral attributes in ornamentals. The unavailability of transformation protocols and candidate gene resources for several ornamental crops presents an obstacle for tackling the functional studies on disease resistance. Recently, multiomics technologies, in combination with genome editing tools, have provided shortcuts to examine the molecular and genetic regulatory mechanisms underlying fungal disease resistance, ultimately leading to the subsequent advances in the development of novel cultivars with desired fungal disease-resistant traits, in ornamental crops. Although fungal diseases constitute the majority of ornamental plant diseases, a comprehensive overview of this highly important fungal disease resistance seems to be insufficient in the field of ornamental horticulture. Hence, in this review, we highlight the representative mechanisms of the fungal infection-related resistance to pathogens in plants, with a focus on ornamental crops. Recent progress in molecular breeding, genetic engineering strategies, and RNAi technologies, such as HIGS and SIGS for the enhancement of fungal disease resistance in various important ornamental crops, is also described.     

Chemical Probes for Profiling of MALT1 Protease Activity

The paracaspase MALT1 is a key regulator of the human immune response. It is implicated in a variety of human diseases. For example, deregulated protease activity drives the survival of malignant lymphomas and is involved in the pathophysiology of autoimmune/inflammatory diseases. Thus, MALT1 has attracted attention as promising drug target. Although many MALT1 inhibitors have been identified, molecular tools to study MALT1 activity, target engagement and inhibition in complex biological samples, such as living cells and patient material, are still scarce. Such tools are valuable to validate MALT1 as a drug target in vivo and to assess yet unknown biological roles of MALT1. In this review, we discuss the recent literature on the development and biological application of molecular tools to study MALT1 activity and inhibition.     

The Lung Microbiome during Health and Disease

Healthy human lungs have traditionally been considered to be a sterile organ. However, culture-independent molecular techniques have reported that large numbers of microbes coexist in the lung and airways. The lungs harbor diverse microbial composition that are undetected by previous approaches. Many studies have found significant differences in microbial composition between during health and respiratory disease. The lung microbiome is likely to not only influence susceptibility or causes of diseases but be affected by disease activities or responses to treatment. Although lung microbiome research has some limitations from study design to reporting, it can add further dimensionality to host-microbe interactions. Moreover, there is a possibility that extending understanding to the lung microbiome with new multiple omics approaches would be useful for developing both diagnostic and prognostic biomarkers for respiratory diseases in clinical settings.