bluuebunny/crossref_metadata_2025 huggingface dataset:
Stability Analysis for Distributed Secondary Control with Consideration of Diverse Input and Communication Delays for Distributed Generations in a DC Integrated Energy System
Authors: Wang Tao , Rong Chunyan , Tang Shuai , Hong Yinqiu
Published: February 2021

An integrated energy system is a promising approach to synthesize various forms of energy, where cooperative control is indispensable for stable and efficient operation. During the information exchange of cooperative distributed secondary control (DSC) in an integrated energy system, the effect of time delays on system performance cannot be ignored, which mainly consist of input delays and communication delays. Compared with most of the existing literature which only address DSC considering communication delays, this paper investigates the stability robustness of an integrated energy system in the case of both input and communication delays. First, the impacts of input and communication delays on DSC are analyzed based on the Gerschgorin theorem and Nyquist criterion, where the system stability is principally dependent on input delays while has little correlation with communication delays and the inconsistency of the two delays may result in steady-state deviation. Then, on the assumption of identical input and communication delays, a closed-loop small-signal model equipped with a distributed secondary controller is established for stability analysis and the delay-dependent criteria are formulated to determine the stability margin of the system based on critical characteristic root tracking. By a series of trial declarations, the delay margins with regard to different controller gains are determined and the qualitative relationship between delay margins and controller gains can be utilized to guide the controller design for improved system performance. The effectiveness of the theoretical results is verified by case studies on a test system.
Mercury Methylating Microbial Community Structure in Boreal Wetlands Explained by Local Physicochemical Conditions
Authors: Xu Jingying , Liem-Nguyen Van , Buck Moritz , Bertilsson Stefan , Björn Erik , Bravo Andrea G.
Published: February 2021

The potent neurotoxin methylmercury (MeHg) is a major concern due to its negative effects on wildlife and human health. Boreal wetlands play a crucial role in Hg cycling on a global scale, and therefore, it is crucial to understand the biogeochemical processes involved in MeHg formation in this landscape element. By combining high-throughput hgcA amplicon sequencing with molecular barcoding, we reveal diverse clades of potential HgII methylators in a wide range of wetland soils. Among Bacteria, Desulfuromonadota (14% of total reads), Desulfurobacterota_A, and Desulfurobacterota (up to 6% of total reads), previously classified as Deltaproteobacteria, were important members of the hgcA+ microbial community in the studied wetlands. We also identified Actinobacteriota (9.4% of total reads), Bacteroidota (2% of total reads), and Firmicutes (1.2% of total reads) as members of the hgcA+ microbial community. Within Archaea, Methanosarcinales represented up to 2.5% of the total reads. However, up to half of the hgcA+ community could not be resolved beyond domain Bacteria. Our survey also shows that local physicochemical conditions, such as pH, nutrient concentrations, water content, and prevailing redox states, are important for shaping the hgcA+ microbial community structure across the four studied wetlands. Furthermore, we observed a significant correlation between HgII methylation rate constants and the structure of the hgcA+ microbial community. Our findings expand the current knowledge on the hgcA+ microbial community composition in wetlands and the physicochemical factors underpinning spatial heterogeneity in such communities.
Spatial Distribution of Highland Cattle in Alnus viridis Encroached Subalpine Pastures
Authors: Svensk Mia , Pittarello Marco , Nota Ginevra , Schneider Manuel K. , Allan Eric , Mariotte Pierre , Probo Massimiliano
Published: February 2021

Green alder (Alnus viridis) is a shrub species that has expanded over former pastures in Central Europe due to land abandonment, leading to negative agri-environmental impacts, such as a reduction in forage yield and quality and an increase in nitrate leaching. Robust livestock breeds such as Highland cattle could be used to control A. viridis encroachment. The objectives of this study were to investigate the impact of A. viridis encroachment on plant community composition and diversity and to map the spatial distribution of Highland cattle in A. viridis-encroached pastures. During the summer of 2019, three different Highland cattle herds were placed along an A. viridis encroachment gradient. A total of 58 botanical surveys were carried out before grazing to assess plant community composition, pastoral value, and ecological indicator values. The spatial distribution of cattle was studied during the whole grazing period by monitoring six to eight cows equipped with GPS collars in each herd. Plant species associated with higher pastoral values of the vegetation were found in areas with lower A. viridis cover, while highly encroached areas were dominated by a few nitrophilus and shade-tolerant broad-leaved species and by ferns. Cattle spent more time in areas with higher pastoral value but did not avoid areas with high cover of A. viridis, on steep slopes or far from water. These results show that Highland cattle are able to tolerate harsh environmental conditions and that they can exploit A. viridis-encroached pastures. This suggests that they have a high potential to reduce A. viridis encroachment in the long-term.
Influence of Larval Habitat Environmental Characteristics on Culicidae Immature Abundance and Body Size of Adult Aedes aegypti
Authors: David Mariana Rocha , Dantas Edson Santos , Maciel-de-Freitas Rafael , Codeço Cláudia Torres , Prast Alex Enrich , Lourenço-de-Oliveira Ricardo
Published: February 2021

Aedes aegypti is adapted to live in close association with human dwellings, where it lays eggs in several man-made container types with a broad range of size, shape, and material. Biotic and abiotic conditions of larval habitats determine the abundance and body size of emerging adult mosquitoes. Here, we estimated the predictive potential of physicochemical water variables for Culicidae immature abundance and Ae. aegypti adult body size in four neighborhoods with distinct urban landscapes in Rio de Janeiro, Brazil. Domestic water holding containers (N = 240) were inspected for the presence of Culicidae immatures and had several physiochemical parameters measured. Larvae and pupae were counted, and pupae were reared to the adult stage for taxonomic identification. Dry weight and wing size were measured for Ae. aegypti adult mosquitoes (N = 981). The association between larval habitat parameters with Culicidae abundance and Ae. aegypti body size data was estimated through linear mixed models and generalized linear mixed models, respectively, with the neighborhood as random effect. The abundance of immature Culicidae in larval habitats (from which >90% of adults emerging from field collected pupae were Ae. aegypti) was positively associated with container volume and the dissolved organic carbon concentration (DOC). Female average dry weight and male and female wing lengths were positively associated with larval habitat temperature whereas male average dry weight was positively related to water conductivity. Aedes aegypti originating from larval habitats with Ae. albopictus exhibited no differences in median wing length and dry body weight when compared with specimens collected in containers exclusively colonized by Ae. aegypti. These results demonstrate that container water volume (characteristic easily observed in the field) and DOC (often higher in unmanaged water holding recipients) is related to higher Ae. aegypti immature density. Estimating the effects of physicochemical water variables on immature abundance and adult body size can provide valuable information for predicting arbovirus transmission risk in endemic settings.
Circular RNAs Sparkle in the Diagnosis and Theranostics of Hepatocellular Carcinoma
Authors: Wang Menglan , Wu Minjie , Xie Tian , Chen Jianxiang
Published: February 2021

Exonic circular RNAs (circRNAs) are a novel subgroup of non-coding RNAs, which are generated by a back-splicing mechanism of the exons or introns. Unlike the linear RNA, circRNA forms a covalently closed loop, and it normally appears more abundant than the linear products of its host gene. Due to the relatively high specificity and stability of circular RNAs in tissues and body fluid, circular RNAs have attracted widely scientific interest for its potential application in cancer diagnosis and as a guide for preclinical therapy, especially for hard-to-treat cancers with high heterogeneity, such as hepatocellular carcinoma (HCC). Thus, we summarize the updated knowledge of circular RNAs, including the mechanism of the generation of endogenous circular RNAs and their regulatory, diagnostic, and therapeutic roles in HCC.
Associations Among Methylene Tetrahydrofolate Reductase rs1801133 C677T Gene Variant, Food Groups, and Non-alcoholic Fatty Liver Disease Risk in the Chinese Population
Authors: Hao Xiaoyan , Ma Cong , Xiang Tianyuan , Ou Lei , Zeng Qiang
Published: February 2021

Objectives

To investigate the associations among the methylene tetrahydrofolate reductase rs1801133 C677T gene variant, food groups, and the risk of non-alcoholic fatty liver disease in the Chinese population.

Methods

A study of gene polymorphism was conducted using the polymerase chain reaction method. A total of 4,049 adults participated in the study, and all underwent physical examination and genotyping. Participants filled out a dietary questionnaire to enable us to assess the frequency and quantity of food consumption.

Results

The important variables identified as risk factors of non-alcoholic fatty liver disease were age, smoking, sex, body mass index, hyperlipidemia, diabetes, and methylene tetrahydrofolate reductase genotype (T – allele carriers). The homocysteine content was higher in the non-alcoholic fatty liver disease group than in the control group, and was higher in the T- allele than C- allele carriers. The homocysteine content was the highest in the T- allele carriers. Additionally, certain food groups such as milk and beans were associated with a lower risk of non-alcoholic fatty liver disease. Food groups such as meat, were associated with a higher risk of non-alcoholic fatty liver disease. Fresh fruit and vegetables, salted and smoked foods, desserts, cereals, fish, and eggs were not associated with the risk of non-alcoholic fatty liver disease. However, the influence of salted and smoked foods on non-alcoholic fatty liver disease was different in the C-allele and T-allele carriers of methylene tetrahydrofolate reductase (CT + TT vs. CC, OR = 1.196, P = 0.041 for 1–4 times food per week, OR = 1.580, P = 0.004 for 5–7 times per week). Similarly, salted and smoked foods were also a risk factor for the development of non-alcoholic steatohepatitis in patients with non-alcoholic fatty liver disease.

Conclusion

This study found that the T-allele of the C677T variant of methylene tetrahydrofolate reductase was a risk factor for non-alcoholic fatty liver disease among Chinese people. These results can likely aid the development of novel approaches for managing non-alcoholic fatty liver disease risk.
Multi-Omics Analysis to Examine Gene Expression and Metabolites From Multisite Adipose-Derived Mesenchymal Stem Cells
Authors: Yang Chuanxi , Zhang Jing , Wu Tingting , Zhao Kun , Wu Xiaoguang , Shi Jing , Sun Wei , Kong Xiangqing
Published: February 2021

This study aimed at exploring the gene expression and metabolites among multisite adipose-derived mesenchymal stem cells (ASCs) and investigate the metabolic pathway using a multi-omics analysis. Subcutaneous adipose-derived mesenchymal stem cells (SASCs), perirenal adipose-derived mesenchymal stem cells (PASCs), and epididymal adipose-derived mesenchymal stem cells (EASCs) were isolated from Sprague Dawley rats. RNA and metabolites were extracted and sequenced using transcriptomics and metabolomics analyses, respectively. There were 720 differentially expressed genes (DEGs) in EASCs and 688 DEGs in PASCs compared with SASCs; there were 166 unique DEGs in EASCs, 134 unique DEGs in PASCs, and 554 common DEGs between EASCs and PASCs. Furthermore, there were 226 differential metabolites in EASCs, 255 differential metabolites in PASCs, 83 unique differential metabolites in EASCs, 112 unique differential metabolites in PASCs, and 143 common differential metabolites between EASCs and PASCs. The transcriptomics and metabolomics analyses identified four hub genes, one in EASCs and three in PASCs. There are functional differences among multisite ASCs that may be related to the hub genes Atac2, Rrm1, Rrm2, and Gla. The relevant signaling pathways are the Ras signaling pathway, HIF-1 signaling pathway, and the p53 signaling pathway. In conclusion, compared with SASCs, our multi-omics analysis identified that EASCs with higher Acat2 expression may be more correlated to fat metabolism and insulin resistance, while PASCs with abnormal expression of Rrm1/2 and Gla may be more correlated with some malignant tumors and cardiac-cerebral vascular disease.
Integrative Analysis of Omics Data Reveals Regulatory Network of CDK10 in Vitiligo Risk
Authors: Cai Minglong , Yuan Tao , Huang He , Gui Lan , Zhang Li , Meng Ziyuan , Wu Wenjuan , Sheng Yujun , Zhang Xuejun
Published: February 2021

Vitiligo is a multifactorial polygenic disorder, characterized by acquired depigmented skin and overlying hair resulting from the destruction of melanocytes. Genome-wide association studies (GWASs) of vitiligo have identified approximately 100 genetic variants. However, the identification of functional genes and their regulatory elements remains a challenge. To prioritize putative functional genes and DNAm sites, we performed a Summary data-based Mendelian Randomization (SMR) and heterogeneity in dependent instruments (HEIDI) test to integrate omics summary statistics from GWAS, expression quantitative trait locus (eQTL), and methylation quantitative trait loci (meQTL) analysis of large sample size. By integrating omics data, we identified two newly putative functional genes (SPATA2LandCDK10) associated with vitiligo and further validatedCDK10by qRT-PCR in independent samples. We also identified 17 vitiligo-associated DNA methylation (DNAm) sites in Chr16, of which cg05175606 was significantly associated with the expression ofCDK10and vitiligo. Colocalization analyses detected transcript ofCDK10in the blood and skin colocalizing with cg05175606 at single nucleotide polymorphism (SNP) rs77651727. Our findings revealed that a shared genetic variant rs77651727 alters the cg05175606 as well as up-regulates gene expression ofCDK10and further decreases the risk of vitiligo.
When the Value of Cooperating Scales: Collective Intelligence, Information Processing, and the Leadership Meta-Capability
Authors: Hazy James K.
Published: February 2021

This article explores the nexus where purposeful individual-driven collective action, what is called organizational leadership, interacts with collective intelligence and agency. Based on recent numerical models from complex network theory and empirical studies of collective dynamics in social biology, it describes how intelligent collective agency forms around three order parameters: expectancy alignment, instrumentality inside the collective, and a subjective belief by individual agents in the generalized trustworthiness of other members of a collective. When the value of one or more of these scaling metrics becomes dynamically stable, fractal structures in the collective provide useful information to individuals that informs their choices during interactions including leadership activities. The theory contributes fifteen testable assertions that if supported empirically suggest fruitful ways that new information technology applications could enhance organizational effectiveness.
Insulin Reduces Inflammation by Regulating the Activation of the NLRP3 Inflammasome
Authors: Chang Yu-Wei , Hung Ling-Chien , Chen Yu-Cheng , Wang Wen-Hung , Lin Chun-Yu , Tzeng Hsin-Han , Suen Jau-Ling , Chen Yen-Hsu
Published: February 2021

The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is the platform for IL-1β maturation, aimed at mediating a rapid immune response against danger signals which must be tightly regulated. Insulin is well known as the critical hormone in the maintenance of glucose in physiologic response. Previous studies have proved insulin has the anti-inflammatory effect but the molecular mechanism of immunomodulation provided by insulin is not clear so far. Here we investigated whether insulin reduces inflammation by regulating the NLRP3 inflammasome. In the present study, we used LPS and ATP to induce the intracellular formation of the NLRP3 inflammasome. Insulin inhibited the secretion of IL-1β by preventing the assembly of the ASC in THP-1 cells and human CD14+ monocyte-derived macrophages. The phosphorylation status of Syk, p38 mitogen−activated protein kinase (MAPK) and ASC were altered by insulin. These effects were attenuated in THP-1 cells transfected with small interfering RNA targeting insulin receptors. In vivo, administration of glucose–insulin–potassium reduced serum IL-1β level, intestinal ASC speck formation, local macrophage infiltration and alleviated intestinal injury in mice exposed to LPS. Insulin may play an immunomodulatory role in anti-inflammation by regulating the NLRP3 inflammasome.
Ebolavirus: Comparison of Survivor Immunology and Animal Models in the Search for a Correlate of Protection
Authors: Longet Stephanie , Mellors Jack , Carroll Miles W. , Tipton Tom
Published: February 2021

Ebola viruses are enveloped, single-stranded RNA viruses belonging to the Filoviridae family and can cause Ebola virus disease (EVD), a serious haemorrhagic illness with up to 90% mortality. The disease was first detected in Zaire (currently the Democratic Republic of Congo) in 1976. Since its discovery, Ebola virus has caused sporadic outbreaks in Africa and was responsible for the largest 2013–2016 EVD epidemic in West Africa, which resulted in more than 28,600 cases and over 11,300 deaths. This epidemic strengthened international scientific efforts to contain the virus and develop therapeutics and vaccines. Immunology studies in animal models and survivors, as well as clinical trials have been crucial to understand Ebola virus pathogenesis and host immune responses, which has supported vaccine development. This review discusses the major findings that have emerged from animal models, studies in survivors and vaccine clinical trials and explains how these investigations have helped in the search for a correlate of protection.
Characterization and Monitoring of Antigen-Responsive T Cell Clones Using T Cell Receptor Gene Expression Analysis
Authors: Pollastro Sabrina , de Bourayne Marie , Balzaretti Giulia , Jongejan Aldo , van Schaik Barbera D. C. , Niewold Ilse T. G. , van Kampen Antoine H. C. , Maillère Bernard , de Vries Niek
Published: February 2021

High-throughput T-cell receptor repertoire sequencing constitutes a powerful tool to study T cell responses at the clonal level. However, it does not give information on the functional phenotype of the responding clones and lacks a statistical framework for quantitative evaluation. To overcome this, we combined datasets from different experiments, all starting from the same blood samples. We used a novel, sensitive, UMI-based protocol to perform repertoire analysis on experimental replicates. Applying established bioinformatic routines for transcriptomic expression analysis we explored the dynamics of antigen-induced clonal expansion after in vitro stimulation, identified antigen-responsive clones, and confirmed their activation status using the expression of activation markers upon antigen re-challenge. We demonstrate that the addition of IL-4 after antigen stimulation drives the expansion of T cell clones encoding unique receptor sequences. We show that our approach represents a scalable, high-throughput immunological tool, which can be used to identify and characterize antigen-responsive T cells at clonal level.
Pre- and Neonatal Imprinting on Immunological Homeostasis and Epithelial Barrier Integrity by Escherichia coli Nissle 1917 Prevents Allergic Poly-Sensitization in Mice
Authors: Sarate Priya J. , Srutkova Dagmar , Geissler Nora , Schwarzer Martin , Schabussova Irma , Inic-Kanada Aleksandra , Kozakova Hana , Wiedermann Ursula
Published: February 2021

A steady rise in the number of poly-sensitized patients has increased the demand for effective prophylactic strategies against multi-sensitivities. Probiotic bacteria have been successfully used in clinics and experimental models to prevent allergic mono-sensitization. In the present study, we have investigated whether probiotic bacteria could prevent poly-sensitization by imprinting on the immune system early in life. We used two recombinant variants of probioticEscherichia coliNissle 1917 (EcN): i) EcN expressing birch and grass pollen, poly-allergen chimera construct (EcN-Chim), and ii) an “empty” EcN without allergen expression (EcN-Ctrl). Conventional mice (CV) were treated with either EcN-Chim or EcN-Ctrl in the last week of the gestation and lactation period. Gnotobiotic mice received one oral dose of either EcN-Chim or EcN-Ctrl before mating. The offspring from both models underwent systemic allergic poly-sensitization and intranasal challenge with recombinant birch and grass pollen allergens (rBet v 1, rPhl p 1, and rPhl p 5). In the CV setting, the colonization of offspringviatreatment of mothers reduced allergic airway inflammation (AAI) in offspring compared to poly-sensitized controls. Similarly, in a gnotobiotic model, AAI was reduced in EcN-Chim and EcN-Ctrl mono-colonized offspring. However, allergy prevention was more pronounced in the EcN-Ctrl mono-colonized offspring as compared to EcN-Chim. Mono-colonization with EcN-Ctrl was associated with a shift toward mixed Th1/Treg immune responses, increased expression of TLR2 and TLR4 in the lung, and maintained levels of zonulin-1 in lung epithelial cells as compared to GF poly-sensitized and EcN-Chim mono-colonized mice. This study is the first one to establish the model of allergic poly-sensitization in gnotobiotic mice. Using two different settings, gnotobiotic and conventional mice, we demonstrated that an early life intervention with the EcN without expressing an allergen is a powerful strategy to prevent poly-sensitization later in life.
TLR7 Is Critical for Anti-Viral Humoral Immunity to EV71 Infection in the Spinal Cord
Authors: Lin Ya-Lin , Lu Mei-Yi , Chuang Chi-Fen , Kuo Yali , Lin Hong-En , Li Fu-An , Wang Jen-Ren , Hsueh Yi-Ping , Liao Fang
Published: February 2021

Enterovirus 71 (EV71) is a positive single-stranded RNA (ssRNA) virus from the enterovirus genus of Picornaviridae family and causes diseases ranged from the mild disease of hand, foot and mouth disease (HFMD) to the severe disease of neurological involvement in young children. TLR7 is an intracellular pattern recognition receptor (PRR) recognizing viral ssRNA. In this study, we investigated the role of TLR7 in EV71 infection in mouse pups (10-12 days old) and found that wild-type (WT) and TLR7 knock-out (TLR7KO) mice infected with EV71 showed similar limb paralysis at the onset and peak of the disease, comparable loss of motor neurons, and similar levels of antiviral molecules in the spinal cord. These results suggest that TLR7 is not the absolute PRR for EV71 in the spinal cord. Interestingly, TLR7KO mice infected with EV71 exhibited significantly delayed recovery from limb paralysis compared with WT mice. TLR7KO mice infected with EV71 showed significantly decreased levels of IgM and IgG2, important antibodies for antiviral humoral immunity. Furthermore, TLR7KO mice infected with EV71 showed a decrease of germinal center B cells in the spleen compared with WT mice. Altogether, our study suggests that TLR7 plays a critical role in anti-viral humoral immunity rather than in being a PRR in the spinal cord during EV71 infection in young mice.
Cancer Vaccines: Adjuvant Potency, Importance of Age, Lifestyle, and Treatments
Authors: Cuzzubbo Stefania , Mangsbo Sara , Nagarajan Divya , Habra Kinana , Pockley Alan Graham , McArdle Stephanie E. B.
Published: February 2021

Although the discovery and characterization of multiple tumor antigens have sparked the development of many antigen/derived cancer vaccines, many are poorly immunogenic and thus, lack clinical efficacy. Adjuvants are therefore incorporated into vaccine formulations to trigger strong and long-lasting immune responses. Adjuvants have generally been classified into two categories: those that ‘depot’ antigens (e.g. mineral salts such as aluminum hydroxide, emulsions, liposomes) and those that act as immunostimulants (Toll Like Receptor agonists, saponins, cytokines). In addition, several novel technologies using vector-based delivery of antigens have been used. Unfortunately, the immune system declines with age, a phenomenon known as immunosenescence, and this is characterized by functional changes in both innate and adaptive cellular immunity systems as well as in lymph node architecture. While many of the immune functions decline over time, others paradoxically increase. Indeed, aging is known to be associated with a low level of chronic inflammation—inflamm-aging. Given that the median age of cancer diagnosis is 66 years and that immunotherapeutic interventions such as cancer vaccines are currently given in combination with or after other forms of treatments which themselves have immune-modulating potential such as surgery, chemotherapy and radiotherapy, the choice of adjuvants requires careful consideration in order to achieve the maximum immune response in a compromised environment. In addition, more clinical trials need to be performed to carefully assess how less conventional form of immune adjuvants, such as exercise, diet and psychological care which have all be shown to influence immune responses can be incorporated to improve the efficacy of cancer vaccines. In this review, adjuvants will be discussed with respect to the above-mentioned important elements.
TLR Agonists as Mediators of Trained Immunity: Mechanistic Insight and Immunotherapeutic Potential to Combat Infection
Authors: Owen Allison M. , Fults Jessica B. , Patil Naeem K. , Hernandez Antonio , Bohannon Julia K.
Published: February 2021

Despite advances in critical care medicine, infection remains a significant problem that continues to be complicated with the challenge of antibiotic resistance. Immunocompromised patients are highly susceptible to development of severe infection which often progresses to the life-threatening condition of sepsis. Thus, immunotherapies aimed at boosting host immune defenses are highly attractive strategies to ward off infection and protect patients. Recently there has been mounting evidence that activation of the innate immune system can confer long-term functional reprogramming whereby innate leukocytes mount more robust responses upon secondary exposure to a pathogen for more efficient clearance and host protection, termed trained immunity. Toll-like receptor (TLR) agonists are a class of agents which have been shown to trigger the phenomenon of trained immunity through metabolic reprogramming and epigenetic modifications which drive profound augmentation of antimicrobial functions. Immunomodulatory TLR agonists are also highly beneficial as vaccine adjuvants. This review provides an overview on TLR signaling and our current understanding of TLR agonists which show promise as immunotherapeutic agents for combating infection. A brief discussion on our current understanding of underlying mechanisms is also provided. Although an evolving field, TLR agonists hold strong therapeutic potential as immunomodulators and merit further investigation for clinical translation.
Evolving Antibody Therapies for the Treatment of Type 1 Diabetes
Authors: Ke Qi , Kroger Charles J. , Clark Matthew , Tisch Roland M.
Published: February 2021

Type 1 diabetes (T1D) is widely considered to be a T cell driven autoimmune disease resulting in reduced insulin production due to dysfunction/destruction of pancreatic β cells. Currently, there continues to be a need for immunotherapies that selectively reestablish persistent β cell-specific self-tolerance for the prevention and remission of T1D in the clinic. The utilization of monoclonal antibodies (mAb) is one strategy to target specific immune cell populations inducing autoimmune-driven pathology. Several mAb have proven to be clinically safe and exhibit varying degrees of efficacy in modulating autoimmunity, including T1D. Traditionally, mAb therapies have been used to deplete a targeted cell population regardless of antigenic specificity. However, this treatment strategy can prove detrimental resulting in the loss of acquired protective immunity. Nondepleting mAb have also been applied to modulate the function of immune effector cells. Recent studies have begun to define novel mechanisms associated with mAb-based immunotherapy that alter the function of targeted effector cell pools. These results suggest short course mAb therapies may have persistent effects for regaining and maintaining self-tolerance. Furthermore, the flexibility to manipulate mAb properties permits the development of novel strategies to target multiple antigens and/or deliver therapeutic drugs by a single mAb molecule. Here, we discuss current and potential future therapeutic mAb treatment strategies for T1D, and T cell-mediated autoimmunity.
Dynamic 3D Locus Organization and Its Drivers Underpin Immunoglobulin Recombination
Authors: Rogers Carolyn H. , Mielczarek Olga , Corcoran Anne E.
Published: February 2021

A functional adaptive immune system must generate enormously diverse antigen receptor (AgR) repertoires from a limited number of AgR genes, using a common mechanism, V(D)J recombination. The AgR loci are among the largest in the genome, and individual genes must overcome huge spatial and temporal challenges to co-localize with optimum variability. Our understanding of the complex mechanisms involved has increased enormously, due in part to new technologies for high resolution mapping of AgR structure and dynamic movement, underpinning mechanisms, and resulting repertoires. This review will examine these advances using the paradigm of the mouse immunoglobulin heavy chain (Igh) locus. We will discuss the key regulatory elements implicated in Igh locus structure. Recent next generation repertoire sequencing methods have shown that local chromatin state at V genes contribute to recombination efficiency. Next on the multidimensional scale, we will describe imaging studies that provided the first picture of the large-scale dynamic looping and contraction the Igh locus undergoes during recombination. We will discuss chromosome conformation capture (3C)-based technologies that have provided higher resolution pictures of Igh locus structure, including the different models that have evolved. We will consider the key transcription factors (PAX5, YY1, E2A, Ikaros), and architectural factors, CTCF and cohesin, that regulate these processes. Lastly, we will discuss a plethora of recent exciting mechanistic findings. These include Rag recombinase scanning for convergent RSS sequences within DNA loops; identification of Igh loop extrusion, and its putative role in Rag scanning; the roles of CTCF, cohesin and cohesin loading factor, WAPL therein; a new phase separation model for Igh locus compartmentalization. We will draw these together and conclude with some horizon-scanning and unresolved questions.
TANK-Binding Kinase 1 (TBK1) Serves as a Potential Target for Hepatocellular Carcinoma by Enhancing Tumor Immune Infiltration
Authors: Jiang Yuchuan , Chen Siliang , Li Qiang , Liang Junjie , Lin Weida , Li Jinying , Liu Zhilong , Wen Mingbo , Cao Mingrong , Hong Jian
Published: February 2021

Background

Numerous cancer types present the aberrant TANK-binding kinase 1 (TBK1) expression, which plays an important role in driving inflammation and innate immunity. However, the prognostic role of TBK1 and its relationship with immune cell infiltration in hepatocellular carcinoma (HCC) remain unclear.

Methods

The expression and prognostic value of TBK1 was analyzed by Tumor Immune Estimation Resource (TIMER), Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA), Clinical Proteomic Tumor Analysis Consortium (CPTAC) and further confirmed in the present cohort of patients with HCC. The association between TBK1 and HCC immune infiltrates, and its potential mechanism were investigated via analyses of the Tumor Immune Estimation Resource, tumor-immune system interactions database (TISIDB), CIBERSORT, STRING, and Metascape. The effect of TBK1 on immune infiltrates and the therapeutic value of targeting TBK1 were further investigated in a HCC mouse model by treatment with a TBK1 antagonist.

Results

The level of TBK1 expression in HCC was higher than that measured in normal tissues, and associated with poorer overall survival (GEPIA: hazard ratio [HR]=1.80, P=0.038; Kaplan–Meier plotter: HR=1.87, P<0.001; CPTAC: HR=2.23, P=0.007; Our cohort: HR=2.92, P=0.002). In addition, high TBK1 expression was found in HCC with advanced TNM stage and identified as an independent poor prognostic factor for overall survival among patients with HCC. In terms of immune infiltration, tumor tissues from HCC patients with high TBK1 expression had a low proportion of CD8+ T cells, and TBK1 expression did not show prognostic value in HCC patients with enriched CD8+ T cells. Furthermore, TBK1 expression was positively correlated with the markers of T cell exhaustion and immunosuppressive cells in the HCC microenvironment. Mechanistically, the promotion of HCC immunosuppression by TBK1 was involved in the regulation of inflammatory cytokines. In vivo experiments revealed that treatment with a TBK1 antagonist delayed HCC growth by increasing the number of tumor-infiltrating CD8+ T cells.

Conclusions

The up-regulated expression of TBK1 may be useful in predicting poor prognosis of patients with HCC. In addition, TBK1, which promotes the HCC immunosuppressive microenvironment, may be a potential immunotherapeutic target for patients with HCC.
Plasma Membrane Integrates Biophysical and Biochemical Regulation to Trigger Immune Receptor Functions
Authors: Zhang Tongtong , Hu Wei , Chen Wei
Published: February 2021

Plasma membrane provides a biophysical and biochemical platform for immune cells to trigger signaling cascades and immune responses against attacks from foreign pathogens or tumor cells. Mounting evidence suggests that the biophysical-chemical properties of this platform, including complex compositions of lipids and cholesterols, membrane tension, and electrical potential, could cooperatively regulate the immune receptor functions. However, the molecular mechanism is still unclear because of the tremendous compositional complexity and spatio-temporal dynamics of the plasma membrane. Here, we review the recent significant progress of dynamical regulation of plasma membrane on immune receptors, including T cell receptor, B cell receptor, Fc receptor, and other important immune receptors, to proceed mechano-chemical sensing and transmembrane signal transduction. We also discuss how biophysical-chemical cues couple together to dynamically tune the receptor’s structural conformation or orientation, distribution, and organization, thereby possibly impacting theirin-situligand binding and related signal transduction. Moreover, we propose that electrical potential could potentially induce the biophysical-chemical coupling change, such as lipid distribution and membrane tension, to inevitably regulate immune receptor activation.
Interleukin-6 Is a Biomarker for the Development of Fatal Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia
Authors: Santa Cruz André , Mendes-Frias Ana , Oliveira Ana Isabel , Dias Luís , Matos Ana Rita , Carvalho Alexandre , Capela Carlos , Pedrosa Jorge , Castro António Gil , Silvestre Ricardo
Published: February 2021

Hyper-inflammatory responses induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are a major cause of disease severity and death. Predictive prognosis biomarkers to guide therapeutics are critically lacking. Several studies have indicated a “cytokine storm” with the release of interleukin-1 (IL-1), IL-6, and IL-8, along with tumor necrosis factor alpha (TNFα) and other inflammatory mediators. Here, we proposed to assess the relationship between IL-6 and outcomes of patients with coronavirus disease 2019 (COVID-19). Our cohort consisted of 46 adult patients with PCR-proven SARS-CoV-2 infection admitted in a COVID-19 ward of the Hospital de Braga (HB) from April 7 to May 7, 2020, whose IL-6 levels were followed over time. We found that IL-6 levels were significantly different between the disease stages. Also, we found a significant negative correlation between IL-6 levels during stages IIb and III, peripheral oxygen saturation (SpO2), and partial pressure of oxygen in arterial blood (PaO2), showing that IL-6 correlates with respiratory failure. Compared to the inflammatory markers available in the clinic routine, we found a positive correlation between IL-6 and C-reactive protein (CRP). However, when we assessed the predictive value of these two markers, IL-6 behaves as a better predictor of disease progression. In a binary logistic regression, IL-6 level was the most significant predictor of the non-survivors group, when compared to age and CRP. Herein, we present IL-6 as a relevant tool for prognostic evaluation, mainly as a predictor of outcome.
Immunological Responses of Marine Bivalves to Contaminant Exposure: Contribution of the -Omics Approach
Authors: Balbi Teresa , Auguste Manon , Ciacci Caterina , Canesi Laura
Published: February 2021

The increasing number of data studies on the biological impact of anthropogenic chemicals in the marine environment, together with the great development of invertebrate immunology, has identified marine bivalves as a key invertebrate group for studies on immunological responses to pollutant exposure. Available data on the effects of contaminants on bivalve immunity, evaluated with different functional and molecular endpoints, underline that individual functional parameters (cellular or humoral) and the expression of selected immune-related genes can distinctly react to different chemicals depending on the conditions of exposure. Therefore, the measurement of a suite of immune biomarkers in hemocytes and hemolymph is needed for the correct evaluation of the overall impact of contaminant exposure on the organism's immunocompetence. Recent advances in -omics technologies are revealing the complexity of the molecular players in the immune response of different bivalve species. Although different -omics represent extremely powerful tools in understanding the impact of pollutants on a key physiological function such as immune defense, the -omics approach has only been utilized in this area of investigation in the last few years. In this work, available information obtained from the application of -omics to evaluate the effects of pollutants on bivalve immunity is summarized. The data shows that the overall knowledge on this subject is still quite limited and that to understand the environmental relevance of any change in immune homeostasis induced by exposure to contaminants, a combination of both functional assays and cutting-edge technology (transcriptomics, proteomics, and metabolomics) is required. In addition, the utilization of metagenomics may explain how the complex interplay between the immune system of bivalves and its associated bacterial communities can be modulated by pollutants, and how this may in turn affect homeostatic processes of the host, host–pathogen interactions, and the increased susceptibility to disease. Integrating different approaches will contribute to knowledge on the mechanism responsible for immune dysfunction induced by pollutants in ecologically and economically relevant bivalve species and further explain their sensitivity to multiple stressors, thus resulting in health or disease.
Antigen-Specific Treatment Modalities in MS: The Past, the Present, and the Future
Authors: Derdelinckx Judith , Cras Patrick , Berneman Zwi N. , Cools Nathalie
Published: February 2021

Antigen-specific therapy for multiple sclerosis may lead to a more effective therapy by induction of tolerance to a wide range of myelin-derived antigens without hampering the normal surveillance and effector function of the immune system. Numerous attempts to restore tolerance toward myelin-derived antigens have been made over the past decades, both in animal models of multiple sclerosis and in clinical trials for multiple sclerosis patients. In this review, we will give an overview of the current approaches for antigen-specific therapy that are in clinical development for multiple sclerosis as well provide an insight into the challenges for future antigen-specific treatment strategies for multiple sclerosis.
High-Dose Intravenous Immunoglobulin in Severe Coronavirus Disease 2019: A Multicenter Retrospective Study in China
Authors: Cao Wei , Liu Xiaosheng , Hong Ke , Ma Zhiyong , Zhang Yuelun , Lin Ling , Han Yang , Xiong Yong , Liu Zhengyin , Ruan Lianguo , Li Taisheng
Published: February 2021

Background

The effective treatment of coronavirus disease 2019 (COVID-19) remains unclear. We reported successful use of high-dose intravenous immunoglobulin (IVIg) in cases of severe COVID-19, but evidence from larger case series is still lacking.

Methods

A multi-center retrospective study was conducted to evaluate the effectiveness of IVIg administered within two weeks of disease onset at a total dose of 2 g/kg body weight, in addition to standard care. The primary endpoint was 28-day mortality. Efficacy of high-dose IVIg was assessed by using the Cox proportional hazards regression model and the Kaplan-Meier curve adjusted by inverse probability of treatment weighting (IPTW) analysis, and IPTW after multiple imputation (MI) analysis.

Results

Overall, 26 patients who received high-dose IVIg with standard therapy and 89 patients who received standard therapy only were enrolled in this study. The IVIg group was associated with a lower 28-day mortality rate and less time to normalization of inflammatory markers including IL-6, IL-10, and ferritin compared with the control. The adjusted HR of 28-day mortality in high-dose IVIg group was 0.24 (95% CI 0.06–0.99, p<0.001) in IPTW model, and 0.27 (95% CI 0.10–0.57, p=0.031) in IPTW-MI model. In subgroup analysis, patients with no comorbidities or treated in the first week of disease were associated with more benefit from high-dose IVIg.

Conclusions

High-dose IVIg administered in severe COVID-19 patients within 14 days of onset was linked to reduced 28-day mortality, more prominent with those having no comorbidities or treated at earlier stage.
Inflammation and Antiviral Immune Response Associated With Severe Progression of COVID-19
Authors: Zhang Qiong , Meng Yuting , Wang Kaihang , Zhang Xujun , Chen Wenbiao , Sheng Jifang , Qiu Yunqing , Diao Hongyan , Li Lanjuan
Published: February 2021

Coronavirus disease-2019 (COVID-19) is a novel respiratory disease induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It remains poorly understood how the host immune system responds to the infection during disease progression. We applied microarray analysis of the whole genome transcriptome to peripheral blood mononuclear cells (PBMCs) taken from severe and mild COVID-19 patients as well as healthy controls. Functional enrichment analysis of genes associated with COVID-19 severity indicated that disease progression is featured by overactivation of myeloid cells and deficient T cell function. The upregulation of TLR6 and MMP9, which promote the neutrophils-mediated inflammatory response, and the downregulation of SKAP1 and LAG3, which regulate T cells function, were associated with disease severity. Importantly, the regulation of these four genes was absent in patients with influenza A (H1N1). And compared with stimulation with hemagglutinin (HA) of H1N1 virus, the regulation pattern of these genes was unique in PBMCs response to Spike protein of SARS-CoV-2 ex vivo. Our data also suggested that severe SARS-CoV-2 infection largely silenced the response of type I interferons (IFNs) and altered the proportion of immune cells, providing a potential mechanism for the hypercytokinemia. This study indicates that SARS-CoV-2 infection impairs inflammatory and immune signatures in patients, especially those at severe stage. The potential mechanisms underpinning severe COVID-19 progression include overactive myeloid cells, impaired function of T cells, and inadequate induction of type I IFNs signaling.
Case Report: Transformation From Cold to Hot Tumor in a Case of NSCLC Neoadjuvant Immunochemotherapy Pseudoprogression
Authors: Jia Wenxiao , Zhu Hui , Gao Qianqian , Sun Jian , Tan Fujian , Liu Qun , Guo Hongbo , Yu Jinming
Published: February 2021

A 56-year-old male was diagnosed with right lung upper lobe squamous cancer with right hilar and mediastinum lymph node metastasis. After four cycles of neoadjuvant immunochemotherapy, reexamination by computed tomography showed progressive disease of the primary lesion. Then, the patient underwent a right lung upper lobectomy, and hilar and mediastinum lymph node dissection. Surgical pathology showed a partial response to immunochemotherapy. Single-cell RNA sequencing was used to characterize the infiltrating immune cell atlas after neoadjuvant immunochemotherapy; the most common infiltrating immune cell types were cytotoxic CD8+ T cells, monocyte-derived dendritic cells, and macrophages. Imaging mass cytometry revealed a transformation from cold to hot tumor after neoadjuvant immunochemotherapy. In this case study, we are the first to report a case of neoadjuvant immunochemotherapy pseudoprogression, proved by surgical pathology, single-cell RNA sequencing, and imaging mass cytometry. Both single-cell RNA sequencing and imaging mass cytometry revealed an activated immune microenvironment after neoadjuvant immunochemotherapy.
Case Report: A Novel Synonymous ARPC1B Gene Mutation Causes a Syndrome of Combined Immunodeficiency, Asthma, and Allergy With Significant Intrafamilial Clinical Heterogeneity
Authors: Papadatou Ioanna , Marinakis Nikolaos , Botsa Evanthia , Tzanoudaki Marianna , Kanariou Maria , Orfanou Irene , Kanaka-Gantenbein Christina , Traeger-Synodinos Joanne , Spoulou Vana
Published: February 2021

Recently, a novel syndrome of combined immune deficiency, infections, allergy, and inflammation has been attributed to mutations in the gene encoding actin-related protein 2/3 complex subunit 1B (ARPC1B), which is a key molecule driving the dynamics of the cytoskeleton. Homozygous mutations in the ARPC1B gene have been found to result in the disruption of the protein structure and cause an autosomal recessive syndrome of combined immune deficiency, impaired T-cell migration and proliferation, increased levels of immunoglobulin E (IgE) and immunoglobulin A (IgA), and thrombocytopenia. To date, only a few individuals have been diagnosed with the ARPC1B deficiency syndrome worldwide. In this case series, we report the wide spectrum of phenotype in 3 siblings of a consanguineous family from Afghanistan with a novel homozygous synonymous pathogenic variant c.783G>A, p. (Ala261Ala) of the ARPC1B gene that causes a similar syndrome but no thrombocytopenia. Targeted RNA studies demonstrated that the variant affects the splicing process of mRNA, resulting in a marked reduction of the levels of primary (normal) RNA transcript of the ARPC1B gene in the affected patients and likely premature termination from the abnormally spliced mRNA. The next generation sequencing (NGS) studies facilitated the diagnosis of this rare combined immunodeficiency and led to the decision to treat the affected patients with hematopoietic cell transplant (HCT) from an human leukocyte antigen (HLA)-matched healthy sibling.