scholarly journals Hyposialylation Must Be Considered to Develop Future Therapies in Autoimmune Diseases

2021 ◽  
Vol 22 (7) ◽  
pp. 3402
Author(s):  
Anne Bordron ◽  
Marie Morel ◽  
Cristina Bagacean ◽  
Maryvonne Dueymes ◽  
Pierre Pochard ◽  
...  
Keyword(s):  
Immune System ◽  
Sialic Acid ◽  
Autoimmune Disease ◽  
Disease Development ◽  
Detailed Characterization ◽  
Multiple Factors ◽  
Innovative Therapies ◽  
Future Treatments ◽  
The Impact

Autoimmune disease development depends on multiple factors, including genetic and environmental. Abnormalities such as sialylation levels and/or quality have been recently highlighted. The adjunction of sialic acid at the terminal end of glycoproteins and glycolipids is essential for distinguishing between self and non-self-antigens and the control of pro- or anti-inflammatory immune reactions. In autoimmunity, hyposialylation is responsible for chronic inflammation, the anarchic activation of the immune system and organ lesions. A detailed characterization of this mechanism is a key element for improving the understanding of these diseases and the development of innovative therapies. This review focuses on the impact of sialylation in autoimmunity in order to determine future treatments based on the regulation of hyposialylation.

scholarly journals Examining the Role of CD30 in an Anaplastic Large Cell Lymphoma Mouse Model

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2542-2542
Author(s):  
Teresa Poggio ◽  
Linda Graessel ◽  
Stefanie Kreutmair ◽  
Cornelius Miething ◽  
Dietmar Pfeifer ◽  
...  
Keyword(s):  
Immune System ◽  
T Cell ◽  
Mouse Model ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Disease Development ◽  
Large Cell Lymphoma ◽  
The Impact

Anaplastic large cell lymphoma (ALCL) represents a heterogeneous group of T-cell non-Hodgkin lymphoma (NHL) mainly affecting children and young adults. About 70% of systemic ALCLs are associated with a characteristic chromosomal translocation, t(2;5)(p23;35) which fuses the anaplastic lymphoma kinase (ALK) gene on chromosome 2 with the nucleophosmin (NPM) gene on chromosome 5, resulting in the NPM-ALK fusion gene, its over-expression and constitutive kinase activity. Immunophenotypic characterization of human ALCL revealed highly CD30-positive cells of T- or Null-Cell-origin and resulted in promising clinical trials with CD30-coupled antibodies. However, the impact of CD30 on disease development remains unclear and the relationship between NPM-ALK and CD30 has been investigated mostly using cell line models. Syngeneic mouse models of cancer can serve as useful models since the tumors develop in situ where the contribution made by the immune system and the extracellular matrix can be investigated. Here, we focus on the involvement of CD30 in a retroviral murine bone marrow transplantation model of ALCL. In this model, the BM of Lck-Cre-transgenic mice is infected with a MSCV-Stop-NPM-ALK-IRES-EGFP vector leading to expression of NPM-ALK in early T-cells. With a latency of 3-4 months, mice develop lymphomas and die from neoplastic T-cell-infiltration of BM and lymphatic organs. To investigate the impact of abrogation of CD30 signals on the development of NPM-ALK+ ALCL in our model, CD30 knockout mice were crossed with Lck-Cre mice. Both Lck-Cre NPM-ALK CD30 wt and Lck-Cre NPM-ALK CD30 ko recipients develop a human ALCL-like lymphoma with a pure T-cell phenotype characterized by Thy1.2+ cells infiltrating the thymus, lymph nodes, spleen and BM. First results from Lck-Cre NPM-ALK CD30 ko transplanted mice showed impaired disease induction and prolonged survival compared to CD30 wt animals. Moreover, secondary transplantation of NPM-ALK thymic lymphomas led to distinct deceleration of disease development upon CD30 deletion. Microarray analyses have shed some light on the mechanisms underlying the delayed lymphoma progression of CD30 deleted tumors with an upregulation of inflammatory pathways and proteins that are master players in inflammation and immune responses. Further characterization of the role of CD30-mediated immune response in disease progression using this mouse model and immunocompromised mice is ongoing. An improved understanding of how the immune system affects tumor progression will extend the rationale in translational strategies to use immunotherapies for patients with T-NHLs. Disclosures No relevant conflicts of interest to declare.

scholarly journals Clonal approaches to understanding the impact of mutations on hematologic disease development

Blood ◽  
2019 ◽  
Vol 133 (13) ◽  
pp. 1436-1445 ◽  
Author(s):  
Jyoti Nangalia ◽  
Emily Mitchell ◽  
Anthony R. Green
Keyword(s):  
Somatic Mutations ◽  
Clonal Selection ◽  
Single Cells ◽  
Driver Mutations ◽  
Great Promise ◽  
Tumor Evolution ◽  
Disease Development ◽  
Hematopoietic Tissue ◽  
The Impact

Abstract Interrogation of hematopoietic tissue at the clonal level has a rich history spanning over 50 years, and has provided critical insights into both normal and malignant hematopoiesis. Characterization of chromosomes identified some of the first genetic links to cancer with the discovery of chromosomal translocations in association with many hematological neoplasms. The unique accessibility of hematopoietic tissue and the ability to clonally expand hematopoietic progenitors in vitro has provided fundamental insights into the cellular hierarchy of normal hematopoiesis, as well as the functional impact of driver mutations in disease. Transplantation assays in murine models have enabled cellular assessment of the functional consequences of somatic mutations in vivo. Most recently, next-generation sequencing–based assays have shown great promise in allowing multi-“omic” characterization of single cells. Here, we review how clonal approaches have advanced our understanding of disease development, focusing on the acquisition of somatic mutations, clonal selection, driver mutation cooperation, and tumor evolution.

scholarly journals The Potential Roles of Bisphenol A (BPA) Pathogenesis in Autoimmunity

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Datis Kharrazian
Keyword(s):  
Autoimmune Disease ◽  
Bisphenol A ◽  
Molecular Mimicry ◽  
Signal Transduction Pathway ◽  
Immune Reactivity ◽  
Cytochrome P450 Enzyme ◽  
Disease Development ◽  
Aryl Hydrocarbon ◽  
P450 Enzyme ◽  
The Impact

Bisphenol A (BPA) is a monomer found in commonly used consumer plastic goods. Although much attention in recent years has been placed on BPA’s impact as an endocrine disruptor, it also appears to activate many immune pathways involved in both autoimmune disease development and autoimmune reactivity provocation. The current scientific literature is void of research papers linking BPA directly to human or animal onset of autoimmunity. This paper explores the impact of BPA on immune reactivity and the potential roles these mechanisms may have on the development or provocation of autoimmune diseases. Potential mechanisms by which BPA may be a contributing risk factor to autoimmune disease development and progression include its impact on hyperprolactinemia, estrogenic immune signaling, cytochrome P450 enzyme disruption, immune signal transduction pathway alteration, cytokine polarization, aryl hydrocarbon activation of Th-17 receptors, molecular mimicry, macrophage activation, lipopolysaccharide activation, and immunoglobulin pathophysiology. In this paper a review of these known autoimmune triggering mechanisms will be correlated with BPA exposure, thereby suggesting that BPA has a role in the pathogenesis of autoimmunity.

scholarly journals A Linkage-specific Sialic Acid Labeling Strategy Reveals Different Site-specific Glycosylation Patterns in SARS-CoV-2 Spike Protein Produced in CHO and HEK Cell Substrates

2021 ◽  
Vol 9 ◽  
Author(s):  
Qiong Wang ◽  
Yan Wang ◽  
Shuang Yang ◽  
Changyi Lin ◽  
Lateef Aliyu ◽  
...  
Keyword(s):  
Immune System ◽  
Sialic Acid ◽  
Viral Envelope ◽  
Site Specific ◽  
S Protein ◽  
Hek Cells ◽  
High Mannose ◽  
The Impact ◽  
S Proteins ◽  
Spike Proteins

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus utilizes the extensively glycosylated spike (S) protein protruding from the viral envelope to bind to angiotensin-converting enzyme-related carboxypeptidase (ACE2) as its primary receptor to mediate host-cell entry. Currently, the main recombinant S protein production hosts are Chinese hamster ovary (CHO) and human embryonic kidney (HEK) cells. In this study, a recombinant S protein truncated at the transmembrane domain and engineered to express a C-terminal trimerization motif was transiently produced in CHO and HEK cell suspensions. To further evaluate the sialic acid linkages presenting on S protein, a two-step amidation process, employing dimethylamine and ammonium hydroxide reactions in a solid support system, was developed to differentially modify the sialic acid linkages on the glycans and glycopeptides from the S protein. The process also adds a charge to Asp and Glu which aids in ionization. We used MALDI-TOF and LC-MS/MS with electron-transfer/higher-energy collision dissociation (EThcD) fragmentation to determine global and site-specific N-linked glycosylation patterns. We identified 21 and 19 out of the 22 predicted N-glycosites of the SARS-CoV-2 S proteins produced in CHO and HEK, respectively. It was found that the N-glycosite at 1,158 position (N1158) and at 122, 282 and 1,158 positions (N122, N282 and N1158) were absent on S from CHO and HEK cells, respectively. The structural mapping of glycans of recombinant human S proteins reveals that CHO-Spike exhibits more complex and higher sialylation (α2,3-linked) content while HEK-Spike exhibits more high-mannose and a small amount of α2,3- and α2,6-linked sialic acids. The N74 site represents the most abundant glycosite on both spike proteins. The relatively higher amount of high-mannose abundant sites (N17, N234, N343, N616, N709, N717, N801, and N1134) on HEK-Spike suggests that glycan-shielding may differ among the two constructs. HEK-Spike can also provide different host immune system interaction profiles based on known immune system active lectins. Collectively, these data underscore the importance of characterizing the site-specific glycosylation of recombinant human spike proteins from HEK and CHO cells in order to better understand the impact of the production host on this complex and important protein used in research, diagnostics and vaccines.

scholarly journals Characterization of the Impact of Oncolytic Vesicular Stomatitis Virus on the Trafficking, Phenotype, and Antigen Presentation Potential of Neutrophils and Their Ability to Acquire a Non-Structural Viral Protein

2020 ◽  
Vol 21 (17) ◽  
pp. 6347 ◽  
Author(s):  
Ashley A. Stegelmeier ◽  
Lily Chan ◽  
Yeganeh Mehrani ◽  
James J. Petrik ◽  
Sarah K. Wootton ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune System ◽  
Antigen Presentation ◽  
Vesicular Stomatitis Virus ◽  
Oncolytic Virus ◽  
Substantial Proportion ◽  
Antigen Uptake ◽  
Vesicular Stomatitis ◽  
The Impact

Neutrophils are innate leukocytes that mount a rapid response to invading pathogens and sites of inflammation. Although neutrophils were traditionally considered responders to bacterial infections, recent advances have demonstrated that they are interconnected with both viral infections and cancers. One promising treatment strategy for cancers is to administer an oncolytic virus to activate the immune system and directly lyse cancerous cells. A detailed characterization of how the innate immune system responds to a viral-based therapy is paramount in identifying its systemic effects. This study analyzed how administering the rhabdovirus vesicular stomatitis virus (VSV) intravenously at 1 × 109 PFU acutely influenced neutrophil populations. Bone marrow, blood, lungs, and spleen were acquired three- and 24-h after administration of VSV for analysis of neutrophils by flow cytometry. Infection with VSV caused neutrophils to rapidly egress from the bone marrow and accumulate in the lungs. A dramatic increase in immature neutrophils was observed in the lungs, as was an increase in the antigen presentation potential of these cells within the spleen. Furthermore, the potential for neutrophils to acquire viral transgene-encoded proteins was monitored using a variant of VSV that expressed enhanced green fluorescent protein (GFP). If an in vitro population of splenocytes were exposed to αCD3 and αCD28, a substantial proportion of the neutrophils would become GFP-positive. This suggested that the neutrophils could either acquire more virus-encoded antigens from infected splenocytes or were being directly infected. Five different dosing regimens were tested in mice, and it was determined that a single dose of VSV or two doses of VSV administered at a 24-h interval, resulted in a substantial proportion of neutrophils in the bone marrow becoming GFP-positive. This correlated with a decrease in the number of splenic neutrophils. Two doses administered at intervals longer than 24-h did not have these effects, suggesting that neutrophils became resistant to antigen uptake or direct infection with VSV beyond 24-h of activation. These findings implicated neutrophils as major contributors to oncolytic rhabdoviral therapies. They also provide several clear future directions for research and suggest that neutrophils should be carefully monitored during the development of all oncolytic virus-based treatment regimens.

scholarly journals Creative and innovative: an assay of workers

2019 ◽  
Vol 7 (1) ◽  
pp. 32-54
Author(s):  
Sara Ibérico Nogueira ◽  
Leonor Almeida ◽  
Leonor Almeida ◽  
Tiago Jossé Souza Lima ◽  
Tiago Jossé Souza Lima
Keyword(s):  
Organizational Climate ◽  
Creative Thinking ◽  
Organizational Context ◽  
Education Level ◽  
Detailed Characterization ◽  
Creativity Research ◽  
Gender And Age ◽  
The Impact ◽  
Contemporary Approach

A contemporary approach to creativity research emphasizes the fact that all people, in their work context, can contribute with creative ideas in some domain. In this sense, the organizational context has a determining influence (Amabile, 1996). The objective of this study is to analyse the impact of organization type (private- versus public-sector), education level, gender and age on creativity and perceived innovativeness with a sample of 611 Portuguese workers. These variables were operationalized by the Test for Creative Thinking- Drawing Production (TCT-DP) and the Innovativeness Inventory (II). Organization type and education level seem to be the best predictors for creativity and innovativeness, respectively.In the future, it intends to undertake a detailed characterization of the variables involved in the organizational climate as these may explain the lower creativity levels of public workersto some extent.

scholarly journals Exploring the Impact of Ketodeoxynonulosonic Acid in Host-Pathogen Interactions Using Uptake and Surface Display by Nontypeable Haemophilus influenzae

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sudeshna Saha ◽  
Alison Coady ◽  
Aniruddha Sasmal ◽  
Kunio Kawanishi ◽  
Biswa Choudhury ◽  
...  
Keyword(s):  
Immune System ◽  
Sialic Acid ◽  
Haemophilus Influenzae ◽  
Pathogenic Bacteria ◽  
Molecular Mimicry ◽  
Surface Display ◽  
Sialic Acids ◽  
Complement C3 ◽  
Nontypeable Haemophilus Influenzae ◽  
The Impact

ABSTRACT Surface expression of the common vertebrate sialic acid (Sia) N-acetylneuraminic acid (Neu5Ac) by commensal and pathogenic microbes appears structurally to represent “molecular mimicry” of host sialoglycans, facilitating multiple mechanisms of host immune evasion. In contrast, ketodeoxynonulosonic acid (Kdn) is a more ancestral Sia also present in prokaryotic glycoconjugates that are structurally quite distinct from vertebrate sialoglycans. We detected human antibodies against Kdn-terminated glycans, and sialoglycan microarray studies found these anti-Kdn antibodies to be directed against Kdn-sialoglycans structurally similar to those on human cell surface Neu5Ac-sialoglycans. Anti-Kdn-glycan antibodies appear during infancy in a pattern similar to those generated following incorporation of the nonhuman Sia N-glycolylneuraminic acid (Neu5Gc) onto the surface of nontypeable Haemophilus influenzae (NTHi), a human commensal and opportunistic pathogen. NTHi grown in the presence of free Kdn took up and incorporated the Sia into its lipooligosaccharide (LOS). Surface display of the Kdn within NTHi LOS blunted several virulence attributes of the pathogen, including Neu5Ac-mediated resistance to complement and whole blood killing, complement C3 deposition, IgM binding, and engagement of Siglec-9. Upper airway administration of Kdn reduced NTHi infection in human-like Cmah null (Neu5Gc-deficient) mice that express a Neu5Ac-rich sialome. We propose a mechanism for the induction of anti-Kdn antibodies in humans, suggesting that Kdn could be a natural and/or therapeutic “Trojan horse” that impairs colonization and virulence phenotypes of free Neu5Ac-assimilating human pathogens. IMPORTANCE All cells in vertebrates are coated with a dense array of glycans often capped with sugars called sialic acids. Sialic acids have many functions, including serving as a signal for recognition of “self” cells by the immune system, thereby guiding an appropriate immune response against foreign “nonself” and/or damaged cells. Several pathogenic bacteria have evolved mechanisms to cloak themselves with sialic acids and evade immune responses. Here we explore a type of sialic acid called “Kdn” (ketodeoxynonulosonic acid) that has not received much attention in the past and compare and contrast how it interacts with the immune system. Our results show potential for the use of Kdn as a natural intervention against pathogenic bacteria that take up and coat themselves with external sialic acid from the environment.

Intramolecular Proton Transfer in the Isomerization of Hydroxyacetone: A Detailed Characterization Based on Reaction Force Analysis and the Bond Fragility Spectrum

2020 ◽  
Author(s):  
Wallace Derricotte ◽  
Huiet Joseph
Keyword(s):  
Chemical Potential ◽  
Reaction Force ◽  
Intramolecular Proton Transfer ◽  
Intermediate Energy ◽  
Force Analysis ◽  
Activation Energy Barrier ◽  
Detailed Characterization ◽  
Proton Transfers ◽  
Reaction Force Constant

The mechanism of isomerization of hydroxyacetone to 2-hydroxypropanal is studied within the framework of reaction force analysis at the M06-2X/6-311++G(d,p) level of theory. Three unique pathways are considered: (i) a step-wise mechanism that proceeds through formation of the Z-isomer of their shared enediol intermediate, (ii) a step-wise mechanism that forms the E-isomer of the enediol, and (iii) a concerted pathway that bypasses the enediol intermediate. Energy calculations show that the concerted pathway has the lowest activation energy barrier at 45.7 kcal mol<sup>-1</sup>. The reaction force, chemical potential, and reaction electronic flux are calculated for each reaction to characterize electronic changes throughout the mechanism. The reaction force constant is calculated in order to investigate the synchronous/asynchronous nature of the concerted intramolecular proton transfers involved. Additional characterization of synchronicity is provided by calculating the bond fragility spectrum for each mechanism.

The Analyses of Learning Strategies in English as a Second Language: Theoretical Classification and Measurement Test

2020 ◽  
Vol 4 (2) ◽  
pp. 118-129
Author(s):  
Asti Gumartifa ◽  
◽  
Indah Windra Dwie Agustiani
Keyword(s):  
Language Learning ◽  
Learning Outcomes ◽  
Learning Strategies ◽  
Learning Process ◽  
English Learners ◽  
English Language ◽  
Point Of View ◽  
Effective Learning ◽  
The Impact

Gaining English language learning effectively has been discussed all years long. Similarly, Learners have various troubles outcomes in the learning process. Creating a joyful and comfortable situation must be considered by learners. Thus, the implementation of effective learning strategies is certainly necessary for English learners. This descriptive study has two purposes: first, to introduce the classification and characterization of learning strategies such as; memory, cognitive, metacognitive, compensation, social, and affective strategies that are used by learners in the classroom and second, it provides some questionnaires item based on Strategy of Inventory for Language Learning (SILL) version 5.0 that can be used to examine the frequency of students’ learning strategies in the learning process. The summary of this study explains and discusses the researchers’ point of view on the impact of learning outcomes by learning strategies used. Finally, utilizing appropriate learning strategies are certainly beneficial for both teachers and learners to achieve the learning target effectively.

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