bluuebunny/crossref_metadata_2025 huggingface dataset:
High Content Image Analysis as a Tool to Morphologically Distinguish Macrophage Activation and Determine Its Importance for Foamy Alveolar Macrophage Responses
Authors: Hoffman Ewelina , Napieralska Paulina , Mahendran Rhamiya , Murnane Darragh , Hutter Victoria
Published: September 2021

Introduction

Lung diseases are an increasing global health burden affecting millions of people worldwide. Only a few new inhaled medicines have reached the market in the last 30 years, in part due to foamy alveolar macrophage (FAM) responses observed in pre-clinical rat studies. The induction mechanism and signaling pathways involved in the development of highly vacuolated ‘foamy’ phenotype is not known. Furthermore, it has not been determined if these observations are adaptive or adverse responses.

Aim

To determine if high content image analysis techniques can distinguish between alveolar macrophage activation (LPS/IFN-γ activated and IL-4 activated macrophages) and if this could be applied to understanding the generation of ‘foamy’ macrophage phenotypes.

Methods

NR8383 rat alveolar macrophages were stimulated with a mix of cytokines (LPS/IFN-γ or IL-4) for 24 h. The cells were further exposed to FAM inducing-compounds amiodarone and staurosporine. Following 24 h incubation, phagocytosis and lipid accumulation were measured using flow cytometry and high content image analysis techniques. The alveolar macrophages responses after exposure to cytokines were assessed by evaluation: (i) cell surface and biochemical markers such as: nitric oxide production, arginase-1 activity and MRC-1 receptor expression (ii) cellular morphology (iii) cellular functionality (phagocytic activity and lipids accumulation).

Results

Macrophages activated with LPS/IFN-γ showed distinct morphological (increased vacuolation) features and functionality (increased lipidosis, decreased phagocytic activity). Foamy macrophage phenotypes induced by amiodarone also displayed characteristics of proinflammatory macrophages (significantly increased nitric oxide production, increased vacuolation and lipidosis and decreased phagocytosis). In contrast, staurosporine treatment resulted in increased NO production, as well as arginase-1 activity.

Conclusion

High content image analysis was able to determine distinct differences in morphology between non-activated and LPS/IFN-γ activated macrophages, characterized by increased vacuolation and lipidosis. When exposed to compounds that induce a FAM phenotype, healthy non-activated macrophages displayed proinflammatory (amiodarone) or pro-apoptotic (staurosporine) characteristics but these responses were independent of a change in activation status. This technique could be applied in early drug discovery safety assessment to identify immune responses earlier and increase the understanding of alveolar macrophage responses to new molecules challenge in development of new inhalation therapies, which in turn will enhance decision-making in an early safety assessment of novel drug candidates.
Mitochondria in Injury, Inflammation and Disease of Articular Skeletal Joints
Authors: Early James Orman , Fagan Lauren E. , Curtis Annie M. , Kennedy Oran D.
Published: September 2021

Inflammation is an important biological response to tissue damage caused by injury, with a crucial role in initiating and controlling the healing process. However, dysregulation of the process can also be a major contributor to tissue damage. Related to this, although mitochondria are typically thought of in terms of energy production, it has recently become clear that these important organelles also orchestrate the inflammatory response via multiple mechanisms. Dysregulated inflammation is a well-recognised problem in skeletal joint diseases, such as rheumatoid arthritis. Interestingly osteoarthritis (OA), despite traditionally being known as a ‘non-inflammatory arthritis’, now appears to involve an element of chronic inflammation. OA is considered an umbrella term for a family of diseases stemming from a range of aetiologies (age, obesity etc.), but all with a common presentation. One particular OA sub-set called Post-Traumatic OA (PTOA) results from acute mechanical injury to the joint. Whether the initial mechanical tissue damage, or the subsequent inflammatory response drives disease, is currently unclear. In the former case; mechanobiological properties of cells/tissues in the joint are a crucial consideration. Many such cell-types have been shown to be exquisitely sensitive to their mechanical environment, which can alter their mitochondrial and cellular function. For example, in bone and cartilage cells fluid-flow induced shear stresses can modulate cytoskeletal dynamics and gene expression profiles. More recently, immune cells were shown to be highly sensitive to hydrostatic pressure. In each of these cases mitochondria were central to these responses. In terms of acute inflammation, mitochondria may have a pivotal role in linking joint tissue injury with chronic disease. These processes could involve the immune cells recruited to the joint, native/resident joint cells that have been damaged, or both. Taken together, these observations suggest that mitochondria are likely to play an important role in linking acute joint tissue injury, inflammation, and long-term chronic joint degeneration - and that the process involves mechanobiological factors. In this review, we will explore the links between mechanobiology, mitochondrial function, inflammation/tissue-damage in joint injury and disease. We will also explore some emerging mitochondrial therapeutics and their potential for application in PTOA.
Immune Recovery Following Autologous Hematopoietic Stem Cell Transplantation in HIV-Related Lymphoma Patients on the BMT CTN 0803/AMC 071 Trial
Authors: Shindiapina Polina , Pietrzak Maciej , Seweryn Michal , McLaughlin Eric , Zhang Xiaoli , Makowski Mat , Ahmed Elshafa Hassan , Schlotter Sarah , Pearson Rebecca , Kitzler Rhonda , Mozhenkova Anna , Le-Rademacher Jennifer , Little Richard F. , Akpek Gorgun , Ayala Ernesto , Devine Steven M. , Kaplan Lawrence D. , Noy Ariela , Popat Uday R. , Hsu Jack W. , Morris Lawrence E. , Mendizabal Adam M. , Krishnan Amrita , Wachsman William , Williams Nita , Sharma Nidhi , Hofmeister Craig C. , Forman Stephen J. , Navarro Willis H. , Alvarnas Joseph C. , Ambinder Richard F. , Lozanski Gerard , Baiocchi Robert A.
Published: September 2021

We report a first in-depth comparison of immune reconstitution in patients with HIV-related lymphoma following autologous hematopoietic cell transplant (AHCT) recipients (n=37, lymphoma, BEAM conditioning), HIV(-) AHCT recipients (n=30, myeloma, melphalan conditioning) at 56, 180, and 365 days post-AHCT, and 71 healthy control subjects. Principal component analysis showed that immune cell composition in HIV(+) and HIV(-) AHCT recipients clustered away from healthy controls and from each other at each time point, but approached healthy controls over time. Unsupervised feature importance score analysis identified activated T cells, cytotoxic memory and effector T cells [higher in HIV(+)], and naïve and memory T helper cells [lower HIV(+)] as a having a significant impact on differences between HIV(+) AHCT recipient and healthy control lymphocyte composition (p<0.0033). HIV(+) AHCT recipients also demonstrated lower median absolute numbers of activated B cells and lower NK cell sub-populations, compared to healthy controls (p<0.0033) and HIV(-) AHCT recipients (p<0.006). HIV(+) patient T cells showed robust IFNγ production in response to HIV and EBV recall antigens. Overall, HIV(+) AHCT recipients, but not HIV(-) AHCT recipients, exhibited reconstitution of pro-inflammatory immune profiling that was consistent with that seen in patients with chronic HIV infection treated with antiretroviral regimens. Our results further support the use of AHCT in HIV(+) individuals with relapsed/refractory lymphoma.
Thymus Degeneration and Regeneration
Authors: Duah Maxwell , Li Lingling , Shen Jingyi , Lan Qiu , Pan Bin , Xu Kailin
Published: September 2021

The immune system’s ability to resist the invasion of foreign pathogens and the tolerance to self-antigens are primarily centered on the efficient functions of the various subsets of T lymphocytes. As the primary organ of thymopoiesis, the thymus performs a crucial role in generating a self-tolerant but diverse repertoire of T cell receptors and peripheral T cell pool, with the capacity to recognize a wide variety of antigens and for the surveillance of malignancies. However, cells in the thymus are fragile and sensitive to changes in the external environment and acute insults such as infections, chemo- and radiation-therapy, resulting in thymic injury and degeneration. Though the thymus has the capacity to self-regenerate, it is often insufficient to reconstitute an intact thymic function. Thymic dysfunction leads to an increased risk of opportunistic infections, tumor relapse, autoimmunity, and adverse clinical outcome. Thus, exploiting the mechanism of thymic regeneration would provide new therapeutic options for these settings. This review summarizes the thymus’s development, factors causing thymic injury, and the strategies for improving thymus regeneration.
Complication and Sequelae of COVID-19: What Should We Pay Attention to in the Post-Epidemic Era
Authors: Yang Keda , Wen Guangfu , Wang Jinpeng , Zhou Siming , Da Wacili , Meng Yan , Xue Yuchuan , Tao Lin
Published: September 2021

COVID-19 is widespread worldwide and seriously affects the daily life and health of humans. Countries around the world are taking necessary measures to curb the spread. However, COVID-19 patients often have at least one organ complication and sequelae in addition to respiratory symptoms. Controlling the epidemic is only a phased victory, and the complication and sequelae of COVID-19 will need more attention in the post-epidemic era. We collected general information from over 1000 articles published in 2020 after the COVID-19 outbreak and systematically analyzed the complication and sequelae associated with eight major systems in COVID-19 patients caused by ACE2 intervention in the RAS regulatory axis. The autoimmune response induced by 2019-nCoV attacks and damages the normal tissues and organs of the body. Our research will help medical workers worldwide address COVID-19 complication and sequelae.
Artificial Intelligence Predicts Severity of COVID-19 Based on Correlation of Exaggerated Monocyte Activation, Excessive Organ Damage and Hyperinflammatory Syndrome: A Prospective Clinical Study
Authors: Krysko Olga , Kondakova Elena , Vershinina Olga , Galova Elena , Blagonravova Anna , Gorshkova Ekaterina , Bachert Claus , Ivanchenko Mikhail , Krysko Dmitri V. , Vedunova Maria
Published: September 2021

Background

Prediction of the severity of COVID-19 at its onset is important for providing adequate and timely management to reduce mortality.

Objective

To study the prognostic value of damage parameters and cytokines as predictors of severity of COVID-19 using an extensive immunologic profiling and unbiased artificial intelligence methods.

Methods

Sixty hospitalized COVID-19 patients (30 moderate and 30 severe) and 17 healthy controls were included in the study. The damage indicators high mobility group box 1 (HMGB1), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), extensive biochemical analyses, a panel of 47 cytokines and chemokines were analyzed at weeks 1, 2 and 7 along with clinical complaints and CT scans of the lungs. Unbiased artificial intelligence (AI) methods (logistic regression and Support Vector Machine and Random Forest algorithms) were applied to investigate the contribution of each parameter to prediction of the severity of the disease.

Results

On admission, the severely ill patients had significantly higher levels of LDH, IL-6, monokine induced by gamma interferon (MIG), D-dimer, fibrinogen, glucose than the patients with moderate disease. The levels of macrophage derived cytokine (MDC) were lower in severely ill patients. Based on artificial intelligence analysis, eight parameters (creatinine, glucose, monocyte number, fibrinogen, MDC, MIG, C-reactive protein (CRP) and IL-6 have been identified that could predict with an accuracy of 83−87% whether the patient will develop severe disease.

Conclusion

This study identifies the prognostic factors and provides a methodology for making prediction for COVID-19 patients based on widely accepted biomarkers that can be measured in most conventional clinical laboratories worldwide.
Critical Role of Synovial Tissue–Resident Macrophage and Fibroblast Subsets in the Persistence of Joint Inflammation
Authors: Kemble Samuel , Croft Adam P.
Published: September 2021

Rheumatoid arthritis (RA) is a chronic prototypic immune-mediated inflammatory disease which is characterized by persistent synovial inflammation, leading to progressive joint destruction. Whilst the introduction of targeted biological drugs has led to a step change in the management of RA, 30-40% of patients do not respond adequately to these treatments, regardless of the mechanism of action of the drug used (ceiling of therapeutic response). In addition, many patients who acheive clinical remission, quickly relapse following the withdrawal of treatment. These observations suggest the existence of additional pathways of disease persistence that remain to be identified and targeted therapeutically. A major barrier for the identification of therapeutic targets and successful clinical translation is the limited understanding of the cellular mechanisms that operate within the synovial microenvironment to sustain joint inflammation. Recent insights into the heterogeneity of tissue resident synovial cells, including macropahges and fibroblasts has revealed distinct subsets of these cells that differentially regulate specific aspects of inflammatory joint pathology, paving the way for targeted interventions to specifically modulate the behaviour of these cells. In this review, we will discuss the phenotypic and functional heterogeneity of tissue resident synovial cells and how this cellular diversity contributes to joint inflammation. We discuss how critical interactions between tissue resident cell types regulate the disease state by establishing critical cellular checkpoints within the synovium designed to suppress inflammation and restore joint homeostasis. We propose that failure of these cellular checkpoints leads to the emergence of imprinted pathogenic fibroblast cell states that drive the persistence of joint inflammation. Finally, we discuss therapeutic strategies that could be employed to specifically target pathogenic subsets of fibroblasts in RA.
TAMs in Brain Metastasis: Molecular Signatures in Mouse and Man
Authors: Schulz Michael , Sevenich Lisa
Published: September 2021

Macrophages not only represent an integral part of innate immunity but also critically contribute to tissue and organ homeostasis. Moreover, disease progression is accompanied by macrophage accumulation in many cancer types and is often associated with poor prognosis and therapy resistance. Given their critical role in modulating tumor immunity in primary and metastatic brain cancers, macrophages are emerging as promising therapeutic targets. Different types of macrophages infiltrate brain cancers, including (i) CNS resident macrophages that comprise microglia (TAM-MG) as well as border-associated macrophages and (ii) monocyte-derived macrophages (TAM-MDM) that are recruited from the periphery. Controversy remained about their disease-associated functions since classical approaches did not reliably distinguish between macrophage subpopulations. Recent conceptual and technological advances, such as large-scale omic approaches, provided new insight into molecular profiles of TAMs based on their cellular origin. In this review, we summarize insight from recent studies highlighting similarities and differences of TAM-MG and TAM-MDM at the molecular level. We will focus on data obtained from RNA sequencing and mass cytometry approaches. Together, this knowledge significantly contributes to our understanding of transcriptional and translational programs that define disease-associated TAM functions. Cross-species meta-analyses will further help to evaluate the translational significance of preclinical findings as part of the effort to identify candidates for macrophage-targeted therapy against brain metastasis.
TREM2: Keeping Pace With Immune Checkpoint Inhibitors in Cancer Immunotherapy
Authors: Qiu Hui , Shao Zhiying , Wen Xin , Jiang Jinghua , Ma Qinggong , Wang Yan , Huang Long , Ding Xin , Zhang Longzhen
Published: September 2021

To date, immune checkpoint inhibitors have been successively approved and widely used in clinical cancer treatments, however, the overall response rates are very low and almost all cancer patients eventually progressed to drug resistance, this is mainly due to the intricate tumor microenvironment and immune escape mechanisms of cancer cells. One of the main key mechanisms leading to the evasion of immune attack is the presence of the immunosuppressive microenvironment within tumors. Recently, several studies illustrated that triggering receptor expressed on myeloid cells-2 (TREM2), a transmembrane receptor of the immunoglobulin superfamily, was a crucial pathology-induced immune signaling hub, and it played a vital negative role in antitumor immunity, such as inhibiting the proliferation of T cells. Here, we reviewed the recent advances in the study of TREM2, especially focused on its regulation of tumor-related immune signaling pathways and its role as a novel target in cancer immunotherapy.
Current Clinical and Pre-Clinical Imaging Approaches to Study the Cancer-Associated Immune System
Authors: Mueller Christopher G. , Gaiddon Christian , Venkatasamy Aïna
Published: September 2021

In the light of the success and the expected growth of its arsenal, immuno-therapy may become the standard neoadjuvant procedure for many cancers in the near future. However, aspects such as the identity, organization and the activation status of the peri- and intra-tumoral immune cells would represent important elements to weigh in the decision for the appropriate treatment. While important progress in non-invasive imaging of immune cells has been made over the last decades, it falls yet short of entering the clinics, let alone becoming a standard procedure. Here, we provide an overview of the different intra-vital imaging approaches in the clinics and in pre-clinical settings and discuss their benefits and drawbacks for assessing the activity of the immune system, globally and on a cellular level. Stimulated by further research, the future is likely to see many technological advances both on signal detection and emission as well as image specificity and resolution to tackle current hurdles. We anticipate that the ability to precisely determine an immune stage of cancer will capture the attention of the oncologist and will create a change in paradigm for cancer therapy.
Signatures of Multi-Omics Reveal Distinct Tumor Immune Microenvironment Contributing to Immunotherapy in Lung Adenocarcinoma
Authors: Huang Ziqi , Li Baihui , Guo Yan , Wu Lei , Kou Fan , Yang Lili
Published: September 2021

Background

Lung adenocarcinoma (LUAD) contains a variety of genomic and epigenomic abnormalities; the effective tumor markers related to these abnormalities need to be further explored.

Methods

Clustering analysis was performed based on DNA methylation (MET), DNA copy number variation (CNV), and mRNA expression data, and the differences in survival and tumor immune microenvironment (TIME) between subtypes were compared. Further, we evaluated the signatures in terms of both prognostic value and immunological characteristics.

Results

There was a positive correlation between MET and CNV in LUAD. Integrative analysis of multi-omics data from 443 samples determined molecular subtypes, iC1 and iC2. The fractions of CD8+ T cells and activated CD4+ T cells were higher, the fraction of Tregs was lower, and the expression level of programmed death-ligand 1 (PD-L1) was higher in iC2 with a poor prognosis showing a higher TIDE score. We selected PTTG1, SLC2A1, and FAM83A as signatures of molecular subtypes to build a prognostic risk model and divided patients into high-risk group and low-risk group representing poor prognosis and good prognosis, respectively, which were validated in 180 patients with LUAD. Further, the low-risk group with lower TIDE score had more infiltrating immune cells. In 100 patients with LUAD, the high-risk group with an immunosuppressive state had a higher expression of PD-L1 and lower counts of CD8+ T cells and dendritic cells.

Conclusions

These findings demonstrated that combined multi-omics data could determine molecular subtypes with significant differences of prognosis and TIME in LUAD and suggested potent utility of the signatures to guide immunotherapy.
The First Chemically-Synthesised, Highly Immunogenic Anti-SARS-CoV-2 Peptides in DNA Genotyped Aotus Monkeys for Human Use
Authors: Patarroyo Manuel E. , Patarroyo Manuel A. , Alba Martha P. , Pabon Laura , Rugeles María T. , Aguilar-Jimenez Wbeimar , Florez Lizdany , Bermudez Adriana , Rout Ashok K. , Griesinger Christian , Suarez Carlos F. , Aza-Conde Jorge , Reyes César , Avendaño Catalina , Samacá Jhoan , Camargo Anny , Silva Yolanda , Forero Martha , Gonzalez Edgardo
Published: September 2021

Thirty-five peptides selected from functionally-relevant SARS-CoV-2 spike (S), membrane (M), and envelope (E) proteins were suitably modified for immunising MHC class II (MHCII) DNA-genotyped Aotus monkeys and matched with HLA-DRβ1* molecules for use in humans. This was aimed at producing the first minimal subunit-based, chemically-synthesised, immunogenic molecules (COLSARSPROT) covering several HLA alleles. They were predicted to cover 48.25% of the world’s population for 6 weeks (short-term) and 33.65% for 15 weeks (long-lasting) as they induced very high immunofluorescent antibody (IFA) and ELISA titres against S, M and E parental native peptides, SARS-CoV-2 neutralising antibodies and host cell infection. The same immunological methods that led to identifying new peptides for inclusion in the COLSARSPROT mixture were used for antigenicity studies. Peptides were analysed with serum samples from patients suffering mild or severe SARS-CoV-2 infection, thereby increasing chemically-synthesised peptides’ potential coverage for the world populations up to 62.9%. These peptides’ 3D structural analysis (by 1H-NMR acquired at 600 to 900 MHz) suggested structural-functional immunological association. This first multi-protein, multi-epitope, minimal subunit-based, chemically-synthesised, highly immunogenic peptide mixture highlights such chemical synthesis methodology’s potential for rapidly obtaining very pure, highly reproducible, stable, cheap, easily-modifiable peptides for inducing immune protection against COVID-19, covering a substantial percentage of the human population.
Compromised Protein Prenylation as Pathogenic Mechanism in Mevalonate Kinase Deficiency
Authors: Politiek Frouwkje A. , Waterham Hans R.
Published: September 2021

Mevalonate kinase deficiency (MKD) is an autoinflammatory metabolic disorder characterized by life-long recurring episodes of fever and inflammation, often without clear cause. MKD is caused by bi-allelic pathogenic variants in theMVKgene, resulting in a decreased activity of the encoded enzyme mevalonate kinase (MK). MK is an essential enzyme in the isoprenoid biosynthesis pathway, which generates both non-sterol and sterol isoprenoids. The inflammatory symptoms of patients with MKD point to a major role for isoprenoids in the regulation of the innate immune system. In particular a temporary shortage of the non-sterol isoprenoid geranylgeranyl pyrophosphate (GGPP) is increasingly linked with inflammation in MKD. The shortage of GGPP compromises protein prenylation, which is thought to be one of the main causes leading to the inflammatory episodes in MKD. In this review, we discuss current views and the state of knowledge of the pathogenetic mechanisms in MKD, with particular focus on the role of compromised protein prenylation.
Optimal Isolation Protocols for Examining and Interrogating Mononuclear Phagocytes From Human Intestinal Tissue
Authors: Doyle Chloe M. , Vine Erica E. , Bertram Kirstie M. , Baharlou Heeva , Rhodes Jake W. , Dervish Suat , Gosselink Martijn P. , Di Re Angelina , Collins Geoffrey P. , Reza Faizur , Toh James W. T. , Pathma-Nathan Nimalan , Ahlenstiel Golo , Ctercteko Grahame , Cunningham Anthony L. , Harman Andrew N. , Byrne Scott N.
Published: September 2021

The human intestine contains numerous mononuclear phagocytes (MNP), including subsets of conventional dendritic cells (cDC), macrophages (Mf) and monocytes, each playing their own unique role within the intestinal immune system and homeostasis. The ability to isolate and interrogate MNPs from fresh human tissue is crucial if we are to understand the role of these cells in homeostasis, disease settings and immunotherapies. However, liberating these cells from tissue is problematic as many of the key surface identification markers they express are susceptible to enzymatic cleavage and they are highly susceptible to cell death. In addition, the extraction process triggers immunological activation/maturation which alters their functional phenotype. Identifying the evolving, complex and highly heterogenous repertoire of MNPs by flow cytometry therefore requires careful selection of digestive enzyme blends that liberate viable cells and preserve recognition epitopes involving careful selection of antibody clones to enable analysis and sorting for functional assays. Here we describe a method for the anatomical separation of mucosa and submucosa as well as isolating lymphoid follicles from human jejunum, ileum and colon. We also describe in detail the optimised enzyme digestion methods needed to acquire functionally immature and biologically functional intestinal MNPs. A comprehensive list of screened antibody clones is also presented which allows for the development of high parameter flow cytometry panels to discriminate all currently identified human tissue MNP subsets including pDCs, cDC1, cDC2 (langerin+ and langerin-), newly described DC3, monocytes, Mf1, Mf2, Mf3 and Mf4. We also present a novel method to account for autofluorescent signal from tissue macrophages. Finally, we demonstrate that these methods can successfully be used to sort functional, immature intestinal DCs that can be used for functional assays such as cytokine production assays.
Sleep Deprivation Disturbs Immune Surveillance and Promotes the Progression of Hepatocellular Carcinoma
Authors: Huang Jing , Song Peiwen , Hang Kaibin , Chen Zeka , Zhu Zidan , Zhang Yuye , Xu Jietian , Qin Jie , Wang Binghua , Qu Weimin , Huang Zhili , Liang Chunmin
Published: September 2021

Sleep disturbance is common in patients with cancer and is associated with poor prognosis. However, the effects of sleep deprivation (SD) on immune surveillance during the development of hepatocellular carcinoma (HC) and the underlying mechanisms are not known. This was investigated in the present study using mouse models of SD and tumorigenesis. We determined that acute and chronic sleep deprivation (CSD) altered the relative proportions of various immune cell types in blood and peripheral organs. CSD increased tumor volume and weight, an effect that was enhanced with increasing CSD time. Expression of the cell proliferation marker Ki-67 was elevated in tumor tissues, and tumor cell infiltration into adjacent muscles was enhanced by CSD. Multicolor flow cytometry analysis revealed that CSD significantly reduced the numbers of antitumor CD3+ T cells and natural killer (NK) cells and increased that of immunosuppressive CD11b+ cells infiltrating into the tumor microenvironment from the spleen via the peripheral blood. These results indicate that CSD impairs immune surveillance mechanisms and promotes immunosuppression in the tumor microenvironment to accelerate tumor growth, underscoring the importance of alleviating sleep disturbance in HC patients in order to prevent HC progression.
p53 Activation Effect in the Balance of T Regulatory and Effector Cell Subsets in Patients With Thyroid Cancer and Autoimmunity
Authors: Arena Andrea , Stigliano Antonio , Belcastro Eugenia , Giorda Ezio , Rosado Maria Manuela , Grossi Armando , Assenza Maria Rita , Moretti Fabiola , Fierabracci Alessandra
Published: September 2021

Carcinomas evade the host immune system by negatively modulating CD4+ and CD8+ T effector lymphocytes through forkhead box protein 3 (FOXP3) positive T regulatory cells’ increased activity. Furthermore, interaction of the programmed cell death 1 (PD1) molecule and its ligand programmed cell death ligand 1 (PDL1) inhibits the antitumor activity of PD1+ T lymphocytes. Immunotherapy has become a powerful strategy for tailored cancer patients’ treatment both in adult and pediatric patients aiming to generate potent antitumor responses. Nevertheless, immunotherapies can generate autoimmune responses. This study aimed to investigate the potential effect of the transformation-related protein 53 (p53) reactivation by a peptide-based inhibitor of the MDM2/MDM4 heterodimer (Pep3) on the immune response in a solid cancer,i.e., thyroid carcinoma frequently presenting with thyroid autoimmunity. In peripheral blood mononuclear cell of thyroid cancer patients, Pep3 treatment alters percentages of CD8+ and CD4+ T regulatory and CD8+ and CD4+ T effector cells and favors an anticancer immune response. Of note that reduced frequencies of activated CD8+ and CD4+ T effector cells do not support autoimmunity progression. In evaluating PD1 expression under p53 activation, a significant decrease of activated CD4+PD1+ cells was detected in thyroid cancer patients, suggesting a defective regulation in the initial activation stage, therefore generating a protective condition toward autoimmune progression.
Regulatory T Cells in Autoimmunity and Cancer: A Duplicitous Lifestyle
Authors: Hatzioannou Aikaterini , Boumpas Athina , Papadopoulou Miranta , Papafragkos Iosif , Varveri Athina , Alissafi Themis , Verginis Panayotis
Published: September 2021

Regulatory T (Treg) cells, possess a strategic role in the maintenance of immune homeostasis, and their function has been closely linked to development of diverse pathologies including autoimmunity and cancer. Comprehensive studies in various disease contexts revealed an increased plasticity as a characteristic of Treg cells. Although Treg cell plasticity comes in various flavors, the major categories enclose the loss of Foxp3 expression, which is the master regulator of Treg cell lineage, giving rise to “ex-Treg” cells and the “fragile” Treg cells in whichFOXP3expression is retained but accompanied by the engagement of an inflammatory program and attenuation of the suppressive activity. Treg cell plasticity possess a tremendous therapeutic potential either by inducing Treg cell de-stabilization to promote anti-tumor immunity, or re-enforcing Treg cell stability to attenuate chronic inflammation. Herein, we review the literature on the Treg cell plasticity with lessons learned in autoimmunity and cancer and discuss challenges and open questions with potential therapeutic implications.
Glycoprotein Pathways Altered in Frontotemporal Dementia With Autoimmune Disease
Authors: Bright Fiona , Katzeff Jared S. , Hodges John R. , Piguet Olivier , Kril Jillian J. , Halliday Glenda M. , Kim Woojin Scott
Published: September 2021

Behavioral variant frontotemporal dementia (bvFTD) is a younger onset form of neurodegeneration initiated in the frontal and/or temporal lobes with a slow clinical onset but rapid progression. bvFTD is highly complex biologically with different pathological signatures and genetic variants that can exhibit a spectrum of overlapping clinical manifestations. Although the role of innate immunity has been extensively investigated in bvFTD, the involvement of adaptive immunity in bvFTD pathogenesis is poorly understood. We analyzed blood serum proteomics to identify proteins that are associated with autoimmune disease in bvFTD. Eleven proteins (increased: ATP5B, CALML5, COLEC11, FCGBP, PLEK, PLXND1; decreased: APOB, ATP8B1, FAM20C, LOXL3, TIMD4) were significantly altered in bvFTD with autoimmune disease compared to those without autoimmune disease. The majority of these proteins were enriched for glycoprotein-associated proteins and pathways, suggesting that the glycome is targeted in bvFTD with autoimmune disease.
The mRNA-1273 Vaccine Induces Cross-Variant Antibody Responses to SARS-CoV-2 With Distinct Profiles in Individuals With or Without Pre-Existing Immunity
Authors: Tejedor Vaquero Sonia , de Campos-Mata Leire , Ramada José María , Díaz Pilar , Navarro-Barriuso Juan , Ribas-Llaurado Clara , Rodrigo Melero Natalia , Carolis Carlo , Cerutti Andrea , Gimeno Ramon , Magri Giuliana
Published: September 2021

mRNA-based vaccines effectively induce protective neutralizing antibodies against SARS-CoV-2, the etiological agent of COVID-19. Yet, the kinetics and compositional patterns of vaccine-induced antibody responses to the original strain and emerging variants of concern remain largely unknown. Here we characterized serum antibody classes and subclasses targeting the spike receptor-binding domain of SARS-CoV-2 wild type and α, β, γ and δ variants in a longitudinal cohort of SARS-CoV-2 naïve and COVID-19 recovered individuals receiving the mRNA-1273 vaccine. We found that mRNA-1273 vaccine recipients developed a SARS-CoV-2-specific antibody response with a subclass profile comparable to that induced by natural infection. Importantly, these antibody responses targeted both wild type SARS-CoV-2 as well as its α, β, γ and δ variants. Following primary vaccination, individuals with pre-existing immunity showed higher induction of all antibodies but IgG3 compared to SARS-CoV-2-naïve subjects. Unlike naïve individuals, COVID-19 recovered subjects did not mount a recall antibody response upon the second vaccine dose. In these individuals, secondary immunization resulted in a slight reduction of IgG1 against the receptor-binding domain of β and γ variants. Despite the lack of recall humoral response, vaccinees with pre-existing immunity still showed higher titers of IgG1 and IgA to all variants analyzed compared to fully vaccinated naïve individuals. Our findings indicate that mRNA-1273 vaccine triggered cross-variant antibody responses with distinct profiles in vaccinees with or without pre-existing immunity and suggest that individuals with prior history of SARS-CoV-2 infection may not benefit from the second mRNA vaccine dose with the current standard regimen.
24th “Nantes Actualités en Transplantation” and 4th “LabEx Immunotherapy-Graft-Oncology” NAT and IGO Joint Meeting “New Horizons in Immunotherapy”
Authors: Joalland Noémie , Ducoin Kathleen , Cadiou Gwenann , Rabu Catherine , Guillonneau Carole
Published: September 2021

The 24th edition of the annual NAT conference (Nantes Actualités Transplantation) and the 4th edition of the biennial LabEx IGO meeting (Immunotherapy Graft Oncology) were held jointly around a common theme: “New horizons in immunotherapy”, on May 31st and June 1st 2021 to highlight new findings in the fields of transplantation, autoimmunity and cancer.
Compound-Specific Stable Isotope Analysis of Amino Acids in Pelagic Shark Vertebrae Reveals Baseline, Trophic, and Physiological Effects on Bulk Protein Isotope Records
Authors: Magozzi Sarah , Thorrold Simon R. , Houghton Leah , Bendall Victoria A. , Hetherington Stuart , Mucientes Gonzalo , Natanson Lisa J. , Queiroz Nuno , Santos Miguel N. , Trueman Clive N.
Published: September 2021

Variations in stable carbon and nitrogen isotope compositions in incremental tissues of pelagic sharks can be used to infer aspects of their spatial and trophic ecology across life-histories. Interpretations from bulk tissue isotopic compositions are complicated, however, because multiple processes influence these values, including variations in primary producer isotope ratios and consumer diets and physiological processing of metabolites. Here we challenge inferences about shark tropho-spatial ecology drawn from bulk tissue isotope data using data for amino acids. Stable isotope compositions of individual amino acids can partition the isotopic variance in bulk tissue into components associated with primary production on the one hand, and diet and physiology on the other. The carbon framework of essential amino acids (EAAs) can be synthesised de novo only by plants, fungi and bacteria and must be acquired by consumers through the diet. Consequently, the carbon isotopic composition of EAAs in consumers reflects that of primary producers in the location of feeding, whereas that of non-essential amino acids (non-EAAs) is additionally influenced by trophic fractionation and isotope dynamics of metabolic processing. We determined isotope chronologies from vertebrae of individual blue sharks and porbeagles from the North Atlantic. We measured carbon and nitrogen isotope compositions in bulk collagen and carbon isotope compositions of amino acids. Despite variability among individuals, common ontogenetic patterns in bulk isotope compositions were seen in both species. However, while life-history movement inferences from bulk analyses for blue sharks were supported by carbon isotope data from essential amino acids, inferences for porbeagles were not, implying that the observed trends in bulk protein isotope compositions in porbeagles have a trophic or physiological explanation, or are suprious effects. We explored variations in carbon isotope compositions of non-essential amino acids, searching for systematic variations that might imply ontogenetic changes in physiological processing, but patterns were highly variable and did not explain variance in bulk protein δ13C values. Isotopic effects associated with metabolite processing may overwhelm spatial influences that are weak or inconsistently developed in bulk tissue isotope values, but interpreting mechanisms underpinning isotopic variation in patterns in non-essential amino acids remains challenging.
Singing Fin Whale Swimming Behavior in the Central North Pacific
Authors: Guazzo Regina A. , Durbach Ian N. , Helble Tyler A. , Alongi Gabriela C. , Martin Cameron R. , Martin Stephen W. , Henderson E. Elizabeth
Published: September 2021

Male fin whales sing using 20 Hz pulses produced in regular patterns of inter-note intervals, but little is known about fin whale swimming behavior while they are singing. Even less is known about fin whales in Hawaiian waters because they have rarely been sighted during surveys and passive acoustic monitoring has been limited to sparse hydrophone systems that do not have localization capabilities. We hypothesized that fin whale kinematics may be related to their singing behavior, or external variables such as time and sea state. To investigate this hypothesis, we analyzed 115 tracks containing 50,034 unique notes generated from passive acoustic recordings on an array of 14 hydrophones from 2011 to 2017 at the U.S. Navy Pacific Missile Range Facility off Kauai, Hawaii. Fin whales swam at an average speed of 1.1 m/s over relatively direct paths. We incorporated the whales' speed and turning angle into hidden Markov models to identify different behavioral states based on the whales' movements. We found that fin whale kinematic behavioral state was related to the vocalization rate (also known as cue rate) and time of day. When cue rate was higher, fin whales were more likely to swim slower and turn more than when cue rate was lower. During the night, fin whales were also more likely to swim slower and turn more than during the day. In addition, we examined whether the presence of singing fin whales was related to time and sea state using generalized additive models. Fin whale track presence was affected by day of the year and song season, and possibly also wind speed and wave height. Although the track kinematics from the fin whale tracks presented here are limited to a subset of whales that are acoustically active, they provide some of the only detailed movements of fin whales in the region and can be compared against fin whale swim speeds in other regions. Understanding how fin whale swimming behavior varies based on their vocalization patterns, time, and environmental factors will help us to contextualize potential changes in whale behavior during Navy training and testing on the range.
Ecoengineering Solutions for the Impairment of Spreading and Growth of Invasive Spartina patens in Mediterranean Salt Marshes
Authors: Cruz de Carvalho Ricardo , Feijão Eduardo , Duarte Irina , Pinto Vanessa , Silva Marisa , Matos Ana Rita , da Silva Anabela Bernardes , Caçador Isabel , Reis-Santos Patrick , Fonseca Vanessa F. , Duarte Bernardo
Published: September 2021

The invasion of natural communities by non-indigenous species represents one of the most serious threats to biodiversity. Understanding the ecophysiology of invasive species can provide insights into potential physiological handicaps relative to native species. By doing so, we can leverage the development of ecoengineering solutions for the removal of non-indigenous species, preferably using non-chemical methods. Spartina patens is a known invasive species of cordgrass aggressively proliferating in Mediterranean salt marshes, producing impenetrable monospecific stands. As its occurrence is delimited by the upper high tide water level, we hypothesized that S. patens is intolerant to waterlogging. Therefore, we developed a field experiment where strands of S. patens were kept waterlogged over the entire tidal cycle for 30 days. At the end of the experimental period, plants in the trial plots exhibited severe stress symptoms at different physiological levels compared with control plots (no intervention). At the photobiological level, intervened plants exhibited lower efficiency in producing chemical energy from light, whilst at the biochemical level waterlogging impaired the antioxidant system and increased lipid peroxidation products. Furthermore, the application of chlorophyll a pulse amplitude modulated (PAM) fluorometry, a non-invasive technique, allowed us to evaluate the effectiveness of the implemented measures, being the tool that provided the best separation between the control and intervened population. Considering the physiological traits observed here, ecoengineering solutions based on increased waterlogging of S. patens stands, can be a low-cost and efficient measure to reduce the spreading and growth of this invasive species in the Mediterranean and other salt marshes worldwide with little disturbance.
Macroevolutionary Trade-Offs and Trends in Life History Traits of Cephalopods Through a Comparative Phylogenetic Approach
Authors: Ibáñez Christian M. , Díaz-Santana-Iturrios Mariana , Carrasco Sergio A. , Fernández-Álvarez Fernando A. , López-Córdova David A. , Cornejo Claudio F. , Ortiz Nicolás , Rocha Francisco , Vidal Erica A. G. , Pardo-Gandarillas María Cecilia
Published: September 2021

One of the major mechanisms responsible for the animals’ fitness dynamics is fecundity. Fecundity as a trait does not evolve independently, and rather interacts with other traits such as body and egg size. Here, our aim was to correctly infer the macroevolutionary trade-offs between body length, egg length, and potential fecundity, using cephalopods as study model. The correlated evolution among those traits was inferred by comparative phylogenetic methods. Literature data on biological and reproductive traits (body length, egg length, and potential fecundity) was obtained for 90 cephalopod species, and comparative phylogenetic methods based on a previous molecular phylogeny were used to test the correlated evolution hypothesis. Additionally, we estimated the phylogenetic signal and fitted five different evolutionary models to each trait. All traits showed high phylogenetic signal, and the selected model suggested an evolutionary trend toward increasing body length, egg length, and fecundity in relation to the ancestral state. Evidence of correlated evolution between body length and fecundity was observed, although this relationship was not detected between body length and egg length. The robust inverse relationship between fecundity and egg length indicates that cephalopods evolved a directional selection that favored an increase of fecundity and a reduction of egg length in larger species, or an increase in egg length with the concomitant reduction of fecundity and body length in order to benefit offspring survival. The use of phylogenetic comparative methods allowed us to properly detect macroevolutionary trade-offs.
A Global Assessment of Climate Change Adaptation in Marine Protected Area Management Plans
Authors: O’Regan Sacha M. , Archer Stephanie K. , Friesen Sarah K. , Hunter Karen L.
Published: September 2021

Marine protected area (MPA) efficacy is increasingly challenged by climate change. Experts have identified clear climate change adaptation principles that MPA practitioners can incorporate into MPA management; however, adoption of these principles in MPA management remains largely unquantified. We conducted a text analysis of 647 English-language MPA management plans to assess the frequency with which they included climate change-related terms and terms pertaining to ecological, physical, and sociological components of an MPA system that may be impacted by climate change. Next, we manually searched 223 management plans to quantify the plans’ climate change robustness, which we defined as the degree of incorporation of common climate change adaptation principles. We found that climate change is inadequately considered in MPA management plans. Of all plans published since 2010, only 57% contained at least one of the climate change-related terms, “climate change,” “global warming,” “extreme events,” “natural variability,” or “climate variability.” The mean climate change robustness index of climate-considering management plans was 10.9 or 39% of a total possible score of 28. The United States was the only region that had plans with climate robustness indices of 20 or greater. By contrast, Canada lags behind other temperate jurisdictions in incorporating climate change adaptation analysis, planning, and monitoring into MPA management, with a mean climate change robustness index of 6.8. Climate change robustness scores have generally improved over time within the most common MPA designations in Oceania, the United Kingdom, and the United States, though the opposite is true in Canada. Our results highlight the urgent need for practitioners to incorporate climate change adaptation into MPA management in accordance with well-researched frameworks.