bluuebunny/crossref_metadata_2025 huggingface dataset:
The Immunopathology of Giant Cell Arteritis Across Disease Spectra
Authors: Robinette Michelle L. , Rao Deepak A. , Monach Paul A.
Published: February 2021

Giant cell arteritis (GCA) is a granulomatous systemic vasculitis of large- and medium-sized arteries that affects the elderly. In recent years, advances in diagnostic imaging have revealed a greater degree of large vessel involvement than previously recognized, distinguishing classical cranial- from large vessel (LV)- GCA. GCA often co-occurs with the poorly understood inflammatory arthritis/bursitis condition polymyalgia rheumatica (PMR) and has overlapping features with other non-infectious granulomatous vasculitides that affect the aorta, namely Takayasu Arteritis (TAK) and the more recently described clinically isolated aortitis (CIA). Here, we review the literature focused on the immunopathology of GCA on the background of the three settings in which comparisons are informative: LV and cranial variants of GCA; PMR and GCA; the three granulomatous vasculitides (GCA, TAK, and CIA). We discuss overlapping and unique features between these conditions across clinical presentation, epidemiology, imaging, and conventional histology. We propose a model of GCA where abnormally activated circulating cells, especially monocytes and CD4+T cells, enter arteries after an unknown stimulus and cooperate to destroy it and review the evidence for how this mechanistically occurs in active disease and improves with treatment.
Mitochondrial Regulation of Microglial Immunometabolism in Alzheimer’s Disease
Authors: Fairley Lauren H. , Wong Jia Hui , Barron Anna M.
Published: February 2021

Alzheimer’s disease (AD) is an age-associated terminal neurodegenerative disease with no effective treatments. Dysfunction of innate immunity is implicated in the pathogenesis of AD, with genetic studies supporting a causative role in the disease. Microglia, the effector cells of innate immunity in the brain, are highly plastic and perform a diverse range of specialist functions in AD, including phagocytosing and removing toxic aggregates of beta amyloid and tau that drive neurodegeneration. These immune functions require high energy demand, which is regulated by mitochondria. Reflecting this, microglia have been shown to be highly metabolically flexible, reprogramming their mitochondrial function upon inflammatory activation to meet their energy demands. However, AD-associated genetic risk factors and pathology impair microglial metabolic programming, and metabolic derailment has been shown to cause innate immune dysfunction in AD. These findings suggest that immunity and metabolic function are intricately linked processes, and targeting microglial metabolism offers a window of opportunity for therapeutic treatment of AD. Here, we review evidence for the role of metabolic programming in inflammatory functions in AD, and discuss mitochondrial-targeted immunotherapeutics for treatment of the disease.
Shape and Function of Interstitial Chemokine CCL21 Gradients Are Independent of Heparan Sulfates Produced by Lymphatic Endothelium
Authors: Vaahtomeri Kari , Moussion Christine , Hauschild Robert , Sixt Michael
Published: February 2021

Gradients of chemokines and growth factors guide migrating cells and morphogenetic processes. Migration of antigen-presenting dendritic cells from the interstitium into the lymphatic system is dependent on chemokine CCL21, which is secreted by endothelial cells of the lymphatic capillary, binds heparan sulfates and forms gradients decaying into the interstitium. Despite the importance of CCL21 gradients, and chemokine gradients in general, the mechanisms of gradient formation are unclear. Studies on fibroblast growth factors have shown that limited diffusion is crucial for gradient formation. Here, we used the mouse dermis as a model tissue to address the necessity of CCL21 anchoring to lymphatic capillary heparan sulfates in the formation of interstitial CCL21 gradients. Surprisingly, the absence of lymphatic endothelial heparan sulfates resulted only in a modest decrease of CCL21 levels at the lymphatic capillaries and did neither affect interstitial CCL21 gradient shape nor dendritic cell migration toward lymphatic capillaries. Thus, heparan sulfates at the level of the lymphatic endothelium are dispensable for the formation of a functional CCL21 gradient.
Mini-Review: The Administration of Apoptotic Cells for Treating Rheumatoid Arthritis: Current Knowledge and Clinical Perspectives
Authors: Toussirot Eric , Bonnefoy Francis , Vauchy Charline , Perruche Sylvain , Saas Philippe
Published: February 2021

Rheumatoid arthritis (RA) is a chronic immune-mediated disease managed by conventional synthetic drugs, such as methotrexate (MTX), and targeted drugs including biological agents. Cell-based therapeutic approaches are currently developed in RA, mainly mesenchymal stroma cell-based approaches. Early-stage apoptotic cells possess direct and indirect anti-inflammatory properties. During the elimination of dying cells (a process called efferocytosis), specific mechanisms operate to control immune responses. There are compelling evidences in experimental models of arthritis indicating that apoptotic cell administration may benefit joint inflammation, and may even have therapeutic effects on arthritis. Additionally, it has been demonstrated that apoptotic cells could be administered with standard treatments of RA, such as MTX or TNF inhibitors (TNFi), given even a synergistic response with TNFi. Interestingly, apoptotic cell infusion has been successfully experienced to prevent acute graft-vs.-host disease after hematopoietic cell transplantation in patients with hematologic malignancies, with a good safety profile. In this mini-review, the apoptotic cell-based therapy development in arthritis is discussed, as well as its transfer in the short-term to an innovative treatment for patients with RA. The use of apoptotic cell-derived factors, including secretome or phosphatidylserine-containing liposomes, in RA are also discussed.
Inhibition of Dendritic Cell Activation and Modulation of T Cell Polarization by the Platelet Secretome
Authors: Saris Anno , Steuten Juulke , Schrijver David P. , van Schijndel Gijs , Zwaginga Jaap Jan , van Ham S. Marieke , ten Brinke Anja
Published: February 2021

Platelet transfusions are a frequently administered therapy for especially hemato-oncological patients with thrombocytopenia. Next to their primary function in hemostasis, currently there is increased attention for the capacity of platelets to affect the function of various cells of the immune system. Here, we investigate the capacity of platelets to immuno-modulate monocyte-derived dendritic cells (moDC) as well as primary dendritic cells and effects on subsequent T cell responses. Platelets significantly inhibited pro-inflammatory (IL-12, IL-6, TNFα) and increased anti-inflammatory (IL-10) cytokine production of moDCs primed with toll-like receptor (TLR)-dependent and TLR-independent stimuli. Transwell assays and ultracentrifugation revealed that a soluble factor secreted by platelets, but not microvesicles, inhibited DC activation. Interestingly, platelet-derived soluble mediators also inhibited cytokine production by human ex vivo stimulated myeloid CD1c+ conventional DC2. Moreover, platelets and platelet-derived soluble mediators inhibited T cell priming and T helper differentiation toward an IFNγ+ Th1 phenotype by moDCs. Overall, these results show that platelets are able to inhibit the pro-inflammatory properties of DCs, and may even induce an anti-inflammatory DC phenotype, with decreased T cell priming capacity by the DC. The results of this study provide more insight in the potential role of platelets in immune modulation, especially in the context of platelet transfusions.
Non-Epithelial Stromal Cells in Thymus Development and Function
Authors: James Kieran D. , Jenkinson William E. , Anderson Graham
Published: February 2021

The thymus supports T-cell developmentviaspecialized microenvironments that ensure a diverse, functional and self-tolerant T-cell population. These microenvironments are classically defined as distinct cortex and medulla regions that each contain specialized subsets of stromal cells. Extensive research on thymic epithelial cells (TEC) within the cortex and medulla has defined their essential roles during T-cell development. Significantly, there are additional non-epithelial stromal cells (NES) that exist alongside TEC within thymic microenvironments, including multiple subsets of mesenchymal and endothelial cells. In contrast to our current understanding of TEC biology, the developmental origins, lineage relationships, and functional properties, of NES remain poorly understood. However, experimental evidence suggests these cells are important for thymus function by either directly influencing T-cell development, or by indirectly regulating TEC development and/or function. Here, we focus attention on the contribution of NES to thymic microenvironments, including their phenotypic identification and functional classification, and explore their impact on thymus function.
Respiratory FimA-Specific Secretory IgA Antibodies Upregulated by DC-Targeting Nasal Double DNA Adjuvant Are Essential for Elimination of Porphyromonas gingivalis
Authors: Kataoka Kosuke , Kawabata Shigetada , Koyanagi Kayo , Hashimoto Yoshiya , Miyake Tatsuro , Fujihashi Kohtaro
Published: February 2021

Our previous studies showed that a combination of a DNA plasmid encoding Flt3 ligand (pFL) and CpG oligodeoxynucleotides 1826 (CpG ODN) (FL/CpG) as a nasal adjuvant provoked antigen-specific immune responses. In this study, we investigated the efficacy of a nasal vaccine consisting of FimA as the structural subunit ofPorphyromonas gingivalis(P. gingivalis) fimbriae and FL/CpG for the induction of FimA-specific antibody (Ab) responses and their protective roles against nasal and lung infection byP. gingivalis, a keystone pathogen in the etiology of periodontal disease. C57BL/6 mice were nasally immunized with recombinant FimA (rFimA) plus FL/CpG three times at weekly intervals. As a control, mice were given nasalrFimA alone. Nasal washes (NWs) and bronchoalveolar lavage fluid (BALF) of mice given nasalrFimA plus FL/CpG resulted in increased levels ofrFimA-specific secretory IgA (SIgA) and IgG Ab responses when compared with those in controls. Significantly increased numbers of CD8- or CD11b-expressing mature-type dendritic cells (DCs) were detected in the respiratory inductive and effector tissues of mice givenrFimA plus FL/CpG. Additionally, significantly upregulated Th1/Th2-type cytokine responses byrFimA-stimulated CD4+T cells were noted in the respiratory effector tissues. When mice were challenged with liveP. gingivalis viathe nasal route, mice immunized nasally withrFimA plus FL/CpG inhibitedP. gingivaliscolonization in the nasal cavities and lungs. In contrast, controls failed to show protection. Of interest, when IgA-deficient mice given nasalrFimA plus FL/CpG were challenged with nasalP. gingivalis, the inhibition of bacterial colonization in the respiratory tracts was not seen. Taken together, these results show that nasal FL/CpG effectively enhanced DCs and provided balanced Th1- and Th2-type cytokine response-mediatedrFimA-specific IgA protective immunity in the respiratory tract againstP. gingivalis.A nasal administration withrFimA and FL/CpG could be a candidate for potent mucosal vaccines for the elimination of inhaledP. gingivalisin periodontal patients.
Better Together: Current Insights Into Phagosome-Lysosome Fusion
Authors: Nguyen Jenny A. , Yates Robin M.
Published: February 2021

Following phagocytosis, the nascent phagosome undergoes maturation to become a phagolysosome with an acidic, hydrolytic, and often oxidative lumen that can efficiently kill and digest engulfed microbes, cells, and debris. The fusion of phagosomes with lysosomes is a principal driver of phagosomal maturation and is targeted by several adapted intracellular pathogens. Impairment of this process has significant consequences for microbial infection, tissue inflammation, the onset of adaptive immunity, and disease. Given the importance of phagosome-lysosome fusion to phagocyte function and the many virulence factors that target it, it is unsurprising that multiple molecular pathways have evolved to mediate this essential process. While the full range of these pathways has yet to be fully characterized, several pathways involving proteins such as members of the Rab GTPases, tethering factors and SNAREs have been identified. Here, we summarize the current state of knowledge to clarify the ambiguities in the field and construct a more comprehensive phagolysosome formation model. Lastly, we discuss how other cellular pathways help support phagolysosome biogenesis and, consequently, phagocyte function.
Standardization and Quality Assessment Under the Perspective of Automated Computer-Assisted HEp-2 Immunofluorescence Assay Systems
Authors: Cinquanta Luigi , Bizzaro Nicola , Pesce Giampaola
Published: February 2021

The recent availability of automated computer-assisted diagnosis (CAD) systems for the reading and interpretation of the anti-nuclear antibody (ANA) test performed with the indirect immunofluorescence (IIF) method on HEp-2 cells, has improved the reproducibility of the results and initiated a process of harmonization of this test. Furthermore, CAD systems provide quantitative expression of fluorescence intensity, allowing the introduction of objective quality control procedures to the monitoring of the entire process. The calibration of the reading systems and the automated image interpretation are essential prerequisites for obtaining reproducible and harmonized IIF test results and form the basis for standardization, regardless of the computer algorithms used in the different systems. The use of automated CAD systems, facilitating control procedures, represents a step forward for the quality certification of the laboratory.
Evaluation of Host Serum Protein Biomarkers of Tuberculosis in sub-Saharan Africa
Authors: Morris Thomas C. , Hoggart Clive J. , Chegou Novel N. , Kidd Martin , Oni Tolu , Goliath Rene , Wilkinson Katalin A. , Dockrell Hazel M. , Sichali Lifted , Banda Louis , Crampin Amelia C. , French Neil , Walzl Gerhard , Levin Michael , Wilkinson Robert J. , Hamilton Melissa S.
Published: February 2021

Accurate and affordable point-of-care diagnostics for tuberculosis (TB) are needed. Host serum protein signatures have been derived for use in primary care settings, however validation of these in secondary care settings is lacking. We evaluated serum protein biomarkers discovered in primary care cohorts from Africa reapplied to patients from secondary care. In this nested case-control study, concentrations of 22 proteins were quantified in sera from 292 patients from Malawi and South Africa who presented predominantly to secondary care. Recruitment was based upon intention of local clinicians to test for TB. The case definition for TB was culture positivity forMycobacterium tuberculosis; and for other diseases (OD) a confirmed alternative diagnosis. Equal numbers of TB and OD patients were selected. Within each group, there were equal numbers with and without HIV and from each site. Patients were split into training and test sets for biosignature discovery. A nine-protein signature to distinguish TB from OD was discovered comprising fibrinogen, alpha-2-macroglobulin, CRP, MMP-9, transthyretin, complement factor H, IFN-gamma, IP-10, and TNF-alpha. This signature had an area under the receiver operating characteristic curve in the training set of 90% (95% CI 86–95%), and, after adjusting the cut-off for increased sensitivity, a sensitivity and specificity in the test set of 92% (95% CI 80–98%) and 71% (95% CI 56–84%), respectively. The best single biomarker was complement factor H [area under the receiver operating characteristic curve 70% (95% CI 64–76%)]. Biosignatures consisting of host serum proteins may function as point-of-care screening tests for TB in African hospitals. Complement factor H is identified as a new biomarker for such signatures.
Inflammatory Determinants of Differential Tuberculosis Risk in Pre-Adolescent Children and Young Adults
Authors: Baguma Richard , Mbandi Stanley Kimbung , Rodo Miguel J. , Erasmus Mzwandile , Day Jonathan , Makhethe Lebohang , de Kock Marwou , van Rooyen Michele , Stone Lynnett , Bilek Nicole , Steyn Marcia , Africa Hadn , Darboe Fatoumatta , Chegou Novel N. , Tromp Gerard , Walzl Gerhard , Hatherill Mark , Penn-Nicholson Adam , Scriba Thomas J.
Published: February 2021

The risk of progression from Mycobacterium tuberculosis (M.tb) infection to active tuberculosis (TB) disease varies markedly with age. TB disease is significantly less likely in pre-adolescent children above 4 years of age than in very young children or post-pubescent adolescents and young adults. We hypothesized that pro-inflammatory responses to M.tb in pre-adolescent children are either less pronounced or more regulated, than in young adults. Inflammatory and antimicrobial mediators, measured by microfluidic RT-qPCR and protein bead arrays, or by analyzing published microarray data from TB patients and controls, were compared in pre-adolescent children and adults. Multivariate analysis revealed that M.tb-uninfected 8-year-old children had lower levels of myeloid-associated pro-inflammatory mediators than uninfected 18-year-old young adults. Relative to uninfected children, those with M.tb-infection had higher levels of similar myeloid inflammatory responses. These inflammatory mediators were also expressed after in vitro stimulation of whole blood from uninfected children with live M.tb. Our findings suggest that myeloid inflammation is intrinsically lower in pre-pubescent children than in young adults. The lower or more regulated pro-inflammatory responses may play a role in the lower risk of TB disease in this age group.
PLGA Nanoparticles Co-encapsulating NY-ESO-1 Peptides and IMM60 Induce Robust CD8 and CD4 T Cell and B Cell Responses
Authors: Dölen Yusuf , Gileadi Uzi , Chen Ji-Li , Valente Michael , Creemers Jeroen H. A. , Van Dinther Eric A. W. , van Riessen N. Koen , Jäger Eliezer , Hruby Martin , Cerundolo Vincenzo , Diken Mustafa , Figdor Carl G. , de Vries I. Jolanda M.
Published: February 2021

Tumor-specific neoantigens can be highly immunogenic, but their identification for each patient and the production of personalized cancer vaccines can be time-consuming and prohibitively expensive. In contrast, tumor-associated antigens are widely expressed and suitable as an off the shelf immunotherapy. Here, we developed a PLGA-based nanoparticle vaccine that contains both the immunogenic cancer germline antigen NY-ESO-1 and an α-GalCer analog IMM60, as a novel iNKT cell agonist and dendritic cell transactivator. Three peptide sequences (85–111, 117–143, and 157–165) derived from immunodominant regions of NY-ESO-1 were selected. These peptides have a wide HLA coverage and were efficiently processed and presented by dendritic cellsviavarious HLA subtypes. Co-delivery of IMM60 enhanced CD4 and CD8 T cell responses and antibody levels against NY-ESO-1in vivo. Moreover, the nanoparticles have negligible systemic toxicity in high doses, and they could be produced according to GMP guidelines. Together, we demonstrated the feasibility of producing a PLGA-based nanovaccine containing immunogenic peptides and an iNKT cell agonist, that is activating DCs to induce antigen-specific T cell responses.
Dysregulation of IL-17/IL-22 Effector Functions in Blood and Gut Mucosal Gamma Delta T Cells Correlates With Increase in Circulating Leaky Gut and Inflammatory Markers During cART-Treated Chronic SIV Infection in Macaques
Authors: Walker Edith M. , Slisarenko Nadia , Gerrets Giovanni L. , Grasperge Brooke F. , Mattison Julie A. , Kissinger Patricia J. , Welsh David A. , Veazey Ronald S. , Jazwinski S. Michal , Rout Namita
Published: February 2021

HIV-associated inflammation has been implicated in the premature aging and increased risk of age-associated comorbidities in cART-treated individuals. However, the immune mechanisms underlying the chronic inflammatory state of cART-suppressed HIV infection remain unclear. Here, we investigated the role of γδT cells, a group of innate IL-17 producing T lymphocytes, in the development of systemic inflammation and leaky gut phenotype during cART-suppressed SIV infection of macaques. Plasma levels of inflammatory mediators, intestinal epithelial barrier disruption (IEBD) and microbial translocation (MT) biomarkers, and Th1/Th17-type cytokine functions were longitudinally assessed in blood and gut mucosa of SIV-infected, cART-suppressed macaques. Among the various gut mucosal IL-17/IL-22-producing T lymphocyte subsets including Th17, γδT, CD161+CD8+T, and MAIT cells, a specific decline in the Vδ2 subset of γδT cells and impaired IL-17/IL-22 production in γδT cells significantly correlated with the subsequent increase in plasma IEBD/MT markers (IFABP, LPS-binding protein, and sCD14) and pro-inflammatory cytokines (IL-6, IL-1β, IP10, etc.) despite continued viral suppression during long-term cART. Further, the plasma inflammatory cytokine signature during long-term cART was distinct from acute SIV infection and resembled the inflammatory cytokine profile of uninfected aging (inflammaging) macaques. Overall, our data suggest that during cART-suppressed chronic SIV infection, dysregulation of IL-17/IL-22 cytokine effector functions and decline of Vδ2 γδT cell subsets may contribute to gut epithelial barrier disruption and development of a distinct plasma inflammatory signature characteristic of inflammaging. Our results advance the current understanding of the impact of chronic HIV/SIV infection on γδT cell functions and demonstrate that in the setting of long-term cART, the loss of epithelial barrier-protective functions of Vδ2 T cells and ensuing IEBD/MT occurs before the hallmark expansion of Vδ1 subsets and skewed Vδ2/Vδ1 ratio. Thus, our work suggests that novel therapeutic approaches toward restoring IL-17/IL-22 cytokine functions of intestinal Vδ2 T cells may be beneficial in preserving gut epithelial barrier function and reducing chronic inflammation in HIV-infected individuals.
TRAF6 Regulates the Immunosuppressive Effects of Myeloid-Derived Suppressor Cells in Tumor-Bearing Host
Authors: Song Ge , Zhang Yue , Tian Jie , Ma Jie , Yin Kai , Xu Huaxi , Wang Shengjun
Published: February 2021

Myeloid-derived suppressor cells (MDSCs) are immature heterogeneous cells derived from the bone marrow and they are the major component of the tumor-induced immunosuppressive environment. Tumor necrosis factor receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase, catalyzes the polyubiquitination of target proteins. TRAF6 plays a critical role in modulating the immune system. However, whether TRAF6 is involved in the regulation of MDSCs has not been thoroughly elucidated to date. In this study, we found that the expression of TRAF6 in MDSCs derived from tumor tissue was significantly upregulated compared with that of MDSCs from spleen of tumor-bearing mice. Knockdown of TRAF6 remarkably attenuated the immunosuppressive effects of MDSCs. Mechanistically, TRAF6 might improve the immunosuppression of MDSCs by mediating K63-linked polyubiquitination and phosphorylation of signal transducer and activator of transcription 3 (STAT3). Additionally, it was discovered that the accumulation of MDSCs was abnormal in peripheral blood of lung cancer patients. TRAF6 and arginase 1 were highly expressed in MDSCs of patients with lung cancer. Taken together, our study demonstrated that TRAF6 participates in promoting the immunosuppressive function of MDSCs and provided a potential target for antitumor immunotherapy.
The Importance of Values in Predicting and Encouraging Environmental Behavior: Reflections From a Costa Rican Small-Scale Fishery
Authors: Sánchez-Jiménez Astrid , MacMillan Douglas , Wolff Matthias , Schlüter Achim , Fujitani Marie
Published: February 2021

Encouraging people’s pro-environmental behaviors is an objective of Education for Sustainable Development. In the context of small-scale fisheries, unsustainable fishing practices are compromising the integrity of coastal communities and ecosystems. Ecopath with Ecosim (EwE) is an ecosystem modeling software that presents interactions/changes in the food web as a result of fishing. Despite the multiple applications of EwE in fisheries management, it is unknown from a quantitative perspective whether the application of EwE trophic modeling in environmental education processes and management produces effects on norms and ecological beliefs, and if it alters behavioral intentions of the participants receiving ecosystem modeling information. We conducted a behavior change intervention with gillnet fishers in the Gulf of Nicoya, Costa Rica, to compare antecedents of pro-environmental behavior between participants who received an ecosystem-based intervention (lectures containing EwE models; treatment) and those who received lectures that didn’t involve EwE (control). Based on theories of environmental psychology, we used a pre–post survey design, to evaluate changes between control/treatment, and to assess the influence of psychometric constructs and fishing characteristics on the behavioral intentions to support sustainable fishing measures and owning a fishing license (revealed behavior). Personal norms and values were significant at explaining management measures’ support, along with some fishing characteristics (e.g., fishing site). Deliberating about possible future scenarios (via EwE-modeling) helped reduce uncertainties, increasing legitimacy and a perceived behavioral control (PBC) to support measures. Currently, licenses in the Gulf aren’t granted under defined ecological criteria, and although altruistic-biospheric values scored highly before the intervention began, due to mistrust and high illegal-unlicensed fishing, fishers may be underestimating how much others care about the environment. Value-oriented and ecosystem-based interventions may assist to effectively redesign the licensing system and encourage fishers to support sustainable measures. Our research indicates the importance of education interventions that teach about the impacts of fishing in the ecosystem while helping participants to perceive themselves as capable of implementing actions (PBC) and expressing biospheric-altruistic values to restore trust. Redirecting human behaviors to reconnect with ecosystem resilience can be a leverage point for sustainability and for the compliance of small-scale fisheries management measures.
Prolonged Alteration of Neonate Traits Following Maternal Exposure to Fishing-Capture Stress During Late Pregnancy in a Chondrichthyan Species
Authors: Finotto Licia , Walker Terence Ivan , Reina Richard David
Published: February 2021

For animals discarded after fishing capture (unwanted bycatch), the effects of fishing-capture stress can extend beyond immediate or delayed death, causing long-term, sub-lethal effects such as injuries and physiological, behavioral, immune, energetic, and reproductive consequences. Given the importance of successful reproduction for population recruitment, investigating reproductive impairment is essential, even more so for animals with low reproductive rates such as chondrichthyans. However, data for these species are lacking, even though the poor conservation status of many chondrichthyan populations and the threats from overexploitation and discard require a better understanding of fishing-capture stress consequences. In this study, we investigated the reproductive consequences of trawling and air exposure stress when experienced by southern fiddler rays (Trygonorrhina dumerilii) during late pregnancy, with a focus on neonatal traits. Compared with neonates from unstressed mothers, neonates born from mothers subjected to capture simulation had significantly lower body mass and yolk sac volume at birth, showed a granulocyte-to-lymphocyte ratio indicative of a stressed condition, reduced growth, altered burying behavior, reduced boldness, and swam for shorter distances after a simulated predator attack. Smaller size and lower growth rate might expose neonates to a higher rate of predation, and similarly, the altered burying and swimming behaviors may reduce their ability to escape from predators. Decreased boldness could impact neonate survival by reducing their ability to compete and obtain food and resources. Further investigations are needed, but these initial results suggest that capture stress suffered by pregnant rays may alter traits and survival of their offspring with consequences for recruitment and population abundance.
Incidence and Associated Risk Factors for Lactic Acidosis Induced by Linezolid Therapy in a Case–Control Study in Patients Older Than 85 Years
Authors: Liu Tingting , Hu Chao , Wu Jionghe , Liu Miao , Que Yifan , Wang Jiang , Fang Xiangqun , Xu Guogang , Li Hongxia
Published: February 2021

Background: Serum lactic acid is considered a prognostic indicator in critically ill patients. However, studies on linezolid-induced lactic acidosis (LILA) are still limited. Individuals older than 85 years old (very elderly) have limited capacity for organ compensation, and LILA data from these patients are lacking. In this study, we evaluated the risk factors for LILA in patients older than 85 years and established a risk prediction model for geriatric practice.

Methods: In this retrospective cohort study, blood gas analysis data and arterial lactate levels were monitored in patients older than 85 years during the use of teicoplanin or linezolid. After propensity score matching analyses, we compared the incidence of lactic acidosis between the teicoplanin and linezolid therapy groups and identified the risk factors of LILA.

Results: The incidence of lactic acidosis was found to be much lower in the group receiving teicoplanin than those receiving linezolid therapy (0 vs. 35.7%; p < 0.0001). A duration of linezolid therapy ≥ 9 days [odds ratio (OR), 3.541; 95% confidence interval (CI), 1.161–10.793; p = 0.026], an arterial blood glucose level ≥ 8 mmol/L (OR, 4.548; 95% CI, 1.507–13.725; p = 0.007), and a high sequential organ failure assessment score (OR, 1.429; 95% CI, 1.213–1.685; p < 0.0001) were risk factors for LILA. The constructed risk model could be used to predict LILA (area under the curve, 0.849; specificity, 65.1%; sensitivity, 91.4%, with a negative predictive value of 93.2% and a positive predictive value of 59.3%).

Conclusions: LILA can occur in patients older than 85 years after a relatively shorter duration of linezolid therapy. Therefore, close monitoring of blood gas and arterial lactate levels during linezolid therapy in the very elderly population is necessary.
Systemic Bone Density at Disease Onset Is Associated With Joint Erosion Progression in Early Naive to Treatment Rheumatoid Arthritis: A Prospective 12-Month Follow-Up Open-Label Study
Authors: Bruno Dario , Fedele Anna Laura , Tolusso Barbara , Barini Angelina , Petricca Luca , Di Mario Clara , Barini Antonella , Mirone Luisa , Ferraccioli Gianfranco , Alivernini Stefano , Gremese Elisa
Published: February 2021

Objectives:Osteoporosis and bone erosions are hallmarks of rheumatoid arthritis (RA) since disease onset is underpinned by the inflammatory burden. In this observational study, we aimed to dissect the putative RA-related parameters and bone-derived biomarkers associated with systemic and focal bone loss at disease onset and with their progression.

Methods:One-hundred twenty-eight patients with early rheumatoid arthritis (ERA) were recruited at disease onset. At study entry, demographic, clinical, and immunological parameters were recorded. Each ERA patient underwent plain X-rays of the hands and feet at study entry and after 12 months to assess the presence of erosions. After enrollment, each patient was treated according to the recommendations for RA management and followed up based on a treat-to-target (T2T) strategy. At baseline, blood samples for soluble biomarkers were collected from each patient, and plasma levels of osteoprotegerin (OPG), receptor activator of nuclear factor κB ligand (RANKL), Dickkopf-1 (DKK1), and interleukin 6 (IL-6) were assessed by enzyme-linked immunosorbent assay (ELISA). Seventy-one ERA patients underwent bone mineral density (BMD) measurement at the left femoral neck and second to fourth lumbar spine vertebrae (L2–L4) by dual-energy X-ray absorptiometry (DXA).

Results:Among the whole cohort, 34 (26.6%) ERA patients with bone erosions at study entry had a higher disease activity (p= 0.02) and IL-6 plasma levels (p= 0.03) than non-erosive ones. Moreover, at DXA, 33 (46.5%) ERA patients had osteopenia, and 16 (22.5%) had osteoporosis; patients with baseline bone erosions were more likely osteopenic/osteoporotic than non-erosive ones (p= 0.03), regardless of OPG, RANKL, and DKK1 plasma levels. Obese ERA patients were less likely osteopenic/osteoporotic than normal weight ones (p= 0.002), whereas anti-citrullinated protein antibodies (ACPA) positive ERA patients were more likely osteopenic/osteoporotic than ACPA negative ones (p= 0.034). At logistic regression analysis, baseline Disease Activity Score measured on 44 joints (DAS44) [OR: 2.46 (1.11–5.44)] and osteopenic/osteoporosis status [OR: 7.13 (1.27–39.94)] arose as independent factors of erosiveness. Baseline osteopenic/osteoporotic status and ACPA positivity were associated with bone damage progression during the follow-up.

Conclusions:Bone erosions presence is associated with systemic bone loss since the earliest phases of RA, suggesting that the inflammatory burden and autoimmune biology, underpinning RA, represent crucial enhancers of bone remodeling either locally as at systemic level.
Factors Influencing the Live Birth Rate Following Fresh Embryo Transfer Cycles in Infertile Women After Endometrioma Cystectomy
Authors: Liu Wei , Sha Tongye , Huang Yuzhen , Guo Zizhen , Yan Lei , Ma Jinlong
Published: February 2021

Background: Reproductive outcomes after fresh in vitro fertilization/intracytoplasmic sperm injection–embryo transfer (IVF/ICSI–ET) cycles are diverse in infertile women with a history of ovarian cystectomy for endometriomas. We aimed to develop a logistic regression model based on patients' characteristics including number of embryos transferred and stimulation protocols to predict the live birth rate in fresh IVF/ICSI–ET cycles for such patients.

Methods: We recruited 513 infertile women with a history of ovarian cystectomy for endometriomas who underwent their first fresh ET with different stimulation protocols following IVF/ICSI cycles in our unit from January 2014 to December 2018. One or two embryo are implanted. Clinical and laboratory parameters potentially affecting the live birth rate following fresh ET cycles were analyzed. Univariable and multivariable analyses were performed to assess the relationship between predictive factors and live birth rate.

Results: The overall live birth rate was 240/513 (46.8%). Multivariable modified Poisson regression models showed that two factors were significantly lowers the probability of live birth: female age ≥ 5 years (aOR 0.603; 95% CI 0.389–0.933; P = 0.023); BMI range 21–24.99 kg/m2 compared with BMI <21 kg/m2 (aOR 0.572; 95% CI 0.372–0.881, P = 0.011). And two factors significantly increased the probability of live birth: AFC >7 (aOR 1.591; 95% CI 1.075–2.353; P = 0.020); two embryos transferred (aOR 1.607; 95% CI 1.089–2.372; P = 0.017).

Conclusions: For these infertile women who had undergone ovarian cystectomy for endometriosis, female age <35 years, AFC > 7, and two embryos transferred might achieve better clinical fresh IVF/ICSI–ET outcomes. BMI <21 kg/m2 or ≥25 kg/m2 might also have positive effects on the live birth rate, but different ovarian stimulation protocols had no significant effects. However, a larger sample size may be needed for further study.
Challenges in Transition From Childhood to Adulthood Care in Rare Metabolic Diseases: Results From the First Multi-Center European Survey
Authors: Stepien Karolina M. , Kieć-Wilk Beata , Lampe Christina , Tangeraas Trine , Cefalo Graziella , Belmatoug Nadia , Francisco Rita , del Toro Mireia , Wagner Leona , Lauridsen Anne-Grethe , Sestini Sylvia , Weinhold Nathalie , Hahn Andreas , Montanari Chiara , Rovelli Valentina , Bellettato Cinzia M. , Paneghetti Laura , van Lingen Corine , Scarpa Maurizio
Published: February 2021

Inherited Metabolic Diseases (IMDs) are rare diseases caused by genetic defects in biochemical pathways. Earlier diagnosis and advances in treatment have improved the life expectancy of IMD patients over the last decades, with the majority of patients now surviving beyond the age of 20. This has created a new challenge: as they grow up, the care of IMD patients' needs to be transferred from metabolic pediatricians to metabolic physicians specialized in treating adults, through a process called “transition.” The purpose of this study was to assess how this transition is managed in Europe: a survey was sent to all 77 centers of the European Reference Network for Hereditary Metabolic Disorders (MetabERN) to collect information and to identify unmet needs regarding the transition process. Data was collected from 63/77 (81%) healthcare providers (HCPs) from 20 EU countries. Responders were mostly metabolic pediatricians; of these, only ~40% have received appropriate training in health issues of adolescent metabolic patients. In most centers (~67%) there is no designated transition coordinator. About 50% of centers provide a written individualized transition protocol, which is standardized in just ~20% of cases. In 77% of centers, pediatricians share a medical summary, transition letter and emergency plan with the adult team and the patient. According to our responders, 11% of patients remain under pediatric care throughout their life. The main challenges identified by HCPs in managing transition are lack of time and shortage of adult metabolic physician positions, while the implementations that are most required for a successful transition include: medical staff dedicated to transition, a transition coordinator, and specific metabolic training for adult physicians. Our study shows that the transition process of IMD patients in Europe is far from standardized and in most cases is inadequate or non-existent. A transition coordinator to facilitate collaboration between the pediatric and adult healthcare teams should be central to any transition program. Standardized operating procedures, together with adequate financial resources and specific training for adult physicians focused on IMDs are the key aspects that must be improved in the rare metabolic field to establish successful transition processes in Europe.
Influenza B Virus Infection Is Enhanced Upon Heterotypic Co-infection With Influenza A Virus
Authors: Malausse Nicolas , van der Werf Sylvie , Naffakh Nadia , Munier Sandie
Published: February 2021

Homotypic co-infections with influenza viruses are described to increase genetic population diversity, to drive viral evolution and to allow genetic complementation. Less is known about heterotypic co-infections between influenza A (IAV) and influenza B (IBV) viruses. Previous publications showed that IAV replication was suppressed upon co-infection with IBV. However, the effect of heterotypic co-infections on IBV replication was not investigated. To do so, we produced by reverse genetics a pair of replication-competent recombinant IAV (A/WSN/33) and IBV (B/Brisbane/60/2008) expressing a GFP and mCherry fluorescent reporter, respectively. A549 cells were infected simultaneously or 1 h apart at a high MOI with IAV-GFP or IBV-mCherry and the fluorescence was measured at 6 h post-infection by flow cytometry. Unexpectedly, we observed that IBV-mCherry infection was enhanced upon co-infection with IAV-GFP, and more strongly so when IAV was added 1 h prior to IBV. The same effect was observed with wild-type viruses and with various strains of IAV. Using UV-inactivated IAV or type-specific antiviral compounds, we showed that the enhancing effect of IAV infection on IBV infection was dependent on transcription/replication of the IAV genome. Our results, taken with available data in the literature, support the hypothesis that the presence of IAV proteins can enhance IBV genome expression and/or complement IBV defective particles.
Microbial Functional Responses in Marine Biofilms Exposed to Deepwater Horizon Spill Contaminants
Authors: Mugge Rachel L. , Salerno Jennifer L. , Hamdan Leila J.
Published: February 2021

Marine biofilms are essential biological components that transform built structures into artificial reefs. Anthropogenic contaminants released into the marine environment, such as crude oil and chemical dispersant from an oil spill, may disrupt the diversity and function of these foundational biofilms. To investigate the response of marine biofilm microbiomes from distinct environments to contaminants and to address microbial functional response, biofilm metagenomes were analyzed from two short-term microcosms, one using surface seawater (SSW) and the other using deep seawater (DSW). Following exposure to crude oil, chemical dispersant, and dispersed oil, taxonomically distinct communities were observed between microcosms from different source water challenged with the same contaminants and higher Shannon diversity was observed in SSW metagenomes.Marinobacter,Colwellia,Marinomonas, andPseudoalteromonasphylotypes contributed to driving community differences between SSW and DSW. SSW metagenomes were dominated by Rhodobacteraceae, known biofilm-formers, and DSW metagenomes had the highest abundance ofMarinobacter, associated with hydrocarbon degradation and biofilm formation. Association of source water metadata with treatment groups revealed that control biofilms (no contaminant) harbor the highest percentage of significant KEGG orthologs (KOs). While 70% functional similarity was observed among all metagenomes from both experiments, functional differences between SSW and DSW metagenomes were driven primarily by membrane transport KOs, while functional similarities were attributed to translation and signaling and cellular process KOs. Oil and dispersant metagenomes were 90% similar to each other in their respective experiments, which provides evidence of functional redundancy in these microbiomes. When interrogating microbial functional redundancy, it is crucial to consider how composition and function evolve in tandem when assessing functional responses to changing environmental conditions within marine biofilms. This study may have implications for future oil spill mitigation strategies at the surface and at depth and also provides information about the microbiome functional responses of biofilms on steel structures in the marine built environment.
Comparative Genomics of Emerging Lineages and Mobile Resistomes of Contemporary Broiler Strains of Salmonella Infantis and E. coli
Authors: Szmolka Ama , Wami Haleluya , Dobrindt Ulrich
Published: February 2021

Introduction

Commensal and pathogenic strains of multidrug-resistant (MDR)Escherichia coliand non-typhoid strains ofSalmonellarepresent a growing foodborne threat from foods of poultry origin. MDR strains ofSalmonellaInfantis andE. coliare frequently isolated from broiler chicks and the simultaneous presence of these two enteric bacterial species would potentially allow the exchange of mobile resistance determinants.

Objectives

In order to understand possible genomic relations and to obtain a first insight into the potential interplay of resistance genes between enteric bacteria, we compared genomic diversity and mobile resistomes ofS. Infantis andE. colifrom broiler sources.

Results

The core genome MLST analysis of 56S. Infantis and 90E. colicontemporary strains revealed a high genomic heterogeneity of broilerE. coli.It also allowed the first insight into the genomic diversity of the MDR clone B2 ofS. Infantis, which is endemic in Hungary. We also identified new MDR lineages forS. Infantis (ST7081 and ST7082) and forE. coli(ST8702 and ST10088). Comparative analysis of antibiotic resistance genes and plasmid types revealed a relatively narrow interface between the mobile resistomes ofE. coliandS. Infantis. The mobile resistance genestet(A),aadA1, andsul1were identified at an overall high prevalence in both species. This gene association is characteristic to the plasmid pSI54/04 of the epidemic clone B2 ofS. Infantis. Simultaneous presence of these genes and of IncI plasmids of the same subtype in cohabitant caecal strains ofE. coliandS. Infantis suggests an important role of these plasmid families in a possible interplay of resistance genes betweenS. Infantis andE. coliin broilers.

Conclusion

This is the first comparative genomic analysis of contemporary broiler strains ofS. Infantis andE. coli. The diversity of mobile resistomes suggests that commensalE. colicould be potential reservoirs of resistance forS. Infantis, but so far only a few plasmid types and mobile resistance genes could be considered as potentially exchangeable between these two species. Among these, IncI1 plasmids could make the greatest contribution to the microevolution and genetic interaction betweenE. coliandS. Infantis.
A Combinational Strategy Mitigated Old-Aged Petroleum Contaminants: Ineffectiveness of Biostimulation as a Bioremediation Technique
Authors: Garousin Hamidreza , Pourbabaee Ahmad Ali , Alikhani Hossein Ali , Yazdanfar Najmeh
Published: February 2021

Hydrocarbon contamination emerging from the crude oil industrial-related activities has led to severe environmental issues. Prolonged contamination with the constant infiltration of crude oil into the soil is a severe problem in remediating contaminated soils. Hence, the current study focuses on comparing various bioremediation strategies, thereby isolating native bacteria competent to reduce TPH in both liquid and microcosm environments in an old-aged petroleum hydrocarbon contaminated soil. Assays in the modified 6SW-Vit medium after 7 days of incubation revealed that Bacillus altitudinis strain HRG-1 was highly hydrophobic and had a suitable ability to decrease surface tension (40.98%) and TPH (73.3%). The results of biodegradation in the microcosm proved that among the designated treatments, including bio-stimulated microcosm (SM), bacterialized microcosm (BM), a combined bio-stimulated microcosm and bacterialized microcosm (SB), and natural attenuation (NA), the SB treatment was the most effective in mitigating TPH (38.2%). However, the SM treatment indicated the lowest TPH biodegradation (18%). Pearson correlation coefficient among microcosm biological indicators under investigation revealed that soil basal respiration had the highest correlation with the amount of residual TPH (r = −0.73915, P < 0.0001), followed by the microbial population (r = −0.65218, P < 0.0001), catalase activity (r = 0.48323, P = 0.0028), polyphenol oxidase activity (r = −0.43842, P = 0.0075), and dehydrogenase activity (r = −0.34990, P = 0.0364), respectively. Nevertheless, considering the capability of strain HRG-1 and the higher efficiency of the combined technique, their use is recommended to diminish the concentration of petroleum hydrocarbons in hot and dry contaminated areas.