bluuebunny/crossref_metadata_2025 huggingface dataset:
VISTA: A Target to Manage the Innate Cytokine Storm
Authors: ElTanbouly Mohamed A. , Zhao Yanding , Schaafsma Evelien , Burns Christopher M. , Mabaera Rodwell , Cheng Chao , Noelle Randolph J.
Published: February 2021

In recent years, the success of immunotherapy targeting immunoregulatory receptors (immune checkpoints) in cancer have generated enthusiastic support to target these receptors in a wide range of other immune related diseases. While the overwhelming focus has been on blockade of these inhibitory pathways to augment immunity, agonistic triggering via these receptors offers the promise of dampening pathogenic inflammatory responses. V-domain Ig suppressor of T cell activation (VISTA) has emerged as an immunoregulatory receptor with constitutive expression on both the T cell and myeloid compartments, and whose agonistic targeting has proven a unique avenue relative to other checkpoint pathways to suppress pathologies mediated by the innate arm of the immune system. VISTA agonistic targeting profoundly changes the phenotype of human monocytes towards an anti-inflammatory cell state, as highlighted by striking suppression of the canonical markers CD14 and Fcγr3a (CD16), and the almost complete suppression of both the interferon I (IFN-I) and antigen presentation pathways. The insights from these very recent studies highlight the impact of VISTA agonistic targeting of myeloid cells, and its potential therapeutic implications in the settings of hyperinflammatory responses such as cytokine storms, driven by dysregulated immune responses to viral infections (with a focus on COVID-19) and autoimmune diseases. Collectively, these findings suggest that the VISTA pathway plays a conserved, non-redundant role in myeloid cell function.
Interleukin 17 Promotes Expression of Alarmins S100A8 and S100A9 During the Inflammatory Response of Keratinocytes
Authors: Christmann Carolin , Zenker Stefanie , Martens Leonie , Hübner Janina , Loser Karin , Vogl Thomas , Roth Johannes
Published: February 2021

Psoriasis is one of the most common immune-mediated inflammatory skin diseases. Expression and secretion of two pro-inflammatory molecules of the S100-alarmin family, S100A8 and S100A9, in keratinocytes is a hallmark of psoriasis, which is also characterized by an altered differentiation of keratinocytes. Dimers of S100A8/S100A9 (calprotectin) bind to Toll-like receptor 4 and induce an inflammatory response in target cells. Targeted deletion of S100A9 reduced the inflammatory phenotype of psoriasis-like inflammation in mice. A role of S100-alarmins in differentiation and activation of keratinocytes was suggested but has been never shown in primary keratinocytes. We now confirm that induction of S100-alarmins in an imiquimod-induced murine model of psoriasis-like skin inflammation was associated with an increased expression of interleukin (IL)-1α, IL-6, IL-17A, or TNFα. This association was confirmed in transcriptome data obtained from controls, lesional and non-lesional skin of psoriasis patients, and a down-regulation of S100-alarmin expression after IL-17 directed therapy. However, analyzing primary S100A9−/−keratinocytes we found that expression of S100A8/S100A9 has no significant role for the maturation and inflammatory response pattern of keratinocytes. Moreover, keratinocytes are no target cells for the pro-inflammatory effects of S100A8/S100A9. However, different cytokines, especially IL-17A and F, highly abundant in psoriasis, strongly induced expression of S100-alarmins preferentially during early maturation stages of keratinocytes. Our data indicate that expression of S100A8 and S100A9 does not primarily influence maturation or activation of keratinocytes but rather represents the inflammatory response of these cells during psoriasis.
Deposition of the Membrane Attack Complex in Healthy and Diseased Human Kidneys
Authors: Koopman Jacob J. E. , van Essen Mieke F. , Rennke Helmut G. , de Vries Aiko P. J. , van Kooten Cees
Published: February 2021

The membrane attack complex—also known as C5b-9—is the end-product of the classical, lectin, and alternative complement pathways. It is thought to play an important role in the pathogenesis of various kidney diseases by causing cellular injury and tissue inflammation, resulting in sclerosis and fibrosis. These deleterious effects are, consequently, targeted in the development of novel therapies that inhibit the formation of C5b-9, such as eculizumab. To clarify how C5b-9 contributes to kidney disease and to predict which patients benefit from such therapy, knowledge on deposition of C5b-9 in the kidney is essential. Because immunohistochemical staining of C5b-9 has not been routinely conducted and never been compared across studies, we provide a review of studies on deposition of C5b-9 in healthy and diseased human kidneys. We describe techniques to stain deposits and compare the occurrence of deposits in healthy kidneys and in a wide spectrum of kidney diseases, including hypertensive nephropathy, diabetic nephropathy, membranous nephropathy, IgA nephropathy, lupus nephritis, C3 glomerulopathy, and thrombotic microangiopathies such as the atypical hemolytic uremic syndrome, vasculitis, interstitial nephritis, acute tubular necrosis, kidney tumors, and rejection of kidney transplants. We summarize how these deposits are related with other histological lesions and clinical characteristics. We evaluate the prognostic relevance of these deposits in the light of possible treatment with complement inhibitors.
Tolerogenic Effect Elicited by Protein Fraction Derived From Different Formulas for Dietary Treatment of Cow’s Milk Allergy in Human Cells
Authors: Paparo Lorella , Picariello Gianluca , Bruno Cristina , Pisapia Laura , Canale Valentina , Sarracino Antonietta , Nocerino Rita , Carucci Laura , Cosenza Linda , Cozzolino Tommaso , Berni Canani Roberto
Published: February 2021

Several formulas are available for the dietary treatment of cow’s milk allergy (CMA). Clinical data suggest potentially different effect on immune tolerance elicited by these formulas. We aimed to comparatively evaluate the tolerogenic effect elicited by the protein fraction of different formulas available for the dietary treatment of CMA. Five formulas were compared: extensively hydrolyzed whey formula (EHWF), extensively hydrolyzed casein formula (EHCF), hydrolyzed rice formula (HRF), soy formula (SF), and amino acid-based formula (AAF). The formulas were reconstituted in water according to the manufacturer’s instructions and subjected to an in vitro infant gut simulated digestion using a sequential gastric and duodenal static model. Protein fraction was then purified and used for the experiments on non-immune and immune components of tolerance network in human enterocytes and in peripheral mononuclear blood cells (PBMCs). We assessed epithelial layer permeability and tight junction proteins (occludin and zonula occludens-1, ZO-1), mucin 5AC, IL-33, and thymic stromal lymphopoietin (TSLP) in human enterocytes. In addition, Th1/Th2 cytokine response and Tregs activation were investigated in PBMCs from IgE-mediated CMA infants. EHCF-derived protein fraction positively modulated the expression of gut barrier components (mucin 5AC, occludin and ZO-1) in human enterocytes, while SF was able to stimulate the expression of occludin only. EHWF and HRF protein fractions elicited a significant increase in TSLP production, while IL-33 release was significantly increased by HRF and SF protein fractions in human enterocytes. Only EHCF-derived protein fraction elicited an increase of the tolerogenic cytokines production (IL-10, IFN-γ) and of activated CD4+FoxP3+ Treg number, through NFAT, AP1, and Nf-Kb1 pathway. The effect paralleled with an up-regulation of FoxP3 demethylation rate. Protein fraction from all the study formulas was unable to induce Th2 cytokines production. The results suggest a different regulatory action on tolerogenic mechanisms elicited by protein fraction from different formulas commonly used for CMA management. EHCF-derived protein fraction was able to elicit tolerogenic effect through at least in part an epigenetic modulation of FoxP3 gene. These results could explain the different clinical effects observed on immune tolerance acquisition in CMA patients and on allergy prevention in children at risk for atopy observed using EHCF.
Identification of Autoimmunity to Peptides of Collagen V α1 Chain as Newly Biomarkers of Early Stage of Systemic Sclerosis
Authors: Velosa Ana Paula Pereira , Brito Lais , de Jesus Queiroz Zelita Aparecida , Carrasco Solange , Tomaz de Miranda Jurandir , Farhat Cecília , Goldenstein-Schainberg Cláudia , Parra Edwin Roger , de Andrade Danieli Castro Oliveira , Silva Pedro Leme , Capelozzi Vera Luiza , Teodoro Walcy Rosolia
Published: February 2021

Patients with Systemic sclerosis (SSc) presents immune dysregulation, vasculopathy, and fibrosis of the skin and various internal organs. Pulmonary fibrosis leads to SSc-associated interstitial lung disease (ILD), which is the main cause of morbidity and mortality in SSc. Recently autoimmunity to type V collagen (Col V) has been characterized in idiopathic pulmonary fibrosis and show promise to be related to the development in SSc. Our aim was to evaluate autoimmunity to Col V α1(V) and α2(V) chains and to the antigenic peptides of these Col V chains in early-SSc sera employing lung tissue of SSc-ILD, as antigen source. We found that sera samples from patients with early-SSc were reactive to Col V (41.18%) and presented immunoreactivity for Col5A1(1.049) and Col5A1(1.439) peptides. The IgG isolated from early-SSc patients-anti-Col V positive sera (anti-ColV IgG) was adsorbed with α1(V) chain (anti-ColV IgG/ads-α1(V)) and α2(V) chain (anti-ColV IgG/ads-α2(V)) and biotinylated to evaluate the spectrum of reactivity in SSc-ILD patients lung biopsies by immunofluorescence. The SSc-ILD lung tissue samples immunostained with anti-ColV IgG showed increased green fluorescence in the vascular basement membrane, bronchiolar smooth muscle, and adventitial layer, contrasting with the tenue immunostaining in control lungs. Col V protein expression in these pulmonary compartments immunostained with early-SSc anti-ColV IgG was confirmed by immune colocalization assays with commercial anti-human Col V antibodies. In addition, SSc-ILD lung tissues immunostained with anti-ColV IgG/ads-α1(V) (sample in which Col V α1 chain-specific antibodies were removed) showed decreased green fluorescence compared to anti-ColV IgG and anti-ColV IgG/ads-α2(V). Our data show that autoimmunity to Col V in early-SSc was related to peptides of the α1(V) chain, suggesting that these antibodies could be biomarkers of SSc stages and potential target of immunotherapy with Col V immunogenic peptides.
Case Report: Severe Complement-Mediated Thrombotic Microangiopathy in IgG4-Related Disease Secondary to Anti-Factor H IgG4 Autoantibodies
Authors: Breville Gautier , Zamberg Ido , Sadallah Salima , Stephan Caroline , Ponte Belen , Seebach Jörg D.
Published: February 2021

Objective

To first describe and estimate the potential pathogenic role of Ig4 autoantibodies in complement-mediated thrombotic microangiopathy (TMA) in a patient with IgG4-related disease (IgG4-RD).

Methods

This study is a case report presenting a retrospective review of the patient’s medical chart. Plasma complement C3 and C4 levels, immunoglobulin isotypes and subclasses were determined by nephelometry, the complement pathways’ activity (CH50, AP50, MBL) using WIESLAB® Complement System assays. Human complement factor H levels, anti-complement factor H auto-antibodies were analyzed by ELISA, using HRP-labeled secondary antibodies specific for human IgG, IgG4, and IgA, respectively. Genetic analyses were performed by exome sequencing of 14 gens implicated in complement disorders, as well as multiplex ligation-dependent probe amplification looking specifically for CFH, CFHR1-2-3, and 5.

Results

Our brief report presents the first case of IgG4-RD with complement-mediated TMA originating from both pathogenic CFHR 1 and CFHR 4 genes deletions, and inhibitory anti-complement factor H autoantibodies of the IgG4 subclass. Remission was achieved with plasmaphereses, corticosteroids, and cyclophosphamide. Following remission, the patient was diagnosed with lymphocytic meningitis and SARS-CoV-2 pneumonia with an uneventful recovery.

Conclusion

IgG4-RD can be associated with pathogenic IgG4 autoantibodies. Genetic predisposition such as CFHR1 and CFHR4 gene deletions enhance the susceptibility to the formation of inhibitory anti-Factor H IgG4 antibodies.
Bacterial and Fungal Toll-Like Receptor Activation Elicits Type I IFN Responses in Mast Cells
Authors: Kornstädt Lisa , Pierre Sandra , Weigert Andreas , Ebersberger Stefanie , Schäufele Tim J. , Kolbinger Anja , Schmid Tobias , Cohnen Jennifer , Thomas Dominique , Ferreirós Nerea , Brüne Bernhard , Ebersberger Ingo , Scholich Klaus
Published: February 2021

Next to their role in IgE-mediated allergic diseases and in promoting inflammation, mast cells also have antiinflammatory functions. They release pro- as well as antiinflammatory mediators, depending on the biological setting. Here we aimed to better understand the role of mast cells during the resolution phase of a local inflammation induced with the Toll-like receptor (TLR)-2 agonist zymosan. Multiple sequential immunohistology combined with a statistical neighborhood analysis showed that mast cells are located in a predominantly antiinflammatory microenvironment during resolution of inflammation and that mast cell-deficiency causes decreased efferocytosis in the resolution phase. Accordingly, FACS analysis showed decreased phagocytosis of zymosan and neutrophils by macrophages in mast cell-deficient mice. mRNA sequencing using zymosan-induced bone marrow-derived mast cells (BMMC) revealed a strong type I interferon (IFN) response, which is known to enhance phagocytosis by macrophages. Both, zymosan and lipopolysaccharides (LPS) induced IFN-β synthesis in BMMCs in similar amounts as in bone marrow derived macrophages. IFN-β was expressed by mast cells in paws from naïve mice and during zymosan-induced inflammation. As described for macrophages the release of type I IFNs from mast cells depended on TLR internalization and endosome acidification. In conclusion, mast cells are able to produce several mediators including IFN-β, which are alone or in combination with each other able to regulate the phagocytotic activity of macrophages during resolution of inflammation.
Modulation of Immune Responses by Particle Size and Shape
Authors: Baranov Maksim V. , Kumar Manoj , Sacanna Stefano , Thutupalli Shashi , van den Bogaart Geert
Published: February 2021

The immune system has to cope with a wide range of irregularly shaped pathogens that can actively move (e.g., by flagella) and also dynamically remodel their shape (e.g., transition from yeast-shaped to hyphal fungi). The goal of this review is to draw general conclusions of how the size and geometry of a pathogen affect its uptake and processing by phagocytes of the immune system. We compared both theoretical and experimental studies with different cells, model particles, and pathogenic microbes (particularly fungi) showing that particle size, shape, rigidity, and surface roughness are important parameters for cellular uptake and subsequent immune responses, particularly inflammasome activation and T cell activation. Understanding how the physical properties of particles affect immune responses can aid the design of better vaccines.
Characterization of the Signaling Modalities of Prostaglandin E2 Receptors EP2 and EP4 Reveals Crosstalk and a Role for Microtubules
Authors: Vleeshouwers Ward , van den Dries Koen , de Keijzer Sandra , Joosten Ben , Lidke Diane S. , Cambi Alessandra
Published: February 2021

Prostaglandin E2 (PGE2) is a lipid mediator that modulates the function of myeloid immune cells such as macrophages and dendritic cells (DCs) through the activation of the G protein-coupled receptors EP2 and EP4. While both EP2 and EP4 signaling leads to an elevation of intracellular cyclic adenosine monophosphate (cAMP) levels through the stimulating Gαs protein, EP4 also couples to the inhibitory Gαi protein to decrease the production of cAMP. The receptor-specific contributions to downstream immune modulatory functions are still poorly defined. Here, we employed quantitative imaging methods to characterize the early EP2 and EP4 signaling events in myeloid cells and their contribution to the dissolution of adhesion structures called podosomes, which is a first and essential step in DC maturation. We first show that podosome loss in DCs is primarily mediated by EP4. Next, we demonstrate that EP2 and EP4 signaling leads to distinct cAMP production profiles, with EP4 inducing a transient cAMP response and EP2 inducing a sustained cAMP response only at high PGE2 levels. We further find that simultaneous EP2 and EP4 stimulation attenuates cAMP production, suggesting a reciprocal control of EP2 and EP4 signaling. Finally, we demonstrate that efficient signaling of both EP2 and EP4 relies on an intact microtubule network. Together, these results enhance our understanding of early EP2 and EP4 signaling in myeloid cells. Considering that modulation of PGE2 signaling is regarded as an important therapeutic possibility in anti-tumor immunotherapy, our findings may facilitate the development of efficient and specific immune modulators of PGE2 receptors.
Dendritic Cell-Based Immunotherapy in Lung Cancer
Authors: Stevens Dieter , Ingels Joline , Van Lint Sandra , Vandekerckhove Bart , Vermaelen Karim
Published: February 2021

Lung cancer remains the leading cause of cancer-related death worldwide. The advent of immune checkpoint inhibitors has led to a paradigm shift in the treatment of metastatic non-small cell and small cell lung cancer. However, despite prolonged overall survival, only a minority of the patients derive clinical benefit from these treatments suggesting that the full anti-tumoral potential of the immune system is not being harnessed yet. One way to overcome this problem is to combine immune checkpoint blockade with different strategies aimed at inducing or restoring cellular immunity in a tumor-specific, robust, and durable way. Owing to their unique capacity to initiate and regulate T cell responses, dendritic cells have been extensively explored as tools for immunotherapy in many tumors, including lung cancer. In this review, we provide an update on the nearly twenty years of experience with dendritic cell-based immunotherapy in lung cancer. We summarize the main results from the early phase trials and give an overview of the future perspectives within this field.
Iron Metabolism in the Tumor Microenvironment: Contributions of Innate Immune Cells
Authors: Liang Wei , Ferrara Napoleone
Published: February 2021

Cells of the innate immune system are a major component of the tumor microenvironment. They play complex and multifaceted roles in the regulation of cancer initiation, growth, metastasis and responses to therapeutics. Innate immune cells like neutrophils and macrophages are recruited to cancerous tissues by chemotactic molecules released by cancer cells and cancer-associated stromal cells. Once they reach the tumor, they can be instructed by a network of proteins, nucleic acids and metabolites to exert protumoral or antitumoral functions. Altered iron metabolism is a feature of cancer. Epidemiological studies suggest that increased presence of iron and/or iron binding proteins is associated with increased risks of cancer development. It has been shown that iron metabolism is involved in shaping the immune landscapes in inflammatory/infectious diseases and cancer-associated inflammation. In this article, we will dissect the contribution of macrophages and neutrophils to dysregulated iron metabolism in malignant cells and its impact on cancer growth and metastasis. The mechanisms involved in regulating the actions of macrophages and neutrophils will also be discussed. Moreover, we will examine the effects of iron metabolism on the phenotypes of innate immune cells. Both iron chelating and overloading agents are being explored in cancer treatment. This review highlights alternative strategies for management of iron content in cancer cells by targeting the iron donation and modulation properties of macrophages and neutrophils in the tumor microenvironment.
Human IgA-Expressing Bone Marrow Plasma Cells Characteristically Upregulate Programmed Cell Death Protein-1 Upon B Cell Receptor Stimulation
Authors: Wiedemann Annika , Lettau Marie , Wirries Ina , Jungmann Annemarie , Salhab Abdulrahman , Gasparoni Gilles , Mei Henrik E. , Perka Carsten , Walter Jörn , Radbruch Andreas , Lino Andreia C. , Dörner Thomas
Published: February 2021

The functions of bone marrow plasma cells (BMPC) beyond antibody production are not fully elucidated and distinct subsets of BMPC suggest potential different functions. Phenotypic differences were identified for human BMPC depending on CD19 expression. Since CD19 is a co-stimulatory molecule of the B-cell-receptor (BCR), and IgA+ and IgM+ BMPC express the BCR on their surface, we here studied whether CD19 expression affects cellular responses, such as BCR signaling and the expression of checkpoint molecules. We analyzed 132 BM samples from individuals undergoing routine total hip arthroplasty. We found that both CD19+ and CD19− BMPC expressed BCR signaling molecules. Notably, the BCR-associated kinase spleen tyrosine kinase (SYK) including pSYK was higher expressed in CD19+ BMPC compared to CD19− BMPC. BCR stimulation also resulted in increased kinase phosphorylation downstream of the BCR while expression of CD19 remained stable afterwards. Interestingly, the BCR response was restricted to IgA+ BMPC independently of CD19 expression. With regard to the expression of checkpoint molecules, CD19− BMPC expressed higher levels of co-inhibitory molecule programmed cell death protein-1 (PD-1) than CD19+ BMPC. IgA+ BMPC characteristically upregulated PD-1 upon BCR stimulation in contrast to other PC subsets and inhibition of the kinase SYK abrogated PD-1 upregulation. In contrast, expression of PD-1 ligand, B and T lymphocyte attenuator (BTLA) and CD28 did not change upon BCR activation of IgA+ BMPC. Here, we identify a distinct characteristic of IgA+ BMPC that is independent of the phenotypic heterogeneity of the subsets according to their CD19 expression. The data suggest that IgA+ BMPC underlie different regulatory principles and/or exert distinct regulatory functions.
Role of Human Milk Bioactives on Infants' Gut and Immune Health
Authors: Carr Laura E. , Virmani Misty D. , Rosa Fernanda , Munblit Daniel , Matazel Katelin S. , Elolimy Ahmed A. , Yeruva Laxmi
Published: February 2021

Exclusive human milk feeding of the newborn is recommended during the first 6 months of life to promote optimal health outcomes during early life and beyond. Human milk contains a variety of bioactive factors such as hormones, cytokines, leukocytes, immunoglobulins, lactoferrin, lysozyme, stem cells, human milk oligosaccharides (HMOs), microbiota, and microRNAs. Recent findings highlighted the potential importance of adding HMOs into infant formula for their roles in enhancing host defense mechanisms in neonates. Therefore, understanding the roles of human milk bioactive factors on immune function is critical to build the scientific evidence base around breastfeeding recommendations, and to enhance positive health outcomes in formula fed infants through modifications to formulas. However, there are still knowledge gaps concerning the roles of different milk components, the interactions between the different components, and the mechanisms behind health outcomes are poorly understood. This review aims to show the current knowledge about HMOs, milk microbiota, immunoglobulins, lactoferrin, and milk microRNAs (miRNAs) and how these could have similar mechanisms of regulating gut and microbiota function. It will also highlight the knowledge gaps for future research.
Tissue-Specificity of Antibodies Raised Against TrkB and p75NTR Receptors; Implications for Platelets as Models of Neurodegenerative Diseases
Authors: Fleury Samuel , Boukhatem Imane , Le Blanc Jessica , Welman Mélanie , Lordkipanidzé Marie
Published: February 2021

Platelets and neurons share many similarities including comparable secretory granule types with homologous calcium-dependent secretory mechanisms as well as internalization, sequestration and secretion of many neurotransmitters. Thus, platelets present a high potential to be used as peripheral biomarkers to reflect neuronal pathologies. The brain-derived neurotrophic factor (BDNF) acts as a neuronal growth factor involved in learning and memory through the binding of two receptors, the tropomyosin receptor kinase B (TrkB) and the 75 kDa pan-neurotrophic receptor (p75NTR). In addition to its expression in the central nervous system, BDNF is found in much greater quantities in blood circulation, where it is largely stored within platelets. Levels 100- to 1,000-fold those of neurons make platelets the most important peripheral reservoir of BDNF. This led us to hypothesize that platelets would express canonical BDNF receptors, i.e., TrkB and p75NTR, and that the receptors on platelets would bear significant resemblance to the ones found in the brain. However, herein we report discrepancies regarding detection of these receptors using antibody-based assays, with antibodies displaying important tissue-specificity. The currently available antibodies raised against TrkB and p75NTR should therefore be used with caution to study platelets as models for neurological disorders. Rigorous characterization of antibodies and bioassays appears critical to understand the interplay between platelet and neuronal biology of BDNF.
Induced Transient Immune Tolerance in Ticks and Vertebrate Host: A Keystone of Tick-Borne Diseases?
Authors: Boulanger Nathalie , Wikel Stephen
Published: February 2021

Ticks and tick transmitted infectious agents are increasing global public health threats due to increasing abundance, expanding geographic ranges of vectors and pathogens, and emerging tick-borne infectious agents. Greater understanding of tick, host, and pathogen interactions will contribute to development of novel tick control and disease prevention strategies. Tick-borne pathogens adapt in multiple ways to very different tick and vertebrate host environments and defenses. Ticks effectively pharmacomodulate by its saliva host innate and adaptive immune defenses. In this review, we examine the idea that successful synergy between tick and tick-borne pathogen results in host immune tolerance that facilitates successful tick infection and feeding, creates a favorable site for pathogen introduction, modulates cutaneous and systemic immune defenses to establish infection, and contributes to successful long-term infection. Tick, host, and pathogen elements examined here include interaction of tick innate immunity and microbiome with tick-borne pathogens; tick modulation of host cutaneous defenses prior to pathogen transmission; how tick and pathogen target vertebrate host defenses that lead to different modes of interaction and host infection status (reservoir, incompetent, resistant, clinically ill); tick saliva bioactive molecules as important factors in determining those pathogens for which the tick is a competent vector; and, the need for translational studies to advance this field of study. Gaps in our understanding of these relationships are identified, that if successfully addressed, can advance the development of strategies to successfully disrupt both tick feeding and pathogen transmission.
Downregulated Serum Exosomal miR-451a Expression Correlates With Renal Damage and Its Intercellular Communication Role in Systemic Lupus Erythematosus
Authors: Tan Lina , Zhao Ming , Wu Haijing , Zhang Yuezhong , Tong Xiaoliang , Gao Lihua , Zhou Lu , Lu Qianjin , Zeng Jinrong
Published: February 2021

Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease characterized by continuous inflammation and the production of autoantibodies. Exosomes, acting as a critical tool for communication between cells, are involved in the pathogenesis of SLE, particularly in inflammation and immune imbalance. In this study, we aimed to extract and confirm the pro-inflammatory effect of serum exosomes in SLE. Then, we attempted to find differentially expressed exosomal microRNAs in the serum of healthy subjects and SLE patients via miRNA microarray analysis and validated the target exosomal microRNA, exosomal miR-451a, which expression level decreased in serum of SLE patients by RT-qPCR. Furtherly, we analyzed the correlation between exosomal miR-451a and disease activity, kidney damage and typing, and traditional medicine therapy. Finally, we investigated the intercellular communication role of exosomal miR-451a in SLE by co-culture assay in vitro. Taken together, our study demonstrated that downregulated serum exosomal miR-451a expression correlated with SLE disease activity and renal damage as well as its intercellular communication role in SLE which provided potential therapeutic strategies.
Mechanisms of Antibiotic Failure During Staphylococcus aureus Osteomyelitis
Authors: Gimza Brittney D. , Cassat James E.
Published: February 2021

Staphylococcus aureus is a highly successful Gram-positive pathogen capable of causing both superficial and invasive, life-threatening diseases. Of the invasive disease manifestations, osteomyelitis or infection of bone, is one of the most prevalent, with S. aureus serving as the most common etiologic agent. Treatment of osteomyelitis is arduous, and is made more difficult by the widespread emergence of antimicrobial resistant strains, the capacity of staphylococci to exhibit tolerance to antibiotics despite originating from a genetically susceptible background, and the significant bone remodeling and destruction that accompanies infection. As a result, there is a need for a better understanding of the factors that lead to antibiotic failure in invasive staphylococcal infections such as osteomyelitis. In this review article, we discuss the different non-resistance mechanisms of antibiotic failure in S. aureus. We focus on how bacterial niche and destructive tissue remodeling impact antibiotic efficacy, the significance of biofilm formation in promoting antibiotic tolerance and persister cell formation, metabolically quiescent small colony variants (SCVs), and potential antibiotic-protected reservoirs within the substructure of bone.
Potential of Underutilized Marine Organisms for Aquaculture Feeds
Authors: Jusadi Dedi , Ekasari Julie , Suprayudi Muhammad Agus , Setiawati Mia , Fauzi Ichsan Achmad
Published: February 2021

The supply of land-based agricultural products as aquafeed raw materials is challenged by limitations on space and water, and by environmental damage. Marine environments offer a vast opportunity for the expansion of aquaculture, including the production of feed raw materials. Besides fishmeal and fish oil, which are generated from capture fisheries, the use of marine-based feed raw materials from aquaculture production is not yet in common practice. Here, we discuss the potential of underutilized marine organisms that can be cultured by extracting nutrients from their environment and are nutritionally compatible for use as alternative feed materials in aquaculture. We identify marine organisms such as blue and green mussels, Ulva spp., and microbial floc that are nutritionally suitable as aquafeed raw material and may further act as bioremediators. However, environmental factors that affect productivity and the risk of pollutant accumulations, which would potentially reduce the safety of aquaculture products for human consumption, may pose challenges to such applications of extractive organisms. Therefore, the development of pretreatment and processing technologies will be critical for improving the nutritional quality and safety of these raw materials for aquafeed production.
Time-Varying Epipelagic Community Seascapes: Assessing and Predicting Species Composition in the Northeastern Pacific Ocean
Authors: Barceló Caren , Brodeur Richard D. , Ciannelli Lorenzo , Daly Elizabeth A. , Risien Craig M. , Saldías Gonzalo S. , Samhouri Jameal F.
Published: February 2021

The vast spatial extent of the ocean presents a major challenge for monitoring changes in marine biodiversity and connecting those changes to management practices. Remote-sensing offers promise for overcoming this problem in a cost-effective, tractable way, but requires interdisciplinary expertise to identify robust approaches. In this study, we use generalized additive mixed models to evaluate the relationship between an epipelagic fish community in the Northeastern Pacific Ocean and oceanographic predictor variables, quantified in situ as well as via remote-sensing. We demonstrate the utility of using MODIS Rrs555 fields at monthly and interannual timescales to better understand how freshwater input into the Northern California Current region affects higher trophic level biology. These relationships also allow us to identify a gradient in community composition characteristic of warmer, offshore areas and cooler, nearshore areas over the period 2003–2012, and predict community characteristics outside of sampled species data from 2013 to 2015. These spatial maps therefore represent a new, temporally and spatially explicit index of community differences, potentially useful for filling gaps in regional ecosystem status reports and is germane to the broader ecosystem-based fisheries management context.
Looking Back to Move Forward: Lessons From Three Decades of Research and Management of Cetacean Tourism in New Zealand
Authors: Fumagalli Maddalena , Guerra Marta , Brough Tom , Carome William , Constantine Rochelle , Higham James , Rayment Will , Slooten Elisabeth , Stockin Karen , Dawson Steve
Published: February 2021

Cetacean tourism in Aotearoa New Zealand is now over 30 years old and has experienced substantial growth in visitor numbers and operations. The industry is remarkably diverse, targeting several dolphin and whale species, and encompassing varied habitats in coastal waters, fiords and submarine canyons. The knowledge and experience collected over these past 30 years has both advanced the global understanding of cetacean tourism, and influenced scientific practices for its study and management. Here we review the approaches taken in quantifying the impact of cetacean tourism in New Zealand, and critically assess the efficacy of the research and management strategies adopted. We place particular focus on the Bay of Islands, Hauraki Gulf, Kaikoura, Akaroa and Fiordland, areas that include the oldest, and longest studied industries nationally. We propose a set of best research practices, expose the most notable knowledge gaps and identify emerging research questions. Drawing on perspectives from the natural and social sciences, we outline the key determinants of failure and success in protecting cetacean populations from the detrimental impact of tourism. We suggest four golden rules for future management efforts: (1) acknowledge cetacean tourism as a sub-lethal anthropogenic stressor to be managed with precaution, (2) apply integrated and adaptive site- and species-specific approaches, (3) fully conceptualize tourism within its broader social and ecological contexts, and (4) establish authentic collaborations and engagement with the local community. Lastly, we forecast upcoming challenges and opportunities for research and management of this industry in the context of global climate change. Despite New Zealand's early establishment of precautionary legislation and advanced tourism research and management approaches, we detected flaws in current schemes, and emphasize the need for more adaptive and comprehensive strategies. Cetacean tourism remains an ongoing challenge in New Zealand and globally.
Aquatic Wildmeat Consumption of Guiana Dolphins (Sotalia guianensis) in Lake Maracaibo System, Venezuela
Authors: Briceño Yurasi , Sánchez Leonardo , Trujillo Fernando , von Fersen Lorenzo , Ramírez Sonsireé
Published: February 2021

In many regions of the world, the use of cetaceans as bait or protein source has been reported. In most cases the individuals are from bycatch but also from intentionally killed animals. Cetaceans with coastal habits are more susceptible to negative interactions with small-scale fisheries, as in the case of the Guiana dolphin (Sotalia guianensis) in the Lake Maracaibo system. For decades, the use of Guiana dolphins by local communities has been reported in this region and is culturally supported by recipes for its preparation. Most of these data was outdated and some were anecdotal, so the objective of this work was to collect systematically data through surveys using the snowball method in seven artisanal fishing communities and to try to quantify the capture rate and to inquire about the potential impact of this practice on the population of Guiana dolphin. From 2017 to 2019, 95 semi-structured interviews were applied. An average bycatch of 180 individuals/year was obtained, the highest catch rate in the entire geographic distribution, an alarming situation considering that the surveys were not carried out in all the fishing ports, generating an underestimation. A total of 78% of interviewed recognized at least one bycatch event during their fishing effort. Surveys revealed a higher incidence of entanglement of offspring and juveniles (78%). 77% of the respondents deny the sale and commercialization of the species, while 5% mention some type of trade. The most frequent part exploited was the dorsal muscle, confirmed by fishermen (97%,n= 72) and the rest of the animal is discarded. During this investigation three episodes of directed capture were recorded, affecting a total of 23 individuals, two of them were pregnant females. The interviews also revealed that the majority of fishermen (93%) recognize the capture of this species as illegal. Considering the vulnerability of the Guiana dolphin in the country, the high incidence of capture and consumption and the lack of surveillance and sanctions by government entities, it is imperative to immediate actions to mitigate the negative impact on the population.
Synthetic and Semi-Synthetic Microplastic Ingestion by Mesopelagic Fishes From Tristan da Cunha and St Helena, South Atlantic
Authors: McGoran Alexandra R. , Maclaine James S. , Clark Paul F. , Morritt David
Published: February 2021

Mesopelagic fishes were sampled around Tristan da Cunha and St Helena in the South Atlantic from the RRS Discovery at depths down to 1000 m. Sampling was part of the Blue Belt Programme, a marine survey of British Overseas Territories funded by the United Kingdom Government. Thirteen species of mesopelagic fishes identified from 30 specimens were compared with two species (two specimens) collected from rock pools or surface water near the shore. The digestive tracts of all fishes were examined for microplastics. Additionally, one specimen of Opostomias micripnus (Günther, 1878) was analyzed after recovery from the stomach of a commercially fished species, Hyperoglyphe antarctica (Carmichael, 1819). One specimen of Anoplogaster cornuta was found to have ingested a bearded sea devil (Linophryne sp.), a cock-eyed squid (Histioteuthis sp.), a bolitaenid octopus, Japetella diaphana, remains of unidentifiable fish, crustaceans, and possibly salps. These prey items were also examined for microfibres. Both Histioteuthis sp. and Linophryne sp. had ingested fibers and these were considered “ingested particles” for A. cornuta. Neither shallow water dwelling species had ingested microplastics, whilst 11 of the 13 studied mesopelagic species were found to be contaminated. Overall, 66.7% of mesopelagic fishes were found to contain microfibres. Anthropogenic fibers were common especially viscose, a semi-synthetic material which is associated with sanitary products as well as other items.
Integrative Informatics Analysis of Transcriptome and Identification of Interacted Genes in the Glomeruli and Tubules in CKD
Authors: Liu Lingyun , Ma Fuzhe , Hao Yuanyuan , Yi Zhengzi , Yu Xiaoxia , Xu Bo , Wei Chengguo , Hu Jinghai
Published: February 2021

Chronic kidney disease (CKD) is a complex disease in which the renal function is compromised chronically. Many studies have indicated the crosstalk between the tubule and the glomerulus in CKD progression. However, our understanding of the interaction of tubular and glomerular injury remains incomplete. In this study, we applied a meta-analysis approach on the transcriptome of the tubules and glomeruli of CKD patients to identify differentially expressed genes (DEGs) signature. Functional analysis of pathways and Gene Ontology found that tubular DEGs were mainly involved in cell assembly and remodeling, glomerular DEGs in cell proliferation and apoptosis, and overlapping DEGs mainly in immune response. Correlation analysis was performed to identify the associated DEGs in the tubules and glomeruli. Secreted protein comparison and verification experiments indicated that WFDC2 from the tubule could downregulate PEX19 mRNA and protein levels at the glomeruli in diabetic kidney disease (DKD). This study revealed the distinctive pathways of the tubules and glomeruli and identified interacted genes during CKD progression.
Prevalence of Insulin Resistance in Urban Indian School Children Who Are Overweight/Obese: A Cross-Sectional Study
Authors: Das Rashmi Ranjan , Mangaraj Manaswini , Nayak Saurav , Satapathy Amit Kumar , Mahapatro Samarendra , Goyal Jagdish Prasad
Published: February 2021

Background: Limited data are available for insulin resistance (IR) in over-weight/obese children from the Indian subcontinent. Identifying predictors of IR in this population is important, as they may be used as a screening tool for future metabolic complications.

Materials and Methods: This school-based cross-sectional study was conducted in an Eastern Indian city. Anthropometry and blood pressure measurements were carried out as per the published guidelines. Venous blood samples were taken in a fasting state to measure plasma glucose, insulin, and lipid profile. IR was measured quantitatively by a homeostatic model of assessment (HOMA-IR).

Results: A total of 545 (28.2%) children who were overweight or obese were included. The male:female ratio was 1:1.27. The overall prevalence of metabolic syndrome (MS) in these children was 21.8%. Around 32.3% of children had HOMA-IR of ≥2.5, and 22.2% had HOMA-IR of ≥3.16. The mean HOMA-IR in children with MS was 5.46 compared to 2.18 in those without MS. An increased risk of IR with low HDL, high triglyceride, increased waist circumference, and increased BP (both systolic and diastolic) was found. This means that insulin resistance was more common in children who were overweight or obesity and had underlying MS.

Conclusions: The present school-based study found a high prevalence of insulin resistance among children who were overweight or obese. This could predict an increased risk of future adverse cardio-vascular events in the studied children. The findings of this study would help in planning and implementing primary prevention programs targeting weight management and lifestyle change in schoolchildren.
Professional-Grade TCA-Lactic Acid Chemical Peel: Elucidating Mode of Action to Treat Photoaging and Hyperpigmentation
Authors: Bhardwaj Vinay , Sharma Krati , Maksimovic Srdjan , Fan Aixing , Adams-Woodford Alison , Mao Junhong
Published: February 2021

Chemical peeling is usually performed by dermatologists, plastic surgeons, and aestheticians for the treatment of photo-aged skin, dyspigmented skin, skin prone to acne eruption, and pre-cancerous skin lesions, etc. In this research paper, we report our investigative findings to understand the mode of action of a commercial professional chemical peel to treat hyperpigmented and photoaged skin. In the in-vitro experiments, we found that the peel inhibits enzymes that are responsible for degradation of collagen and elastin, and the production of melanin pigment. It was surprising to observe that trichloroacetic acid (TCA), which is considered a workhorse of chemical peels for its cauterant action, could synergistically promote the inhibitory action of lactic acid. The rationale behind this synergistic effect could be the conformational change in TCA from linear structure to ring-like structure, which was elucidated through sequential docking using Rosetta software. The in-vitro results on collagen and elastin were corroborated by up-regulation of COL1A, COL3B, fibronectin, and elastin gene expression from 3D human skin equivalents treated with the peel. The findings were further validated through ex-vivo testing on human skin biopsy. The peel significantly inhibits the production of total melanin, and ameliorates photo-damage that was evident through repair of the collagen in the skin exposed to a biological effective dose of UV daily light (6 J/cm2). These research findings have implications for product developers and users (dermatologists, plastic surgeons, and aestheticians) in improving safety and efficacy of chemical peels/peeling.
High Prevalence of Ultrasound Verified Enthesitis in Patients With Inflammatory Bowel Disease With or Without Spondylarthritis
Authors: Husic Rusmir , Lackner Angelika , Kump Patrizia Katharina , Högenauer Christoph , Graninger Winfried , Dejaco Christian
Published: February 2021

Background: Inflammatory bowel disease (IBD) is closely associated with spondylarthritis (SpA) and enthesitis, as an important feature of SpA, is a common extraintestinal manifestation of IBD. Enthesitis may be clinically silent in a high proportion of patients with IBD without clinical signs or a diagnosis of SpA.

Objectives: The aim of this study was to compare the prevalence of ultrasound (US) verified enthesitis in IBD patients with and without SpA, with patients with irritable bowel syndrome (IBS) and healthy subjects (HC) serving as controls.

Methods: IBD patients with or without SpA, patients with IBS and HC were prospectively recruited and clinically assessed. Ultrasound examination was performed at 14 entheses. The ultrasound abnormalities were scored according to the Madrid Ankylosing Spondylitis Enthesitis Index (MASEI).

Results: We included 33 IBD patients without SpA, 14 IBD patients with SpA, 26 IBS patients and 18 HC. Higher MASEI scores were found in patients with IBD without SpA [median 21.0 range (8.0–53.0)] and IBD associated SpA [33.0 (8–50)] than in IBS patients [10.5 (0–42.0)-p < 0.001 for both comparison] and HC [12.0 (2.0–38.0)-p < 0.01]. PD, enthesophytes and erosions were more common in patients with IBD with or without SpA as compared to IBS patients and HC. IBD patients with SpA compared to IBD without SpA demonstrated significant higher prevalence of erosion and structural irregularity and consequently significant higher MASEI (p < 0.05 for all comparison).

Conclusions: Ultrasound verified enthesitis is more common in patients with IBD with or without SpA as compared to patients with IBS or HC.
Interleukin-31 as a Clinical Target for Pruritus Treatment
Authors: Kabashima Kenji , Irie Hiroyuki
Published: February 2021

In recent years, the published literature has suggested the key involvement of the cytokine interleukin-31 (IL-31) in the symptomatology of pruritus, and both IL-31 and its receptor have become potential therapeutic targets for a range of pruritic diseases. Elevated levels of IL-31 or its receptor have been reported in the tissue or serum of patients with pruritic skin diseases, such as atopic dermatitis, prurigo nodularis, and psoriasis. Pruritus places a heavy burden on patients, and can have a negative impact on daily life, sleep, and mental health. Since current anti-pruritic treatments are often ineffective, affected patients are in urgent need of new therapies. As a result, drug development targeting the IL-31 pathway is evolving rapidly. To date, only nemolizumab, a humanized monoclonal antibody targeting the IL-31 receptor, has successfully completed late-stage clinical studies. This article will highlight our current clinical understanding of the role of IL-31 in pruritic disease, and explore recent progress in drug development as well as the anticipated future advances in this field.