bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychological Stresses in Children Trigger Cytokine- and Kynurenine Metabolite-Mediated Abdominal Pain and Proinflammatory Changes
Authors: Myint Kyaimon , Jacobs Kelly , Myint Aye-Mu , Lam Sau Kuen , Lim Yvonne Ai-Lian , Boey Christopher Chiong-Meng , Hoe See Ziau , Guillemin Gilles J.
Published: September 2021

Recurrent abdominal pain (RAP) is a common medically unexplained symptom among children worldwide. However, the biological mechanisms behind the development of functional and behavioral symptoms and changes in blood markers have not been well explored. This study aimed to assess changes in the concentrations of inflammatory markers, including cytokines and tryptophan catabolites, in the serum of children with RAP compared to those with subclinical infections. Children with RAP but without organic diseases were included, and those with asymptomatic intestinal parasitic infections were used as a subclinical infection cohort. Blood samples were collected and used to measure the cytokine profile using Multiplex Immunoassay and tryptophan catabolites using high performance liquid chromatography. Children with RAP showed significantly higher concentrations of serum tumor necrotic factor-α, p<0.05, but lower concentrations of IL-10, p<0.001, IL-6, p<0.001 and brain-derived neurotrophic factors (BDNF) p<0.01. In addition, a significant increase in the metabolite of the kynurenine pathway, 3-hydroxyanthranilic acid (3-HAA) p<0.01, a significant decrease in the concentrations of anthranilic acid (AA) p<0.001, together with an increased ratio of serum 3-HAA to AA (3-HAA/AA) p<0.001, was found in this cohort. These findings indicate the significant activation of the immune system and presence of inflammation in children with RAP than those with subclinical parasitic infections. Moreover, children with RAP tested with the Strengths and Difficulties Questionnaire (SDQ), displayed high psychological problems though these SDQ scores were not statistically associated with measured cytokines and kynurenine metabolites. We however could hypothesize that the pro-inflammatory state together with concomitant low concentrations of BDNF in those children with RAP could play a role in psychological stress and experiencing medically unexplained symptoms.
Mouse CD38-Specific Heavy Chain Antibodies Inhibit CD38 GDPR-Cyclase Activity and Mediate Cytotoxicity Against Tumor Cells
Authors: Baum Natalie , Eggers Marie , Koenigsdorf Julia , Menzel Stephan , Hambach Julia , Staehler Tobias , Fliegert Ralf , Kulow Frederike , Adam Gerhard , Haag Friedrich , Bannas Peter , Koch-Nolte Friedrich
Published: September 2021

CD38 is the major NAD+-hydrolyzing ecto-enzyme in most mammals. As a type II transmembrane protein, CD38 is also a promising target for the immunotherapy of multiple myeloma (MM). Nanobodies are single immunoglobulin variable domains from heavy chain antibodies that naturally occur in camelids. Using phage display technology, we isolated 13 mouse CD38-specific nanobodies from immunized llamas and produced these as recombinant chimeric mouse IgG2a heavy chain antibodies (hcAbs). Sequence analysis assigned these hcAbs to five distinct families that bind to three non-overlapping epitopes of CD38. Members of families 4 and 5 inhibit the GDPR-cyclase activity of CD38. Members of families 2, 4 and 5 effectively induce complement-dependent cytotoxicity against CD38-expressing tumor cell lines, while all families effectively induce antibody dependent cellular cytotoxicity. Our hcAbs present unique tools to assess cytotoxicity mechanisms of CD38-specific hcAbs in vivo against tumor cells and potential off-target effects on normal cells expressing CD38 in syngeneic mouse tumor models, i.e. in a fully immunocompetent background.
Comparative Metabolomics Reveals the Microenvironment of Common T-Helper Cells and Differential Immune Cells Linked to Unique Periapical Lesions
Authors: Altaie Alaa Muayad , Venkatachalam Thenmozhi , Samaranayake Lakshman P. , Soliman Sameh S. M. , Hamoudi Rifat
Published: September 2021

Periapical abscesses, radicular cysts, and periapical granulomas are the most frequently identified pathological lesions in the alveolar bone. While little is known about the initiation and progression of these conditions, the metabolic environment and the related immunological behaviors were examined for the first time to model the development of each pathological condition. Metabolites were extracted from each lesion and profiled using gas chromatography-mass spectrometry in comparison with healthy pulp tissue. The metabolites were clustered and linked to their related immune cell fractions. Clusters I and J in the periapical abscess upregulated the expression of MMP-9, IL-8, CYP4F3, and VEGF, while clusters L and M were related to lipophagy and apoptosis in radicular cyst, and cluster P in periapical granuloma, which contains L-(+)-lactic acid and ethylene glycol, was related to granuloma formation. Oleic acid, 17-octadecynoic acid, 1-nonadecene, and L-(+)-lactic acid were significantly the highest unique metabolites in healthy pulp tissue, periapical abscess, radicular cyst, and periapical granuloma, respectively. The correlated enriched metabolic pathways were identified, and the related active genes were predicted. Glutamatergic synapse (16–20),-hydroxyeicosatetraenoic acids, lipophagy, and retinoid X receptor coupled with vitamin D receptor were the most significantly enriched pathways in healthy control, abscess, cyst, and granuloma, respectively. Compared with the healthy control, significant upregulation in the gene expression of CYP4F3, VEGF, IL-8, TLR2 (P < 0.0001), and MMP-9 (P < 0.001) was found in the abscesses. While IL-12A was significantly upregulated in cysts (P < 0.01), IL-17A represents the highest significantly upregulated gene in granulomas (P < 0.0001). From the predicted active genes, CIBERSORT suggested the presence of natural killer cells, dendritic cells, pro-inflammatory M1 macrophages, and anti-inflammatory M2 macrophages in different proportions. In addition, the single nucleotide polymorphisms related to IL-10, IL-12A, and IL-17D genes were shown to be associated with periapical lesions and other oral lesions. Collectively, the unique metabolism and related immune response shape up an environment that initiates and maintains the existence and progression of these oral lesions, suggesting an important role in diagnosis and effective targeted therapy.
Genetic Associations Between IL-6 and the Development of Autoimmune Arthritis Are Gender-Specific
Authors: Hong Jianqiao , Qu Zihao , Ji Xiaoxiao , Li Congsun , Zhang Geng , Jin Ciliang , Wang Jie , Zhang Yongxing , Shen Yue , Meng Jiahong , Zhou Chenhe , Fang Chaohua , Wang Wei , Yan Shigui
Published: September 2021

Objectives

To find out the genetic association between IL6 and autoimmune arthritis.

Methods

We performed a two-sample Mendelian randomization (MR) study using multiple genome-wide association studies (GWAS) datasets. Furthermore, a sex-stratified MR study was performed to identify sexual dimorphism in the association between IL6 and autoimmune arthritis. Then, LocusZoom plots were displayed based on the IL6R gene region to present evidence of genetic colocalization between diseases.

Results

The MR result denoted a genetic association between the increased level of IL-6 signaling and risk of RA (β=0.325, 95%CI 0.088, 0.561, p=7.08E-03) and AS (β=1.240, 95%CI 0.495, 1.980, p=1.1E-03). Accordingly, sIL6R was found to have negatively correlation with the onset of RA (β=-0.020, 95%CI -0.0320, -0.008, p=1.18E-03) and AS (β=-0.125, 95%CI -0.177, -0.073, p=2.29E-06). However, no genetic association between IL6/sIL6R and PsA was detected. The gender-stratified MR analysis showed that IL6 was associated with AS in the male population, with RA in the female population, and with PsA in the male population. Additionally, ADAR, a gene identified by a sensitive test, could be the reason for the nonsignificant association between IL6 and PsA in a pooled population.

Conclusion

Our findings showed that the overactive IL6 signal pathway led to autoimmune arthritis, especially in RA and AS. Sexual difference was also observed in IL6-intermediate susceptibility to autoimmune arthritis.
Development of a Novel Immune Infiltration-Based Gene Signature to Predict Prognosis and Immunotherapy Response of Patients With Cervical Cancer
Authors: Yu Sihui , Li Xi , Zhang Jiawen , Wu Sufang
Published: September 2021

Predictive models could indicate the clinical outcome of patients with carcinoma. Cervical cancer is one of the most frequently diagnosed female malignancies. Herein, we proposed an immune infiltration-related gene signature that predicts prognosis of patients with cervical cancer and depicts the immune landscape as well. We utilized the transcriptome data of The Cancer Genome Atlas (TCGA) and estimated the infiltration level of 28 immune cell types. We screened out four immune cell types conducive to patient survival and recognized their shared differentially expressed genes (DEGs). Four core genes (CHIT1, GTSF1L, PLA2G2D, and GNG8) that composed the ultimate signature were identified via univariate and multivariate Cox regression. The optimal model we built up could distinguish patients with cervical cancer into high-score and low-score subgroups. These two subgroups showed disparity in aspects of patient survival, immune infiltration landscape, and response to immune checkpoint inhibitors. Additionally, we found that GTSF1L was decreased gradually along with the severity of cervical lesions, and its potential role in immune contexture and clinical practice were also demonstrated. Our results suggested that the Immunoscore based on four immune-related genes could serve as a supplementary criterion to effectively foresee the survival outcome, tumor infiltration status, and immunotherapy efficacy of cervical cancer patients.
Dissecting Tumor Antigens and Immune Subtypes of Glioma to Develop mRNA Vaccine
Authors: Zhong Hua , Liu Shuai , Cao Fang , Zhao Yi , Zhou Jianguo , Tang Feng , Peng Zhaohua , Li Yangsheng , Xu Shen , Wang Chunlin , Yang Guohua , Li Zhi-Qiang
Published: September 2021

Background

Nowadays, researchers are leveraging the mRNA-based vaccine technology used to develop personalized immunotherapy for cancer. However, its application against glioma is still in its infancy. In this study, the applicable candidates were excavated for mRNA vaccine treatment in the perspective of immune regulation, and suitable glioma recipients with corresponding immune subtypes were further investigated.

Methods

The RNA-seq data and clinical information of 702 and 325 patients were recruited from TCGA and CGGA, separately. The genetic alteration profile was visualized and compared by cBioPortal. Then, we explored prognostic outcomes and immune correlations of the selected antigens to validate their clinical relevance. The prognostic index was measured via GEPIA2, and infiltration of antigen-presenting cells (APCs) was calculated and visualized by TIMER. Based on immune-related gene expression, immune subtypes of glioma were identified using consensus clustering analysis. Moreover, the immune landscape was visualized by graph learning-based dimensionality reduction analysis.

Results

Four glioma antigens, namely ANXA5, FKBP10, MSN, and PYGL, associated with superior prognoses and infiltration of APCs were selected. Three immune subtypes IS1–IS3 were identified, which fundamentally differed in molecular, cellular, and clinical signatures. Patients in subtypes IS2 and IS3 carried immunologically cold phenotypes, whereas those in IS1 carried immunologically hot phenotype. Particularly, patients in subtypes IS3 and IS2 demonstrated better outcomes than that in IS1. Expression profiles of immune checkpoints and immunogenic cell death (ICD) modulators showed a difference among IS1–IS3 tumors. Ultimately, the immune landscape of glioma elucidated considerable heterogeneity not only between individual patients but also within the same immune subtype.

Conclusions

ANXA5, FKBP10, MSN, and PYGL are identified as potential antigens for anti-glioma mRNA vaccine production, specifically for patients in immune subtypes 2 and 3. In summary, this study may shed new light on the promising approaches of immunotherapy, such as devising mRNA vaccination tailored to applicable glioma recipients.
2-Deoxy-D-glucose Alleviates Collagen-Induced Arthritis of Rats and Is Accompanied by Metabolic Regulation of the Spleen and Liver
Authors: Wang Hongxing , Zhang Nanyang , Fang Kehua , Chang Xiaotian
Published: September 2021

Rheumatoid arthritis (RA) is significantly associated with glycolysis. This study used 2-deoxy-D-glucose (2-DG), an inhibitor of glycolysis, to treat rats with collagen-induced arthritis (CIA) and investigate the metabolic regulatory mechanism of glycolysis in the disease. 2-DG significantly alleviated CIA. Metabolomics and transcriptomics, as well as their integrative analysis, detected significant changes in the pathways of bile secretion, cholesterol and linoleic acid metabolism in the plasma, liver and spleen during the CIA process and the opposite changes following 2-DG treatment, whereas the expression of the genes regulating these metabolic pathways were changed only in the spleen. In the rat liver, levels of (S)-5-diphosphomevalonic acid in the terpenoid backbone biosynthesis pathway were significantly decreased during CIA progression and increased following 2-DG treatment, and levels of taurochenodeoxycholic acid in the pentose and glucuronate interconversions pathway showed the opposite results. In the spleen, levels of 3-methoxy-4-hydroxyphenylglycol glucuronide in bile secretion and 12(S)-leukotriene B4 in arachidonic acid metabolism were significantly decreased during CIA progression and increased following 2-DG treatment. The changes in the gene-metabolite network of bile secretion in the spleen correlated with a decreased plasma L-acetylcarnitine level in CIA rats and an increase following 2-DG treatment. Our analysis suggests the involvement of spleen and liver metabolism in CIA under the control of glycolysis.
Cytotoxic T-Cell Trafficking Chemokine Profiles Correlate With Defined Mucosal Microbial Communities in Colorectal Cancer
Authors: Zhang Jiali , Tao Ji , Gao Ruo-Nan , Wei Zhi-Yuan , He Yu-Shan , Ren Chun-Yan , Li Qi-Chun , Liu Yan-Shan , Wang Ke-Wei , Yang Gong , Qian Chengjia , Chen Jian-Huan
Published: September 2021

The involvement of gut microbiota in T-cell trafficking into tumor tissue of colorectal cancer (CRC) remains to be further elucidated. The current study aimed to evaluate the expression of major cytotoxic T-cell trafficking chemokines (CTTCs) and chemokine-associated microbiota profiles in both tumor and adjacent normal tissues during CRC progression. We analyzed the expression of chemokine C-X-C motif ligands 9, 10, and 11 (CXCL9, CXCL10, and CXCL11), and C-C motif ligand 5 (CCL5), characterized gut mucosa-associated microbiota (MAM), and investigated their correlations in CRC patients. Our results showed that the expression of CXCL9, CXCL10, and CXCL11 was significantly higher in tumor than in adjacent normal tissues in 136 CRC patients. Notably, the high expression of CXCL9 in tumor tissues was associated with enhanced CD8+ T-cell infiltration and improved survival. Moreover, the MAM in tumor tissues showed reduction of microbial diversity and increase of oral bacteria. Microbial network analysis identified differences in microbial composition and structure between tumor and adjacent normal tissues. In addition, stronger associations between oral bacteria and other gut microbes were observed. Furthermore, the correlation analysis between the defined MAM and individual CTTCs showed that the CTTCs’ correlated operational taxonomic units (OTUs) in tumor and adjacent normal tissues rarely overlap with each other. Notably, all the enriched OTUs were positively correlated with the CTTCs in either tumor or adjacent normal tissues. Our findings demonstrated stronger interactions between oral bacteria and gut microbes, and a shifted correlation pattern between MAM and major CTTCs in tumor tissues, underlining possible mechanisms of gut microbiota–host interaction in CRC.
The Binary Model of Chronic Diseases Applied to COVID-19
Authors: Elkoshi Zeev
Published: September 2021

A binary model for the classification of chronic diseases has formerly been proposed. The model classifies chronic diseases as “high Treg” or “low Treg” diseases according to the extent of regulatory T cells (Treg) activity (frequency or function) observed. The present paper applies this model to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The model correctly predicts the efficacy or inefficacy of several immune-modulating drugs in the treatment of severe coronavirus disease 2019 (COVID-19) disease. It also correctly predicts the class of pathogens mostly associated with SARS-CoV-2 infection. The clinical implications are the following: (a) any search for new immune-modulating drugs for the treatment of COVID-19 should exclude candidates that do not induce “high Treg” immune reaction or those that do not spare CD8+ T cells; (b) immune-modulating drugs, which are effective against SARS-CoV-2, may not be effective against any variant of the virus that does not induce “low Treg” reaction; (c) any immune-modulating drug, which is effective in treating COVID-19, will also alleviate most coinfections; and (d) severe COVID-19 patients should avoid contact with carriers of “low Treg” pathogens.
Circulating Placental Vesicles Carry HLA-DR in Pre-Eclampsia: A New Potential Marker of the Syndrome
Authors: Tersigni Chiara , Lucchetti Donatella , Franco Rita , Colella Filomena , Neri Caterina , Crispino Laura , Sgambato Alessandro , Lanzone Antonio , Scambia Giovanni , Vatish Manu , Di Simone Nicoletta
Published: September 2021

Background

Pre-eclampsia (PE) is a common disorder of pregnancy that usually presents with hypertension and proteinuria. The clinical presentation arises from soluble factors released into the maternal circulation from the placenta owing to the stress of syncytiotrophoblast, consequence of defective placentation occurring in the first half of pregnancy. Reduced tolerance of the semiallogeneic fetus by the maternal immune system has been proposed as first trigger leading to poor placentation. We previously observed aberrant expression of human leukocyte antigen (HLA)-DR molecules in the syncytiotrophoblast of a subset of women with PE. Aim of this study was to investigate abnormal expression of circulating HLA-DR in syncytiotrophoblast-derived extracellular vesicles (STBEVs) in women with PE compared to normal pregnant women.

Methods

peripheral venous blood was collected from 22 women with PE and 22 normal pregnant women. Circulating STBEVs were collected by ultra-centrifugation (120000 g) and analyzed for the expression of HLA-DR and placental alkaline phosphatase (PLAP), a specific marker of the placenta, by Western blot analysis and flow cytometry.

Results

circulating STBEVs positive for HLA-DR were observed in 64% of PE women while no HLA-DR positivity was detected in any of the controls (P<0.01).

Conclusions

Aberrant expression of HLA-DR in circulating STBEVs is specifically associated to PE. Further studies are required: a) to define the role of aberrant placental expression of HLA-DR molecules in the pathogenesis of PE; b) evaluate a possible application of detecting circulating HLA-DR positive STBEVs in the diagnosis and prediction of PE in the first and second trimester of pregnancy.
The Potential Roles of Mucosa-Associated Invariant T Cells in the Pathogenesis of Gut Graft-Versus-Host Disease After Hematopoietic Stem Cell Transplantation
Authors: Gao Meng-Ge , Hong Yan , Zhao Xiang-Yu , Pan Xin-An , Sun Yu-Qian , Kong Jun , Wang Zhi-Dong , Wang Feng-Rong , Wang Jing-Zhi , Yan Chen-Hua , Wang Yu , Huang Xiao-Jun , Zhao Xiao-Su
Published: September 2021

Gut acute graft-versus-host disease (aGVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with high mortality. Mucosa-associated invariant T (MAIT) cells are a group of innate-like T cells enriched in the intestine that can be activated by riboflavin metabolites from various microorganisms. However, little is known about the function or mechanism of action of MAIT cells in the occurrence of gut aGVHD in humans. In our study, multiparameter flow cytometry (FCM) was used to evaluate the number of MAIT cells and functional cytokines. 16S V34 region amplicon sequencing analysis was used to analyze the intestinal flora of transplant patients. In vitro stimulation and coculture assays were used to study the activation and function of MAIT cells. The number and distribution of MAIT cells in intestinal tissues were analyzed by immunofluorescence technology. Our study showed that the number and frequency of MAIT cells in infused grafts in gut aGVHD patients were lower than those in no-gut aGVHD patients. Recipients with a high number of MAITs in infused grafts had a higher abundance of intestinal flora in the early posttransplantation period (+14 days). At the onset of gut aGVHD, the number of MAIT cells decreased in peripheral blood, and the activation marker CD69, chemokine receptors CXCR3 and CXCR4, and transcription factors Rorγt and T-bet tended to increase. Furthermore, when gut aGVHD occurred, the proportion of MAIT17 was higher than that of MAIT1. The abundance of intestinal flora with non-riboflavin metabolic pathways tended to increase in gut aGVHD patients. MAIT cells secreted more granzyme B, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ under the interleukin (IL)-12/IL-18 stimulation [non-T-cell receptor (TCR) signal] and secreted most of the IL-17 under the cluster of differentiation (CD)3/CD28 stimulation (TCR signal). MAIT cells inhibited the proliferation of CD4+ T cells in vitro. In conclusion, the lower number of MAIT cells in infused grafts was related to the higher incidence of gut aGVHD, and the number of MAIT cells in grafts may affect the composition of the intestinal flora of recipients early after transplantation. The flora of the riboflavin metabolism pathway activated MAIT cells and promoted the expression of intestinal protective factors to affect the occurrence of gut aGVHD in humans.
IL-17 and CCR9+α4β7– Th17 Cells Promote Salivary Gland Inflammation, Dysfunction, and Cell Death in Sjögren’s Syndrome
Authors: Hwang Sun-Hee , Woo Jin Seok , Moon Jeonghyeon , Yang SeungCheon , Park Jin-Sil , Lee JaeSeon , Choi JeongWon , Lee Kun Hee , Kwok Seung-Ki , Park Sung-Hwan , Cho Mi-La
Published: September 2021

Previous studies have evaluated the roles of T and B cells in the pathogenesis of Sjögren’s syndrome (SS); however, their relationships with age-dependent and metabolic abnormalities remain unclear. We examined the impacts of changes associated with aging or metabolic abnormalities on populations of T and B cells and SS disease severity. We detected increased populations of IL-17-producing T and B cells, which regulate inflammation, in the salivary glands of NOD/ShiLtJ mice. Inflammation-induced human submandibular gland cell death, determined based on p-MLKL and RIPK3 expression levels, was significantly increased by IL-17 treatment. Among IL-17-expressing cells in the salivary gland, peripheral blood, and spleen, the α4β7 (gut-homing integrin)-negative population was significantly increased in aged NOD/ShiLtJ mice. The α4β7-positive population markedly increased in the intestines of aged NOD/ShiLtJ mice following retinoic acid (RA) treatment. A significant increase in α4β7-negative IL-17-expressing cells in salivary glands may be involved in the onset and progression of SS. These results suggest the potential therapeutic utility of RA in SS treatment.
Immunological Adverse Events After Autologous Hematopoietic Stem Cell Transplantation in Systemic Sclerosis Patients
Authors: Strunz Patrick-Pascal , Froehlich Matthias , Gernert Michael , Schwaneck Eva Christina , Fleischer Anna , Pecher Ann-Christin , Tony Hans-Peter , Henes Joerg Christoph , Schmalzing Marc
Published: September 2021

Autologous hematopoietic stem cell transplantation (aHSCT) represents an effective treatment for systemic sclerosis (SSc), but it also can cause immunological adverse events (iAEs). Therefore, we aimed to determine the frequency of iAEs [engraftment syndrome (ES) and secondary autoimmune disorder (sAD)] and to identify potential risk factors for their development in a retrospective analysis on 22 patients similarly transplanted due to SSc. While nine patients (41%) suffered from ESs, seven sADs occurred in six patients (27%). Patients who developed ES were older in our cohort (52.45 vs. 42.58 years, p = .0433, Cohen’s d = 0.86), and cardiac involvement by SSc was associated with development of ES (OR = 40.11, p = .0017). Patients with manifestation of sAD had a higher modified Rodnan skin score (mRSS) reduction after aHSCT (90.50% vs. 60.00%, p = .0064, r = .65). Thus, IAEs are common after aHSCT for SSc and can occur in different stages during and after aHSCT with characteristic clinical manifestations. Good cutaneous response after aHSCT might be considered as a risk factor for sAD, and higher age at aHSCT and cardiac involvement might be considered as risk factors for the development of ES.
Tertiary Lymphoid Structures in the Central Nervous System: Implications for Glioblastoma
Authors: van de Walle Tiarne , Vaccaro Alessandra , Ramachandran Mohanraj , Pietilä Ilkka , Essand Magnus , Dimberg Anna
Published: September 2021

Glioblastoma is the most common and aggressive brain tumor, which is uniformly lethal due to its extreme invasiveness and the absence of curative therapies. Immune checkpoint inhibitors have not yet proven efficacious for glioblastoma patients, due in part to the low prevalence of tumor-reactive T cells within the tumor microenvironment. The priming of tumor antigen-directed T cells in the cervical lymph nodes is complicated by the shortage of dendritic cells and lack of appropriate lymphatic vessels within the brain parenchyma. However, recent data suggest that naive T cells may also be primed within brain tumor-associated tertiary lymphoid structures. Here, we review the current understanding of the formation of these structures within the central nervous system, and hypothesize that promotion of tertiary lymphoid structures could enhance priming of tumor antigen-targeted T cells and sensitize glioblastomas to cancer immunotherapy.
Targeting Indoleamine 2,3-Dioxygenase 1: Fighting Cancers via Dormancy Regulation
Authors: Yang Chao , Ng Chan-Tat , Li Dan , Zhang Lei
Published: September 2021

The connection between indoleamine 2,3-dioxygenase 1 (IDO1) and tumour dormancy – a quiescent state of tumour cells which has been consistently linked to metastasis and cancer recurrence – is rarely discussed despite the pivotal role of IDO1 in cancer development and progression. Whilst the underlying mechanisms of IDO1-mediated dormancy are elusive, we summarize the IDO1 pathways which potentially contribute to dormancy in this review. Critically, distinct IDO1 activities are involved in dormancy initiation and maintenance; factors outside the well-studied IDO1/kynurenine/aryl hydrocarbon receptor axis, including the mammalian target of rapamycin and general control nonderepressible 2, appear to be implicated in dormancy. We also discuss various strategies for cancer treatment via regulating IDO1-dependent dormancy and suggest the application of nanotechnology to deliver effective treatment.
Non-Coding RNAs in Human Breast Milk: A Systematic Review
Authors: Tingö Lina , Ahlberg Emelie , Johansson Lovisa , Pedersen Sindre Andre , Chawla Konika , Sætrom Pål , Cione Erika , Simpson Melanie Rae
Published: September 2021

Breast milk is the primary source of nutrition and hydration for the newborn infant but also plays an important role in the child’s first immune defense. Additionally, several breast milk factors have been implicated in immune-related health outcomes later in life, including immunoglobulins, cytokines, chemokines, growth factors and, more recently, non-coding RNA (ncRNA) species. In this systematic review, we provide a comprehensive summary of the current literature on endogenous ncRNAs found in human breast milk. Thirty (30) relevant studies were identified and, whilst the majority studies focused on microRNAs (miRNAs), there is evidence that breast milk contains high quantities of RNA which also include long-coding RNAs, circular RNAs, as well as other short RNAs and fragmented tRNA and rRNAs. Among studies investigating miRNAs, miR-148a-3p, miR-30a/d-5p, miR-22-3p, miR-146b-5p, miR-200a/c-3p, and the 5p end of the let-7 miRNAs were commonly reported among the top 10 miRNAs in the cell, lipid, and skim milk fractions of breast milk. Methodological difference and small sample sizes limit the possibility of conclusively identifying which maternal and infant characteristics affect the miRNA profile. The highly expressed miRNAs were generally reported to be similar across lactational stage, milk fraction, maternal and infant characteristics, or infant growth and health. All the same, individual studies identify potential differences in miRNA expression levels which should be confirmed by future studies. Stability, uptake, and physiological functions of miRNAs were also considered in several studies. Breast milk miRNAs are relatively resistant to a range of harsh conditions and uptake experiments suggest that extracellular vesicles containing miRNAs and circular RNAs can be taken up by intestinal epithelial cells. Although the evidence regarding the functional effect of breast milk miRNAs is limited, the predicted functions range from metabolic and biosynthetic processes to signaling pathways, cellular adhesion, communication, growth, and differentiation. Finally, this systematic review highlights some of the methodological challenges and knowledge gaps which can help direct future research in this field. In particular, it is important to further investigate the bioavailability of miRNAs in different milk fractions, and to characterize other ncRNAs which are largely unstudied.

Systematic Review Registration

PROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=138989, identifier CRD42020138989.
Beyond the Extra Respiration of Phagocytosis: NADPH Oxidase 2 in Adaptive Immunity and Inflammation
Authors: Mortimer Paige M. , Mc Intyre Stacey A. , Thomas David C.
Published: September 2021

Reactive oxygen species (ROS) derived from the phagocyte NADPH oxidase (NOX2) are essential for host defence and immunoregulation. Their levels must be tightly controlled. ROS are required to prevent infection and are used in signalling to regulate several processes that are essential for normal immunity. A lack of ROS then leads to immunodeficiency and autoinflammation. However, excess ROS are also deleterious, damaging tissues by causing oxidative stress. In this review, we focus on two particular aspects of ROS biology: (i) the emerging understanding that NOX2-derived ROS play a pivotal role in the development and maintenance of adaptive immunity and (ii) the effects of excess ROS in systemic disease and how limiting ROS might represent a therapeutic avenue in limiting excess inflammation.
Characterization of the m6A-Associated Tumor Immune Microenvironment in Prostate Cancer to Aid Immunotherapy
Authors: Liu Zezhen , Zhong Jiehui , Zeng Jie , Duan Xiaolu , Lu Jianming , Sun Xinyuan , Liu Qinwei , Liang Yingke , Lin Zhuoyuan , Zhong Weide , Wu Wenzheng , Cai Chao , Zeng Guohua
Published: September 2021

The aim of this study was to elucidate the correlation between m6A modification and the tumor immune microenvironment (TIME) in prostate cancer (PCa) and to identify the m6A regulation patterns suitable for immune checkpoint inhibitors (ICIs) therapy. We evaluated the m6A regulation patterns of PCa based on 24 m6A regulators and correlated these modification patterns with TIME characteristics. Three distinct m6A regulation patterns were determined in PCa. The m6A regulators cluster with the best prognosis had significantly increased METTL14 and ZC3H13 expression and was characterized by low mutation rate, tumor heterogeneity, and neoantigens. The m6A regulators cluster with a poor prognosis had markedly high KIAA1429 and HNRNPA2B1 expression and was characterized by high intratumor heterogeneity and Th2 cell infiltration, while low Th17 cell infiltration and Macrophages M1/M2. The m6Ascore was constructed to quantify the m6A modification pattern of individual PCa patients based on m6A-associated genes. We found that the low-m6Ascore group with poor prognosis had a higher immunotherapeutic response rate than the high-m6Ascore group. The low-m6Ascore group was more likely to benefit from ICIs therapy. This study was determined that immunotherapy is more effective in low-m6Ascore PCa patients with poor prognosis.
Convergent Loss of the Necroptosis Pathway in Disparate Mammalian Lineages Shapes Viruses Countermeasures
Authors: Águeda-Pinto Ana , Alves Luís Q. , Neves Fabiana , McFadden Grant , Jacobs Bertram L. , Castro L. Filipe C. , Rahman Masmudur M. , Esteves Pedro J.
Published: September 2021

Programmed cell death is a vital process in the life cycle of organisms. Necroptosis, an evolutionary form of programmed necrosis, contributes to the innate immune response by killing pathogen-infected cells. This virus-host interaction pathway is organized around two components: the receptor-interacting protein kinase 3 (RIPK3), which recruits and phosphorylates the mixed lineage kinase-like protein (MLKL), inducing cellular plasma membrane rupture and cell death. Critically, the presence of necroptotic inhibitors in viral genomes validates necroptosis as an important host defense mechanism. Here, we show, counterintuitively, that in different mammalian lineages, central components of necroptosis, such as RIPK3 and MLKL, are deleted or display inactivating mutations. Frameshifts or premature stop codons are observed in all the studied species of cetaceans and leporids. In carnivores’ genomes, the MLKL gene is deleted, while in a small number of species from afrotheria and rodentia premature stop codons are observed in RIPK3 and/or MLKL. Interestingly, we also found a strong correlation between the disruption of necroptosis in leporids and cetaceans and the absence of the N-terminal domain of E3-like homologs (responsible for necroptosis inhibition) in their naturally infecting poxviruses. Overall, our study provides the first comprehensive picture of the molecular evolution of necroptosis in mammals. The loss of necroptosis multiple times during mammalian evolution highlights the importance of gene/pathway loss for species adaptation and suggests that necroptosis is not required for normal mammalian development. Moreover, this study highlights a co-evolutionary relationship between poxviruses and their hosts, emphasizing the role of host adaptation in shaping virus evolution.
Social Network Analysis Reveals the Subtle Impacts of Tourist Provisioning on the Social Behavior of a Generalist Marine Apex Predator
Authors: Jacoby David M. P. , Fairbairn Bethany S. , Frazier Bryan S. , Gallagher Austin J. , Heithaus Michael R. , Cooke Steven J. , Hammerschlag Neil
Published: September 2021

Shark dive ecotourism is a lucrative industry in many regions around the globe. In some cases, sharks are provisioned using bait, prompting increased research on how baited dives influence shark behavior and yielding mixed results. Effects on patterns of habitat use and movement seemly vary across species and locations. It is unknown, however, whether wide-ranging, marine apex predators respond to provisioning by changing their patterns of grouping or social behavior. We applied a tiered analytical approach (aggregation-gregariousness-social preferences) examining the impact of provisioning on the putative social behavior of tiger sharks (Galeocerdo cuvier) at a dive tourism location in The Bahamas. Using network inference on three years of acoustic tracking data from 48 sharks, we tested for non-random social structure between non-provisioned and provisioned monitoring sites resulting in 12 distinct networks. Generally considered a solitary nomadic predator, we found evidence of sociality in tiger sharks, which varied spatiotemporally. We documented periods of both random (n = 7 networks) and non-random aggregation (n = 5 networks). Three of five non-random aggregations were at locations unimpacted by provisioning regardless of season, one occurred at an active provisioning site during the dry season and one at the same receivers during the wet season when provision activity is less prevalent. Aggregations lasted longer and occurred more frequently at provisioning sites, where gregariousness was also more variable. While differences in gregariousness among individuals was generally predictive of non-random network structure, individual site preferences, size and sex were not. Within five social preference networks, constructed using generalized affiliation indices, network density was lower at provisioning sites, indicating lower connectivity at these locations. We found no evidence of size assortment on preferences. Our data suggest that sociality may occur naturally within the Tiger Beach area, perhaps due to the unusually high density of individuals there. This study demonstrates the existence of periodic social behavior, but also considerable variation in association between tiger sharks, which we argue may help to mitigate any long-term impacts of provisioning on this population. Finally, we illustrate the utility of combining telemetry and social network approaches for assessing the impact of human disturbance on wildlife behavior.
Spatial Patterns of a Lethal White Syndrome Outbreak in Pseudodiploria strigosa
Authors: Guzmán-Urieta Edgar O. , Jordán-Dahlgren Eric
Published: September 2021

We analyzed the spatial distribution patterns of a white syndrome (WS) outbreak affectingPseudodiploria strigosacolonies in the northern Mexican Caribbean during 2018–2019. The purpose of the study was to describe the outbreak progression in a single species and determine if this WS incidence is related to the nearest diseased neighbor distance. Two separated sites with differentP. strigosacolonial densities (Bocana: 0.08 col/m2; Picudas: 0.2 col/m2) were selected in similar habitats of the same reef complex.P. strigosacolonies within the survey sites were mapped, and their status was recorded (healthy, diseased, or dead) in sequential surveys until colonies died or the study terminated (306 days). Spatial distribution modes were assessed using Ripley’s K function. The spatial colony distribution was random in one site (Bocana) and clustered in the other (Picudas). However, the WS disease incidence per survey was randomly distributed in both sites throughout the observation period of the outbreak, suggesting that WS transmission at small spatial scales was independent of the colony distribution pattern and from the nearest diseased colonies. Survival probability since WS onset in surveyed colonies was different: 0% at Bocana and 14% at Picudas by April 2019. But, eventually, all diseased colonies died in both sites. WS outbreak timing was different at the two sites: Initial prevalence 8% at the Bocana site vs. 44% at Picudas site. Distribution of time to disease onset shown multimodality, with modes varying from 17 to 184 days and wide main modes amplitude suggest a highly variable resistance to the WS. Disease incidence was not abated during winter surveys. Differences between sites in the WS disease outbreak distribution and progression suggest that colony condition, environmental quality, and perhaps several transmission events played an essential role in the complex outbreak dynamics at the local spatial scale of our study.
Validation of Non-photochemical Quenching Corrections for Chlorophyll-a Measurements Aboard Ships of Opportunity
Authors: Travers-Smith Hana , Giannini Fernanda , Sastri Akash R. , Costa Maycira
Published: September 2021

The in vivo fluorescence of chlorophyll-a is commonly used as a proxy for phytoplankton biomass. Measurement of in vivo fluorescence in the field is attractive because it can be made at high spatial temporal, and vertical resolution relative to discrete sampling and pigment extraction. Fluorometers installed on ships of opportunity provide a cost-effective alternative to many of the traditional sampling methods. However, fluorescence-based estimates of chlorophyll-a can be impacted by sensor calibration and biofouling, variations in phytoplankton taxonomy and physiology (such as non-photochemical quenching) and the influence of other fluorescing matters in the water. Several methods have been proposed to address these issues separately, but few studies have addressed the interaction of multiple sources of error in the in vivo Chl-a fluorescence signal. Here, we demonstrate a method to improve the accuracy of chlorophyll-a concentration retrieved from a coastal ferry system, operating in a dynamic estuarine system. First, we used HPLC chlorophyll-a measurements acquired in low-light conditions to correct sensor level bias. Next, we tested three methods to correct the effect of non-photochemical quenching and evaluated the accuracy of each method using HPLC. As our study area is in highly dynamic coastal waters, we also evaluated the accuracy of our correction procedure across a range of irradiance and biogeochemical conditions. We found that sensor bias accounted for a significant portion of error in the fluorescence signal. The NPQ correction developed by Davis et al. (2008) best improved correspondence between in vivo Chl-a fluorescence and HPLC-based measurement of extracted Chl-a. We suggest the use of this correction for in vivo Chl-a measurements along with pre-processing steps to correct potential sensor biofouling and bias.
Costs and Limitations of Marine Synechococcus Blue-Green Chromatic Acclimation
Authors: Lovindeer Raisha , Abbott Lawrence , Medina Hannah , Mackey Katherine R. M.
Published: September 2021

Benefits and trade-offs of blue/green chromatic acclimation (CA4) have received limited study. We investigated the energetic costs associated with executing chromatic acclimation using a fluorescence-based calculation of light use efficiency. Using laboratory cultures and artificial light environments, we show that the delayed response to acclimation known to occur in marine Synechococcus acclimating strains (generalists) in green light do not reduce light use efficiency in green light, but that only one generalist, RCC307, with a much smaller range of acclimation, had higher light use efficiency than blue and green light specialist strains. Generalists with a wider acclimation range either had the same or >30% lower light use efficiencies in blue and green light environments. From this work, we propose that advantages from CA4 may not be geared at direct competition with other Synechococcus specialists with fixed pigment types, but may serve to expand the ecological range of Synechococcus in spectral competition with other genera. As all eight Synechococcus strains tested had higher light use efficiency in green light, regardless of a fixed or flexible light harvesting strategy, we add evidence to the suitability of the Synechococcus genus to greener ocean niches, whether stable, or variable.
Functionality and Effectiveness of Marine Protected Areas in Southeastern Brazilian Waters for Demersal Elasmobranchs
Authors: Karlovic Thamíris C. , Gomes Renata R. , Paiva Paulo C. , Babcock Elizabeth A. , Dias June F.
Published: September 2021

Ensuring the efficacy of Marine Protected Areas (MPAs) requires that adequate management strategies be implemented according to the MPA’s objectives. Within the scope of species conservation, achieving MPA objectives demands understanding of the role played by MPAs for the target species. In 2014, Brazilian stakeholders and experts set the action plan for elasmobranchs’ conservation, which intended to create new protected areas and expand the existing ones. Nevertheless, more than 65% of Brazilian elasmobranch species are threatened by anthropogenic pressures such as fisheries and habitat loss. In addition, their ecological aspects are not well studied, which might jeopardize the success of the proposed actions. To assess the functionality and effectiveness of two no-take MPAs for sixteen demersal species, the Wildlife Refuge of Alcatrazes (WRA) and the Tupinambás Ecological Station (TES), we evaluated the community structure, space-time variations in functional diversity and changes in fishery indicators. Community dynamics were driven by inshore intrusion and time persistent effects of a cold and nutrient-rich water mass, the South Atlantic Central Water, which increased the relative abundance of species, functional groups, and overall diversity. Spatially, the heterogeneity of benthic habitats, due to the action of stronger waves in specific parts of the MPAs, reflects a diverse community of benthic invertebrates, explaining differences in relative abundance and similarities in space use by the functional groups. Regarding effectiveness, the MPAs make up a key network with the surrounding protection areas to support the ecosystem maintenance on the central and northern coast of the São Paulo state. The establishment of the TES has positively influenced the community throughout the years while the recent creation of the WRA may have promoted some improvements in fisheries indicators for a threatened guitarfish. We propose different functions of the Alcatrazes archipelago for each species and suggest some measures to enhance not only elasmobranch conservation but also the MPAs’ effectiveness.
Plasticity of Porites astreoides Early Life History Stages Suggests Mesophotic Coral Ecosystems Act as Refugia in Bermuda
Authors: Goodbody-Gringley Gretchen , Scucchia Federica , Ju Rebecca , Chequer Alex , Einbinder Shai , Martinez Stephane , Nativ Hagai , Mass Tali
Published: September 2021

As the devastating impacts of global climate change and local anthropogenic stressors on shallow-water coral reefs are expected to rise, mesophotic coral ecosystems have increasingly been regarded as potential lifeboats for coral survival, providing a source of propagules to replenish shallower reefs. Yet, there is still limited knowledge of the capacity for coral larvae to adjust to light intensities that change with depth. This study elucidates the mechanisms underlying plasticity during early life stages of the coral Porites astreoides that enable survival across broad depth gradients. We examined physiological and morphological variations in larvae from shallow (8–10 m) and mesophotic (45 m) reefs in Bermuda, and evaluated differences in survival, settlement patterns and size among recruits depending on light conditions using a reciprocal ex situ transplantation experiment. Larvae released from mesophotic adults were found to have significantly lower respiration rates and were significantly larger than those derived from shallow adults, indicating higher content of energetic resources and suggesting a greater dispersal potential for mesophotic larvae compared to their shallow counterparts. Additionally, larvae released from mesophotic adults experienced higher settlement success and larger initial spat size compared to larvae from shallow adults, demonstrating a potential connection between parental origin, offspring quality, and recruitment success. Although both shallow and mesophotic larvae exhibited the capacity to survive and settle under reciprocal light conditions, all larvae had higher survival under mesophotic light conditions regardless of parental origin, suggesting that conditions experienced under low light may enable longer larval life, further extending the dispersal period. These results indicate that larvae from mesophotic Porites astreoides colonies are likely capable of reseeding shallow reefs in Bermuda, thereby supporting the Deep Reef Refugia Hypothesis.