bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptome and Metabolome Analyses of the Flowers and Leaves of Chrysanthemum dichrum
Authors: Liu Hua , Chen Xiaoxi , Chen Hạixia , Lu Jie , Chen Dongliang , Luo Chang , Cheng Xi , Jia Yin , Huang Conglin
Published: September 2021

Chrysanthemum dichrum is an important wild species in the family Asteraceae. However, because of a lack of genetic information, there has been relatively little research conducted on the molecular mechanisms in C. dichrum. There is no report describing the transcriptome and metabolome of C. dichrum flowers and leaves at different developmental stages. In this study, high-throughput sequencing and RNA-seq analyses were used to investigate the transcriptome of C. dichrum leaves, flower buds, and blooming flowers. Additionally, these three tissues also underwent a metabolomics analysis. A total of 447,313,764 clean reads were assembled into 77,683 unigenes, with an average length of 839 bp. Of the 44,204 annotated unigenes, 42,189, 28,531, 23,420, and 17,599 were annotated using the Nr, Swiss-Prot, KOG, and KEGG databases, respectively. Furthermore, 31,848 differentially expressed genes (DEGs) were detected between the leaves and flower buds, whereas 23,197 DEGs were detected between the leaves and blooming flowers, and 11,240 DEGs were detected between the flower buds and blooming flowers. Finally, a quantitative real-time Polymerase Chain Reaction (qRT-PCR) assay was conducted to validate the identified DEGs. The metabolome data revealed several abundant metabolites in C. dichrum leaves, flower buds, and blooming flowers, including raffinose, 1-kestose, asparagine, glutamine, and other medicinal compounds. The expression patterns of significant DEGs revealed by the transcriptome analysis as well as the data for the differentially abundant metabolites in three C. dichrum tissues provide important genetic and metabolic information relevant for future investigations of the molecular mechanisms in C. dichrum. Moreover, the results of this study may be useful for the molecular breeding, development, and application of C. dichrum resources.
Prognostic Value and Immunological Characteristics of a Novel RNA Binding Protein Signature in Cutaneous Melanoma
Authors: Tian Jun , Ma Chongzhi , Yang Li , Sun Yang , Zhang Yuan
Published: September 2021

Background

The existing studies indicate that RNA binding proteins (RBPs) are closely correlated with the genesis and development of cancers. However, the role of RBPs in cutaneous melanoma remains largely unknown. Therefore, the present study aims to establish a reliable prognostic signature based on RBPs to distinguish cutaneous melanoma patients with different prognoses and investigate the immune infiltration of patients.

Methods

After screening RBPs from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, Cox and least absolute shrinkage and selection operator (LASSO) regression analysis were then used to establish a prediction model. The relationship between the signature and the abundance of immune cell types, the tumor microenvironment (TME), immune-related pathways, and immune checkpoints were also analyzed.

Results

In total, 7 RBPs were selected to establish the prognostic signature. Patients categorized as a high-risk group demonstrated worse overall survival (OS) rates compared to those of patients categorized as a low-risk group. The signature was validated in an independent external cohort and indicated a promising prognostic ability. Further analysis indicated that the signature wasan independent prognostic indicator in cutaneous melanoma. A nomogram combining risk score and clinicopathological features was then established to evaluate the 3- and 5-year OS in cutaneous melanoma patients. Analyses of immune infiltrating, the TME, immune checkpoint, and drug susceptibility revealed significant differences between the two groups. GSEA analysis revealed that basal cell carcinoma, notch signaling pathway, melanogenesis pathways were enriched in the high-risk group, resulting in poor OS.

Conclusion

We established and validated a robust 7-RBP signature that could be a potential biomarker to predict the prognosis and immunotherapy response of cutaneous melanoma patients, which provides new insights into cutaneous melanoma immunotherapeutic strategies.
Strengthening Health Systems in Humanitarian Settings: Multi-Stakeholder Insights on Contraception and Postabortion Care Programs in the Democratic Republic of Congo and Somalia
Authors: Tran Nguyen Toan , Meyers Janet , Malilo Bibiche , Chabo Julien , Muselemu Jean-Baptiste , Riziki Bienvenu , Libonga Patrick , Shire Abdikani , Had Hussein , Ali Mohamed , Arab Mohamed Abdi , Da'ar Jama Mohamed , Kahow Mohamed Hussein , Adive Joseph Ege , Gebru Binyam , Monaghan Emily , Morris Catherine N. , Gallagher Meghan , Jouanicot Virginie , Pougnier Natacha , Amsalu Ribka
Published: September 2021

Background: In humanitarian settings, strengthening health systems while responding to the health needs of crisis-affected populations is challenging and marked with evidence gaps. Drawing from a decade of family planning and postabortion care programming in humanitarian settings, this paper aims to identify strategic components that contribute to health system strengthening in such contexts.

Materials and Methods: A diverse range of key informants from North Kivu (Democratic Republic of Congo, DRC) and Puntland (Somalia), including female and male community members, adolescents and adults, healthcare providers, government and community leaders, participated in qualitative interviews, which applied the World Health Organization health system building blocks framework. Data were thematically analyzed according to this framework.

Results: Findings from the focus group discussions (11 in DRC, 7 in Somalia) and key informant interviews (seven in DRC, four in Somalia) involving in total 54 female and 72 male participants across both countries indicate that health programs in humanitarian settings, such as Save the Children's initiative on family planning and postabortion care, could contribute to strengthening health systems by positively influencing national policies and guidance, strengthening local coordination mechanisms, capacitating the healthcare workforce with competency-based training and supportive supervision (benefiting facilities supported by the project and beyond), developing the capacity of Ministry of Health staff in the effective management of the supply chain, actively and creatively mobilizing the community to raise awareness and create demand, and providing quality and affordable services. Financial sustainability is challenged by the chronically limited healthcare expenditure experienced in both humanitarian contexts.

Conclusions: In humanitarian settings, carefully designed healthcare interventions, such as those that address the family planning and postabortion care needs of crisis-affected populations, have the potential not only to increase access to essential services but also contribute to strengthening several components of the health system while increasing the government capacity, ownership, and accountability.
HCV Core Protein Induces Chemokine CCL2 and CXCL10 Expression Through NF-κB Signaling Pathway in Macrophages
Authors: Song Xiaotian , Gao Xue , Wang Yadong , Raja Rameez , Zhang Yaoyu , Yang Shulin , Li Miao , Yao Zhiyan , Wei Lin
Published: September 2021

HCV core protein is the first structural protein synthesized during hepatitis C virus (HCV) infection and replication. It is released from virus infected liver cells and mediates multiple functions to affect host cell response. The innate immune response is the first line of defense against viral infection. After HCV infection, Kupffer cells (KCs) which are liver macrophages play an important role in host innate immune response. Kupffer cells act as phagocytes and release different cytokines and chemokines to counter viral infection and regulate inflammation and fibrosis in liver. Earlier, we have demonstrated that HCV core protein interacts with gC1qR and activates MAPK, NF-κB and PI3K/AKT pathways in macrophages. In this study, we explored the effect of HCV core protein on CCL2 and CXCL10 expression in macrophages and the signaling pathways involved. Upon silencing of gC1qR, we observed a significant decrease expression of CCL2 and CXCL10 in macrophages in the presence of HCV core protein. Inhibiting NF-κB pathway, but not P38, JNK, ERK and AKT pathways greatly reduced the expression of CCL2 and CXCL10. Therefore, our results indicate that interaction of HCV core protein with gC1qR could induce CCL2 and CXCL10 secretion in macrophages via NF-κB signaling pathway. These findings may shed light on the understanding of how leukocytes migrate into the liver and exaggerate host-derived immune responses and may provide novel therapeutic targets in HCV chronic inflammation.
Multidimensional Analyses of Tumor Immune Microenvironment Reveal the Possible Rationality of Immunotherapy and Identify High Immunotherapy Response Subtypes for Renal Papillary Cell Carcinoma
Authors: Wei Baojun , Yu Meng , Yao Jihang , Jiang Mingzhe , An Jun , Yang Jieping , Lin Jiaxing , Zhao Yongkang , Zhu Yuyan
Published: September 2021

Kidney renal papillary cell carcinoma (KIRP), the second most common subtype of renal cell carcinoma, still lacks effective treatment regimens for individualized immunotherapy because of the heterogeneity of its elusive immune microenvironment. Therefore, we aimed to comprehensively evaluate the immune microenvironment of KIRP by using the computational biology strategy to analyze the expression profile data of 289 KIRP patients obtained from The Cancer Genome Atlas database. Based on multidimensional, multi-omics bioinformatics analysis, we found that the tumor of patients with KIRP exhibited “hot” tumor characteristics but the CD8+ T cells in the tumor tissues did not limit tumor progression. Thus, patients with KIRP may realize higher clinical benefits by receiving treatment that can reverse CD8+ T-cell exhaustion. Among them, C1 and C3 immune subtypes could realize the best efficacy of reversing CD8+ T-cell exhaustion. Moreover,CCL5andFASLGexpression may be related to the formation of the immunosuppressive microenvironment in the tumors of patients with KIRP. In conclusion, the immune microenvironment landscape presented in this study provides a novel insight for further experimental and clinical exploration of tailored immunotherapy for patients with KIRP.
Divergent Antiviral Mechanisms of Two Viperin Homeologs in a Recurrent Polyploid Fish
Authors: Mou Cheng-Yan , Li Shun , Lu Long-Feng , Wang Yang , Yu Peng , Li Zhi , Tong Jin-Feng , Zhang Qi-Ya , Wang Zhong-Wei , Zhang Xiao-Juan , Wang Guang-Xin , Zhou Li , Gui Jian-Fang
Published: September 2021

Polyploidy and subsequent diploidization provide genomic opportunities for evolutionary innovations and adaptation. The researches on duplicated gene evolutionary fates in recurrent polyploids have seriously lagged behind that in paleopolyploids with diploidized genomes. Moreover, the antiviral mechanisms of Viperin remain largely unclear in fish. Here, we elaborate the distinct antiviral mechanisms of two viperin homeologs (Cgviperin-A and Cgviperin-B) in auto-allo-hexaploid gibel carp (Carassius gibelio). First, Cgviperin-A and Cgviperin-B showed differential and biased expression patterns in gibel carp adult tissues. Subsequently, using co-immunoprecipitation (Co-IP) screening analysis, both CgViperin-A and CgViperin-B were found to interact with crucian carp (C. auratus) herpesvirus (CaHV) open reading frame 46 right (ORF46R) protein, a negative herpesvirus regulator of host interferon (IFN) production, and to promote the proteasomal degradation of ORF46R via decreasing K63-linked ubiquitination. Additionally, CgViperin-B also mediated ORF46R degradation through autophagosome pathway, which was absent in CgViperin-A. Moreover, we found that the N-terminal α-helix domain was necessary for the localization of CgViperin-A and CgViperin-B at the endoplasmic reticulum (ER), and the C-terminal domain of CgViperin-A and CgViperin-B was indispensable for the interaction with degradation of ORF46R. Therefore, the current findings clarify the divergent antiviral mechanisms of the duplicated viperin homeologs in a recurrent polyploid fish, which will shed light on the evolution of teleost duplicated genes.
An Immune-Associated Genomic Signature Effectively Predicts Pathologic Complete Response to Neoadjuvant Paclitaxel and Anthracycline-Based Chemotherapy in Breast Cancer
Authors: Fu Changfang , Liu Yu , Han Xinghua , Pan Yueyin , Wang Hong-qiang , Wang Hongzhi , Dai Haiming , Yang Wulin
Published: September 2021

Breast cancer is now the leading cause of cancer morbidity and mortality among women worldwide. Paclitaxel and anthracycline-based neoadjuvant chemotherapy is widely used for the treatment of breast cancer, but its sensitivity remains difficult to predict for clinical use. In our study, a LASSO logistic regression method was applied to develop a genomic classifier for predicting pathologic complete response (pCR) to neoadjuvant chemotherapy in breast cancer. The predictive accuracy of the signature classifier was further evaluated using four other independent test sets. Also, functional enrichment analysis of genes in the signature was performed, and the correlations between the prediction score of the signature classifier and immune characteristics were explored. We found a 25-gene signature classifier through the modeling, which showed a strong ability to predict pCR to neoadjuvant chemotherapy in breast cancer. For T/FAC-based training and test sets, and a T/AC-based test set, the AUC of the signature classifier is 1.0, 0.9071, 0.9683, 0.9151, and 0.7350, respectively, indicating that it has good predictive ability for both T/FAC and T/AC schemes. The multivariate model showed that 25-gene signature was far superior to other clinical parameters as independent predictor. Functional enrichment analysis indicated that genes in the signature are mainly enriched in immune-related biological processes. The prediction score of the classifier was significantly positively correlated with the immune score. There were also significant differences in immune cell types between pCR and residual disease (RD) samples. Conclusively, we developed a 25-gene signature classifier that can effectively predict pCR to paclitaxel and anthracycline-based neoadjuvant chemotherapy in breast cancer. Our study also suggests that the immune ecosystem is actively involved in modulating clinical response to neoadjuvant chemotherapy and is beneficial to patient outcomes.
Zebrafish BID Exerts an Antibacterial Role by Negatively Regulating p53, but in a Caspase-8-Independent Manner
Authors: Qi Zhitao , Yan Dong , Cao Lu , Xu Yang , Chang Mingxian
Published: September 2021

Bid (BH3-interacting domain death agonist), a member of the Bcl-2 family, plays a crucial role in the initiation of apoptosis. Independent of its apoptotic function, Bid is also involved in the regulation of inflammation and innate immunity. However, the role of Bid during bacterial pathogen infection remains unclear. In the present study, Bid of zebrafish (Dario rerio) was cloned and its functions during Edwardsiella ictaluri infection were investigated. Zebrafish Bid enhances the apoptosis rate of Epithelioma papulosum cyprini (EPC) cells following E. ictaluri infection. Importantly, in vitro and in vivo bacterial invasion assays showed that overexpressed Bid could significantly inhibit the invasion and proliferation of E. ictaluri. Real-time qPCR analysis revealed that p53 gene expression was downregulated in embryos microinjected with Bid-FLAG. Further, in vitro and in vivo bacterial invasion assays showed that overexpressed p53 increased the invasion and proliferation of E. ictaluri. Moreover, the invasion and proliferation of E. ictaluri were inhibited when co-overexpressing Bid and p53 in vivo and in vitro. Further, the numbers of E. ictaluri in larvae treated with Z-IETD-FMK (caspase-8 inhibitor) were higher than those of larvae without Z-IETD-FMK treatment, while the number of E. ictaluri in larvae microinjected with bid-Flag decreased significantly, even if the larvae were treated in advance with Z-IETD-FMK. Collectively, our study demonstrated a novel antibacterial activity of fish Bid, providing evidence for understanding the function of apoptosis associated gene in pathogen infection.
Modeling HIV-1 Within-Host Dynamics After Passive Infusion of the Broadly Neutralizing Antibody VRC01
Authors: Cardozo-Ojeda E. Fabian , Perelson Alan S.
Published: September 2021

VRC01 is a broadly neutralizing antibody that targets the CD4 binding site of HIV-1 gp120. Passive administration of VRC01 in humans has assessed the safety and the effect on plasma viremia of this monoclonal antibody (mAb) in a phase 1 clinical trial. After VRC01 infusion, the plasma viral load in most of the participants was reduced but had particular dynamics not observed during antiretroviral therapy. In this paper, we introduce different mathematical models to explain the observed dynamics and fit them to the plasma viral load data. Based on the fitting results we argue that a model containing reversible Ab binding to virions and clearance of virus-VRC01 complexes by a two-step process that includes (1) saturable capture followed by (2) internalization/degradation by phagocytes, best explains the data. This model predicts that VRC01 may enhance the clearance of Ab-virus complexes, explaining the initial viral decay observed immediately after antibody infusion in some participants. Because Ab-virus complexes are assumed to be unable to infect cells, i.e., contain neutralized virus, the model predicts a longer-term viral decay consistent with that observed in the VRC01 treated participants. By assuming a homogeneous viral population sensitive to VRC01, the model provides good fits to all of the participant data. However, the fits are improved by assuming that there were two populations of virus, one more susceptible to antibody-mediated neutralization than the other.
A History of Endometriosis Is Associated With Decreased Peripheral NK Cytotoxicity and Increased Infiltration of Uterine CD68+ Macrophages
Authors: Wang Linlin , Li Longfei , Li Yuye , Huang Chunyu , Lian Ruochun , Wu Tonghua , Ma Jingwen , Zhang Yan , Cheng Yanxiang , Diao Lianghui , Zeng Yong
Published: September 2021

Women with endometriosis may have a defective immune system. However, evidence of the immune responses of endometriosis patients with a history of endometriosis surgery is lacking, and the association between the location of endometriosis lesions and immune responses is unclear. This retrospective study included 117 females with reproductive failure and a history of endometriosis and 200 females with reproductive failure but without endometriosis to analyze their endometrial and peripheral immune responses. The results show that endometriosis was associated with decreased peripheral natural killer (NK) cytotoxicity and increased uterine macrophages. Peripheral NK cytotoxicity at effector-to-target ratios of 25:1 and 50:1 was significantly reduced in women with a history of endometriosis from that of the control group (26.6% versus 33.3% and 36.1% versus 43.3%, respectively, both P < 0.001). Furthermore, after further division of patients into three subgroups according to the location of endometriosis lesions, we observed that NK cytotoxicity in the endometriosis subgroups, especially the mixed endometriosis group, was strongly decreased from that of the controls (P = 0.001). The endometrial CD68+ macrophage proportion in the mixed endometriosis subgroup was higher than that in the control group (2.8% versus 2.1%, P = 0.043). In addition, the baseline estradiol (E2) level was weakly correlated with the percentage of endometrial macrophages (r = 0.251, P = 0.009), indicating a potential association among the endocrine system, endometrial immune environment, and endometriosis. This study indicated that peripheral NK cytotoxicity and endometrial immune cell profiles could be useful for diagnosing and treating endometriosis and endometriosis-related reproductive diseases.
Mycobacterium tuberculosis-Specific T Cell Functional, Memory, and Activation Profiles in QuantiFERON-Reverters Are Consistent With Controlled Infection
Authors: Mpande Cheleka A. M. , Steigler Pia , Lloyd Tessa , Rozot Virginie , Mosito Boitumelo , Schreuder Constance , Reid Timothy D. , Bilek Nicole , Ruhwald Morten , Andrews Jason R. , Hatherill Mark , Little Francesca , Scriba Thomas J. , Nemes Elisa
Published: September 2021

Reversion of immune sensitization tests for Mycobacterium tuberculosis (M.tb) infection, such as interferon-gamma release assays or tuberculin skin test, has been reported in multiple studies. We hypothesized that QuantiFERON-TB Gold (QFT) reversion is associated with a decline of M.tb-specific functional T cell responses, and a distinct pattern of T cell and innate responses compared to persistent QFT+ and QFT- individuals. We compared groups of healthy adolescents (n=~30 each), defined by four, 6-monthly QFT tests: reverters (QFT+/+/-/-), non-converters (QFT-/-/-/-) and persistent positives (QFT+/+/+/+). We stimulated peripheral blood mononuclear cells with M.tb antigens (M.tb lysate; CFP-10/ESAT-6 and EspC/EspF/Rv2348 peptide pools) and measured M.tb-specific adaptive T cell memory, activation, and functional profiles; as well as functional innate (monocytes, natural killer cells), donor-unrestricted T cells (DURT: γδ T cells, mucosal-associated invariant T and natural killer T-like cells) and B cells by flow cytometry. Projection to latent space discriminant analysis was applied to determine features that best distinguished between QFT reverters, non-converters and persistent positives. No longitudinal changes in immune responses to M.tb were observed upon QFT reversion. M.tb-specific Th1 responses detected in reverters were of intermediate magnitude, higher than responses in QFT non-converters and lower than responses in persistent positives. About one third of reverters had a robust response to CFP-10/ESAT-6. Among those with measurable responses, lower proportions of TSCM (CD45RA+CCR7+CD27+) and early differentiated (CD45RA-) IFN-γ-TNF+IL-2- M.tb lysate-specific CD4+ cells were observed in reverters compared with non-converters. Conversely, higher proportions of early differentiated and lower proportions of effector (CD45RA-CCR7-) CFP10/ESAT6-specific Th1 cells were observed in reverters compared to persistent-positives. No differences in M.tb-specific innate, DURT or B cell functional responses were observed between the groups. Statistical modelling misclassified the majority of reverters as non-converters more frequently than they were correctly classified as reverters or misclassified as persistent positives. These findings suggest that QFT reversion occurs in a heterogeneous group of individuals with low M.tb-specific T cell responses. In some individuals QFT reversion may result from assay variability, while in others the magnitude and differentiation status of M.tb-specific Th1 cells are consistent with well-controlled M.tb infection.
Harnessing Treg Homeostasis to Optimize Posttransplant Immunity: Current Concepts and Future Perspectives
Authors: Ikegawa Shuntaro , Matsuoka Ken-ichi
Published: September 2021

CD4+CD25+Foxp3+regulatory T cells (Tregs) are functionally distinct subsets of mature T cells with broad suppressive activity and have been shown to play an important role in the establishment of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT). Tregs exhibit an activated phenotype from the stage of emigration from the thymus and maintain continuous proliferation in the periphery. The distinctive feature in homeostasis enables Tregs to respond sensitively to small environmental changes and exert necessary and sufficient immune suppression; however, on the other hand, it also predisposes Tregs to be susceptible to apoptosis in the inflammatory condition post-transplant. Our studies have attempted to define the intrinsic and extrinsic factors affecting Treg homeostasis from the acute to chronic phases after allogeneic HSCT. We have found that altered cytokine environment in the prolonged post-HSCT lymphopenia or peri-transplant use of immune checkpoint inhibitors could hamper Treg reconstitution, leading to refractory graft-versus-host disease. Using murine models and clinical trials, we have also demonstrated that proper intervention with low-dose interleukin-2 or post-transplant cyclophosphamide could restore Treg homeostasis and further amplify the suppressive function after HSCT. The purpose of this review is to reconsider the distinctive characteristics of post-transplant Treg homeostasis and discuss how to harness Treg homeostasis to optimize posttransplant immunity for developing a safe and efficient therapeutic strategy.
Application of Genetic Studies to Flow Cytometry Data and Its Impact on Therapeutic Intervention for Autoimmune Disease
Authors: Orrù Valeria , Steri Maristella , Cucca Francesco , Fiorillo Edoardo
Published: September 2021

In recent years, systematic genome-wide association studies of quantitative immune cell traits, represented by circulating levels of cell subtypes established by flow cytometry, have revealed numerous association signals, a large fraction of which overlap perfectly with genetic signals associated with autoimmune diseases. By identifying further overlaps with association signals influencing gene expression and cell surface protein levels, it has also been possible, in several cases, to identify causal genes and infer candidate proteins affecting immune cell traits linked to autoimmune disease risk. Overall, these results provide a more detailed picture of how genetic variation affects the human immune system and autoimmune disease risk. They also highlight druggable proteins in the pathogenesis of autoimmune diseases; predict the efficacy and side effects of existing therapies; provide new indications for use for some of them; and optimize the research and development of new, more effective and safer treatments for autoimmune diseases. Here we review the genetic-driven approach that couples systematic multi-parametric flow cytometry with high-resolution genetics and transcriptomics to identify endophenotypes of autoimmune diseases for the development of new therapies.
Cellular Therapies in Solid Organ Allotransplantation: Promise and Pitfalls
Authors: Shaw Brian I. , Ord Jeffrey R. , Nobuhara Chloe , Luo Xunrong
Published: September 2021

Donor specific transfusions have been the basis of tolerance inducing protocols since Peter Medawar showed that it was experimentally feasible in the 1950s. Though trials of cellular therapies have become increasingly common in solid organ transplantation, they have not become standard practice. Additionally, whereas some protocols have focused on cellular therapies as a method for donor antigen delivery—thought to promote tolerance in and of itself in the correct immunologic context—other approaches have alternatively focused on the intrinsic immunosuppressive properties of the certain cell types with less emphasis on their origin, including mesenchymal stem cells, regulatory T cells, and regulatory dendritic cells. Regardless of intent, all cellular therapies must contend with the potential that introducing donor antigen in a new context will lead to sensitization. In this review, we focus on the variety of cellular therapies that have been applied in human trials and non-human primate models, describe their efficacy, highlight data regarding their potential for sensitization, and discuss opportunities for cellular therapies within our current understanding of the immune landscape.
Fas/FasL Contributes to HSV-1 Brain Infection and Neuroinflammation
Authors: Krzyzowska Malgorzata , Kowalczyk Andrzej , Skulska Katarzyna , Thörn Karolina , Eriksson Kristina
Published: September 2021

The Fas/FasL pathway plays a key role in immune homeostasis and immune surveillance. In the central nervous system (CNS) Fas/FasL is involved in axonal outgrowth and adult neurogenesis. However, little is known about the role of the Fas/FasL pathway in herpes encephalitis. In this study, we used a neuropathogenic clinical strain of herpes simplex virus type 1 (HSV-1) to explore infection-induced inflammation and immune responses in the mouse brain and the role of Fas/FasL in antiviral CNS immunity. HSV-1 CNS infection induced the infiltration of Fas- FasL-bearing monocytes and T cells in the brain and also to an up-regulation of Fas and FasL expression on resident astrocytes and microglia within infected sites. Upon infection, Fas- and FasL-deficient mice (lpr and gld) were partially protected from encephalitis with a decreased morbidity and mortality compared to WT mice. Fas/FasL deficiency promoted cell-mediated immunity within the CNS. Fas receptor stimulation abrogated HSV-1 induced activation and inflammatory reactions in microglia from WT mice, while lack of Fas or FasL led to a more pronounced activation of monocytes and microglia and also to an enhanced differentiation of these cells into a pro-inflammatory M1 phenotype. Furthermore, the specific immune system was more efficient in Fas- and FasL-deficient mice with significantly higher numbers of infiltrating HSV-1-specific cytotoxic T cells in the brain. Our data indicate that the Fas/FasL pathway leads to excessive neuroinflammation during HSV-1 infection, which is associated with a diminished anti-viral response and an excessive neuroinflammation.
Transcriptional Changes in Regulatory T Cells From Patients With Autoimmune Polyendocrine Syndrome Type 1 Suggest Functional Impairment of Lipid Metabolism and Gut Homing
Authors: Berger Amund Holte , Bratland Eirik , Sjøgren Thea , Heimli Marte , Tyssedal Torgeir , Bruserud Øyvind , Johansson Stefan , Husebye Eystein Sverre , Oftedal Bergithe Eikeland , Wolff Anette Susanne Bøe
Published: September 2021

Autoimmune polyendocrine syndrome type I (APS-1) is a monogenic model disorder of organ-specific autoimmunity caused by mutations in theAutoimmune regulator (AIRE)gene. AIRE facilitates the expression of organ-specific transcripts in the thymus, which is essential for efficient removal of dangerous self-reacting T cells and for inducing regulatory T cells (Tregs). Although reduced numbers and function of Tregs have been reported in APS-I patients, the impact of AIRE deficiency on gene expression in these cells is unknown. Here, we report for the first time on global transcriptional patterns of isolated Tregs from APS-1 patients compared to healthy subjects. Overall, we found few differences between the groups, although deviant expression was observed for the genesTMEM39B, SKIDA1, TLN2, GPR15, FASN, BCAR1, HLA-DQA1, HLA-DQB1, HLA-DRA, GPSM3 and AKR1C3.Of significant interest, the consistent downregulation ofGPR15may indicate failure of Treg gut homing which could be of relevance for the gastrointestinal manifestations commonly seen in APS-1. UpregulatedFASNexpression in APS-1 Tregs points to increased metabolic activity suggesting a putative link to faulty Treg function. Functional studies are needed to determine the significance of these findings for the immunopathogenesis of APS-1 and for Treg immunobiology in general.
Therapeutic Targeting of Immune Cell Autophagy in Multiple Sclerosis: Russian Roulette or Silver Bullet?
Authors: Yang Guan , Van Kaer Luc
Published: September 2021

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) in which the immune system damages the protective insulation surrounding nerve fibers that project from neurons. The pathological hallmark of MS is multiple areas of myelin loss accompanied by inflammation within the CNS, resulting in loss of cognitive function that ultimately leads to paralysis. Recent studies in MS have focused on autophagy, a cellular self-eating process, as a potential target for MS treatment. Here, we review the contribution of immune cell autophagy to the pathogenesis of experimental autoimmune encephalomyelitis (EAE), the prototypic animal model of MS. A better understanding of the role of autophagy in different immune cells to EAE might inform the development of novel therapeutic approaches in MS and other autoimmune and inflammatory diseases.
Common Transcriptomic Effects of Abatacept and Other DMARDs on Rheumatoid Arthritis Synovial Tissue
Authors: Triaille Clement , Durez Patrick , Sokolova Tatiana , Tilman Gaëlle , Méric de Bellefon Laurent , Galant Christine , Coulie Pierre , Lauwerys Bernard R. , Limaye Nisha
Published: September 2021

Objectives

Our goal was to assess for the histological and transcriptomic effects of abatacept on RA synovia, and to compare them with previously published data from four other DMARDs: tocilizumab, rituximab, methotrexate, and adalimumab.

Methods

Synovial tissue was obtained using ultrasound-guided biopsy from affected joints of 14 patients, before and 16 weeks after treatment with subcutaneous abatacept 125 mg weekly. Paraffin-sections were stained and scored for CD3+, CD20+, and CD68+ cell infiltration. Transcriptional profiling was performed using GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix) and analyzed on Genespring GX (Agilent). Pathway analyses were performed on Genespring GX, Metascape, and EnrichR.

Results

Gene expression analysis identified 304 transcripts modulated by abatacept in synovial tissue. Downregulated genes were significantly enriched for immune processes, strongly overlapping with our findings on other therapies. Data were pooled across these studies, revealing that genes downregulated by DMARDs are significantly enriched for both T-cell and myeloid leukocyte activation pathways. Interestingly, DMARDs seem to have coordinate effects on the two pathways, with a stronger impact in good responders to therapy as compared to moderate and non-responders.

Conclusion

We provide evidence that the effects of five DMARDs on the RA synovium culminate in the same pathways. This confirms previous studies suggesting the existence of common mediators downstream of DMARDs, independent of their primary targets.
Varicocele-Mediated Male Infertility: From the Perspective of Testicular Immunity and Inflammation
Authors: Fang Yiwei , Su Yufang , Xu Jia , Hu Zhiyong , Zhao Kai , Liu Chunyan , Zhang Huiping
Published: September 2021

Background

Varicocele (VC) is present in 35 - 40% of men with infertility. However, current surgical and antioxidant treatments are not completely effective. In addition to oxidative stress, it is likely that other factors such as testicular immune microenvironment disorder contribute to irreversible testicular. Evidence suggests that VC is associated with anti-sperm antibodies (ASAs), spermatogenesis and testosterone secretion abnormalities, and testicular cytokine production. Moreover, inhibition of inflammation can alleviate VC-mediated pathogenesis. The normal function of the testis depends on its immune tolerance mechanism. Testicular immune regulation is complex, and many infectious or non-infectious diseases may damage this precision system.

Results

The testicular immune microenvironment is composed of common immune cells and other cells involved in testicular immunity. The former includes testicular macrophages, T cells, dendritic cells (DCs), and mast cells, whereas the latter include Leydig cells and Sertoli cells (SCs). In animal models and in patients with VC, most studies have revealed an abnormal increase in the levels of ASAs and pro-inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha in the seminal plasma, testicular tissue, and even peripheral blood. It is also involved in the activation of potential inflammatory pathways, such as the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing (NLRP)-3 pathway. Finally, the development of VC-mediated infertility (VMI) may be facilitated by abnormal permeability of proteins, such as claudin-11, that constitute the blood-testis barrier (BTB).

Conclusions

The testicular immune response, including the production of ASAs and inflammatory factors, activation of inflammatory pathways, and destruction of the BTB may be involved in the pathogenesis of VMI it is necessary to further explore how patient outcomes can be improved through immunotherapy.
The Toll-Like Receptor 2 Ligand Pam2CSK4 Activates Platelet Nuclear Factor-κB and Bruton’s Tyrosine Kinase Signaling to Promote Platelet-Endothelial Cell Interactions
Authors: Parra-Izquierdo Iván , Lakshmanan Hari Hara Sudhan , Melrose Alexander R. , Pang Jiaqing , Zheng Tony J. , Jordan Kelley R. , Reitsma Stéphanie E. , McCarty Owen J. T. , Aslan Joseph E.
Published: September 2021

Circulating platelets establish a variety of immunological programs and orchestrate inflammatory responses at the endothelium. Platelets express the innate immunity family of Toll-like receptors (TLRs). While TLR2/TLR1 ligands are known to activate platelets, the effects of TLR2/TLR6 ligands on platelet function remain unclear. Here, we aim to determine whether the TLR2/TLR6 agonists Pam2CSK4 and FSL-1 activate human platelets. In addition, human umbilical vein endothelial cells (HUVECs) and platelets were co-cultured to analyze the role of platelet TLR2/TLR6 on inflammation and adhesion to endothelial cells. Pam2CSK4, but not FSL-1, induced platelet granule secretion and integrin αIIbβ3 activation in a concentration-dependent manner. Moreover, Pam2CSK4 promoted platelet aggregation and increased platelet adhesion to collagen-coated surfaces. Mechanistic studies with blocking antibodies and pharmacologic inhibitors demonstrated that the TLR2/Nuclear factor-κB axis, Bruton’s-tyrosine kinase, and a secondary ADP feedback loop are involved in Pam2CSK4-induced platelet functional responses. Interestingly, Pam2CSK4 showed cooperation with immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling to enhance platelet activation. Finally, the presence of platelets increased inflammatory responses in HUVECs treated with Pam2CSK4, and platelets challenged with Pam2CSK4 showed increased adhesion to HUVECs under static and physiologically relevant flow conditions. Herein, we define a functional role for platelet TLR2-mediated signaling, which may represent a druggable target to dampen excessive platelet activation in thrombo-inflammatory diseases.
Dysregulated Maresin Concentrations in Plasma and Nasal Secretions From Patients With Chronic Rhinosinusitis
Authors: Beegun Issa , Koenis Duco S. , Alusi Ghassan , Dalli Jesmond
Published: September 2021

The mechanisms that lead to disease onset and propagation in patients with chronic rhinosinusitis (CRS) are not fully elucidated. Maresins (MaR) are a family of essential fatty acid-derived lipid mediators that play a central role in the regulation of inflammation with several studies demonstrating that these mediators display protective activities in airway inflammation. Therefore, in the present studies we evaluated whether concentrations of these mediators were altered in both peripheral blood and nasal secretions from CRS patients. Herein, we focused on patients with CRS that also develop nasal polyps (CRSwNP), given that therapeutic options for the treatment of these patients are limited. Thereby, insights into disease mechanisms in these patients may help design more effective treatments. For this purpose, we compared maresin concentrations from CRSwNP patients with those found in healthy volunteers or patients with an upper respiratory tract infection (URTI), as a self-resolving inflammatory condition. Using liquid chromatography tandem mass spectrometry, we found that MaR concentrations were significantly decreased in plasma from patients with CRSwNP when compared to healthy volunteers. MaR concentrations were observed to be significantly upregulated in nasal secretions from patients with CRSwNP when compared with both healthy volunteers and URTI subjects. Concentration of these mediators in both plasma and nasal secretions from CRSwNP patients were positively correlated with quality-of-life scores in these patients. Assessment of the concentrations of other pro-resolving and pro-inflammatory lipid mediators (LM) demonstrated that there was a general shift in LM levels in both plasma and nasal secretions from CRSwNP when compared with healthy volunteers and URTI subjects. Of note, incubation of peripheral blood cells from CRSwNP patients with MaR1 downregulated the expression of activation markers on peripheral blood phagocytes, including CD41 and CD62P, markers of platelet-leukocyte heterotypic aggregates. Together these findings demonstrate that both local and systemic LM concentrations, in particularly those of the MaR family, become altered in patients with CRSwNP. They also suggest that therapeutics designed around MaR1 may be useful in regulating the activation of phagocytes in patients with CRSwNP thereby potentially also limiting the local inflammatory response in these patients.
Comparison of Outcomes of Kidney Transplantation From Extremely Low Body Weight ≤5kg Versus Larger Body Weight Pediatric Donors
Authors: Peng Jiawei , Dai Helong , Zhang Hedong , Yu Shaojie , Xie Xubiao , Peng Fenghua , Lan Gongbin , Hu Shanbiao , Wang Yu , Tang Xiaotian , Guo Yong , Gao Chen , Fang Chunhua , Nie Manhua , Yuan Xiaoqiong , Zhong Mingda , Tang Zhouqi , Li Tengfang , Sun Siyu , Yao Hengchang , Hou Jianfei , Huang Ruixue , Peng Longkai
Published: September 2021

Background

Kidney transplantation from donors who weigh ≤5 kg is performed at only a few transplant centers owing to the high complication and low graft survival rates associated with this approach.

Methods

We retrospectively compared the results of kidney transplantation at our center between January 2015 and December 2019 based on the following pediatric donor criteria: donor body weight ≤5 kg (n=32), 5 kg< donor weight ≤20 kg (n=143), and donor weight >20 kg (n=110). We also perform subgroup analysis of kidney transplantation outcomes from ≤5 kg donors, using conventional (dual separate and classic en-bloc KTx)/novel (en-bloc KTx with outflow tract) surgical methods and allocating to adult/pediatric recipients.

Results

The death-censored graft survival rates from extremely low body weight ≤5kg at 1 month, and 1, 3, and 5 years were 90.6%, 80.9%, 77.5%, and 73.9%, respectively, which were significantly lower than that from larger body weight pediatric donors. However, the 3-, and 5-year post-transplantation eGFRs were not significantly different between the pediatric and adult recipient group. The thrombosis (18.8%) and urinary leakage (18.8%) rates were significantly higher in the donor weight ≤5 kg group. Compared with 5 kg< donor weight ≤20 kg group, donor weight ≤5kg group was at elevated risk of graft loss due to thrombosis (OR: 13.4) and acute rejection (OR: 6.7). No significant difference on the outcomes of extremely low body weight donor kidney transplantation was observed between adults and pediatric recipients. Urinary leakage rate is significantly lower in the novel operation (8.7%) than in the conventional operation group (44.4%).

Conclusions

Although the outcomes of donor body weight ≤5kg kidney transplantation is inferior to that from donors with large body weight, it can be improved through technical improvement. Donors with body weight ≤5 kg can be considered as an useful source to expand the donor pool.
Regional Variation in Communities of Demersal Fishes and Scavengers Across the CCZ and Pacific Ocean
Authors: Drazen Jeffrey C. , Leitner Astrid B. , Jones Daniel O. B. , Simon-Lledó Erik
Published: September 2021

We synthesize and analyze data from visual transecting approaches and baited camera studies to evaluate fish and invertebrate scavenger communities across the Clarion-Clipperton Zone (CCZ), an area of intense deep-sea mining interest, and neighboring areas of the abyssal Pacific. In abyssal regions including the CCZ most of the top predators are large mobile fishes and crustaceans, and the majority of these are also opportunistic scavengers. Top predators can exert important ecosystem influences and they can be susceptible to sustained anthropogenic disturbances, necessitating their study in the CCZ mining region. In total 157 baited camera deployments from 3 mining exploration license areas, 4 APEIs (Areas of Particular Environmental Interest – one type of no mining zone) and 4 other areas in the Pacific (Hawaii, California, New Zealand and Guam) and 122 visual transects from 7 exploration license areas, 4 no mining zones, and the Peru Basin (DISCOL area) were examined. Many taxa were observed in both sampling techniques but visual transects viewed few fishes overall. Fish and scavenger communities and diversity varied across the CCZ, significantly for baited camera data with a parallel but insignificant pattern for visual transects suggesting that even for these highly mobile species, not all regions of the CCZ are equivalent and the CCZ cannot be managed as one homogenous region. Further CCZ communities were different than communities elsewhere in the abyssal Pacific. The regional variations in community composition are largely the result of varying abundances of species rather than species presence/absence given that most, but not all, of the fishes and scavengers observed have very large ranges. On a more local scale, seamounts had a significantly different scavenger community than neighboring abyssal plains and thus contribute to regional diversity. Visual transect data revealed a similar but insignificant pattern due to low sample sizes. Given the coarse spatial resolution of sampling of fish and scavenger communities in the CCZ, it is not possible to evaluate if no mining zones (APEIs) adequately represent these communities nor where, or if, any biogeographic boundaries exist in the CCZ region. It is possible to conclude that a network of APEIs that covers the spectrum of available habitats at regional and more local scales will be key to conserving fish and scavenger biodiversity.
3D Photogrammetry Modeling Highlights Efficient Reserve Effect Apparition After 5 Years and Stillness After 40 for Red Coral (Corallium rubrum) Conservation in French MPAs
Authors: Richaume Justine , Cheminée Adrien , Drap Pierre , Bonhomme Patrick , Cadene Frederic , Ferrari Bruno , Hartmann Virginie , Michez Noëmie , Bianchimani Olivier
Published: September 2021

Imaging the marine environment is more and more useful to understand relationships between species, as well as natural processes. Developing photogrammetry allowed the use of 3D measuring to study populations dynamics of sessile organisms at various scales: from colony to population. This study focuses on red coral (Corallium rubrum), as known as precious coral. Metrics measured at a colony scale (e.g., maximum height, diameter and number of branches) allowed population understanding and a comparison between an old (Cerbère-Banyuls reserve) vs. a new (Calanques National Park) MPA. Our results suggested a 5-year time step allows the appearance of a significant difference between populations inside vs. outside the Calanques National Park no-take zones. Red coral colonies were taller and had more branches inside no-take zones. A significant difference was still observable for the populations inside the Cerbère-Banyuls reserve after 40 years of protection, reflecting the sustainability and effectiveness of precautionary measures set by the reserve. The impacts at the local level (mechanical destruction) and those presumed to occur via global change (climatic variations) underline the need to develop strategies both to follow the evolutions of red coral populations but also to understand their resilience. Photogrammetry induced modeling is a time and cost effective as well as non-invasive method which could be used to understand population dynamics at a seascape scale on coralligenous reefs.