bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural plasticity in I-Ag7 links autoreactivity to hybrid insulin peptides in type I diabetes
Authors: Erausquin Elena , Serra Pau , Parras Daniel , Santamaria Pere , López-Sagaseta Jacinto
Published: July 2022

We recently provided evidence for promiscuous recognition of several different hybrid insulin peptides (HIPs) by the highly diabetogenic, I-Ag7-restricted 4.1-T cell receptor (TCR). To understand the structural determinants of this phenomenon, we solved the structure of an agonistic HIP/I-Ag7complex, both in isolation as well as bound to the 4.1-TCR. We find that HIP promiscuity of the 4.1-TCR is dictated, on the one hand, by an amino acid sequence pattern that ensures I-Ag7binding and, on the other hand, by the presence of three acidic residues at positions P5, P7 and P8 that favor an optimal engagement by the 4.1-TCR’s complementary determining regions. Surprisingly, comparison of the TCR-bound and unbound HIP/I-Ag7structures reveals that 4.1-TCR binding triggers several novel and unique structural motions in both the I-Ag7molecule and the peptide that are essential for docking. This observation indicates that the type 1 diabetes-associated I-Ag7molecule is structurally malleable and that this plasticity allows the recognition of multiple peptides by individual TCRs that would otherwise be unable to do so.
Emerging translational strategies and challenges for enhancing regulatory T cell therapy for graft-versus-host disease
Authors: Hippen Keli L. , Hefazi Mehrdad , Larson Jemma H. , Blazar Bruce R.
Published: July 2022

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for many types of cancer. Genetic disparities between donor and host can result in immune-mediated attack of host tissues, known as graft versus host disease (GVHD), a major cause of morbidity and mortality following HSCT. Regulatory CD4+ T cells (Tregs) are a rare cell type crucial for immune system homeostasis, limiting the activation and differentiation of effector T cells (Teff) that are self-reactive or stimulated by foreign antigen exposure. Adoptive cell therapy (ACT) with Treg has demonstrated, first in murine models and now in patients, that prophylactic Treg infusion can also suppress GVHD. While clinical trials have demonstrated Treg reduce severe GVHD occurrence, several impediments remain, including Treg variability and practical need for individualized Treg production for each patient. Additionally, there are challenges in the use of in vitro expansion techniques and in achieving in vivo Treg persistence in context of both immune suppressive drugs and in lymphoreplete patients being treated for GVHD. This review will focus on 3 main translational approaches taken to improve the efficacy of tTreg ACT in GVHD prophylaxis and development of treatment options, following HSCT: genetic modification, manipulating TCR and cytokine signaling, and Treg production protocols. In vitro expansion for Treg ACT presents a multitude of approaches for gene modification to improve efficacy, including: antigen specificity, tissue targeting, deletion of negative regulators/exhaustion markers, resistance to immunosuppressive drugs common in GVHD treatment. Such expansion is particularly important in patients without significant lymphopenia that can drive Treg expansion, enabling a favorable Treg:Teff ratio in vivo. Several potential therapeutics have also been identified that enhance tTreg stability or persistence/expansion following ACT that target specific pathways, including: DNA/histone methylation status, TCR/co-stimulation signaling, and IL-2/STAT5 signaling. Finally, this review will discuss improvements in Treg production related to tissue source, Treg subsets, therapeutic approaches to increase Treg suppression and stability during tTreg expansion, and potential for storing large numbers of Treg from a single production run to be used as an off-the-shelf infusion product capable of treating multiple recipients.
Cystic fibrosis transmembrane regulator correction attenuates heart failure-induced lung inflammation
Authors: Uhl Franziska E. , Vanherle Lotte , Meissner Anja
Published: July 2022

Heart failure (HF) affects 64 million people worldwide. Despite advancements in prevention and therapy, quality of life remains poor for many HF patients due to associated target organ damage. Pulmonary manifestations of HF are well-established. However, difficulties in the treatment of HF patients with chronic lung phenotypes remain as the underlying patho-mechanistic links are still incompletely understood. Here, we aim to investigate the cystic fibrosis transmembrane regulator (CFTR) involvement in lung inflammation during HF, a concept that may provide new mechanism-based therapies for HF patients with pulmonary complications. In a mouse model of HF, pharmacological CFTR corrector therapy (Lumacaftor (Lum)) was applied systemically or lung-specifically for 2 weeks, and the lungs were analyzed using histology, flow cytometry, western blotting, and qPCR. Experimental HF associated with an apparent lung phenotype characterized by vascular inflammation and remodeling, pronounced tissue inflammation as evidenced by infiltration of pro-inflammatory monocytes, and a reduction of pulmonary CFTR+ cells. Moreover, the elevation of a classically-activated phenotype of non-alveolar macrophages coincided with a cell-specific reduction of CFTR expression. Pharmacological correction of CFTR with Lum mitigated the HF-induced downregulation of pulmonary CFTR expression and increased the proportion of CFTR+ cells in the lung. Lum treatment diminished the HF-associated elevation of classically-activated non-alveolar macrophages, while promoting an alternatively-activated macrophage phenotype within the lungs. Collectively, our data suggest that downregulation of CFTR in the HF lung extends to non-alveolar macrophages with consequences for tissue inflammation and vascular structure. Pharmacological CFTR correction possesses the capacity to alleviate HF-associated lung inflammation.
Bacterial subversion of NLR-mediated immune responses
Authors: Kienes Ioannis , Johnston Ella L. , Bitto Natalie J. , Kaparakis-Liaskos Maria , Kufer Thomas A.
Published: July 2022

Members of the mammalian Nod-like receptor (NLR) protein family are important intracellular sensors for bacteria. Bacteria have evolved under the pressure of detection by host immune sensing systems, leading to adaptive subversion strategies to dampen immune responses for their benefits. These include modification of microbe-associated molecular patterns (MAMPs), interception of innate immune pathways by secreted effector proteins and sophisticated instruction of anti-inflammatory adaptive immune responses. Here, we summarise our current understanding of subversion strategies used by bacterial pathogens to manipulate NLR-mediated responses, focusing on the well-studied members NOD1/2, and the inflammasome forming NLRs NLRC4, and NLRP3. We discuss how bacterial pathogens and their products activate these NLRs to promote inflammation and disease and the range of mechanisms used by bacterial pathogens to evade detection by NLRs and to block or dampen NLR activation to ultimately interfere with the generation of host immunity. Moreover, we discuss how bacteria utilise NLRs to facilitate immunotolerance and persistence in the host and outline how various mechanisms used to attenuate innate immune responses towards bacterial pathogens can also aid the host by reducing immunopathologies. Finally, we describe the therapeutic potential of harnessing immune subversion strategies used by bacteria to treat chronic inflammatory conditions.
MDA5 signaling induces type 1 IFN- and IL-1-dependent lung vascular permeability which protects mice from opportunistic fungal infection
Authors: Davis Michael J. , Martin Rachel E. , Pinheiro Giovana M. , Hoke Elizabeth S. , Moyer Shannon , Mayer-Barber Katrin D. , Chang Yun C. , Kwon-Chung Kyung J.
Published: July 2022

Lungs balance threat from primary viral infection, secondary infection, and inflammatory damage. Severe pulmonary inflammation induces vascular permeability, edema, and organ dysfunction. We previously demonstrated that poly(I:C) (pICLC) induced type 1 interferon (t1IFN) protected mice fromCryptococcus gattii(Cg)vialocal iron restriction. Here we show pICLC increased serum protein and intravenously injected FITC-dextran in the lung airspace suggesting pICLC induces vascular permeability. Interestingly, pICLC induced a pro-inflammatory signature with significant expression of IL-1 and IL-6 which depended on MDA5 and t1IFN. Vascular permeability depended on MDA5, t1IFN, IL-1, and IL-6. T1IFN also induced MDA5 and other MDA5 signaling components suggesting that positive feedback contributes to t1IFN dependent expression of the pro-inflammatory signature. Vascular permeability, induced by pICLC or another compound, inhibited Cg by limiting iron. These data suggest that pICLC induces t1IFN which potentiates pICLC-MDA5 signaling increasing IL-1 and IL-6 resulting in leakage of antimicrobial serum factors into lung airspace. Thus, induced vascular permeability may act as an innate defense mechanism against opportunistic fungal infection, such as cryptococcosis, and may be exploited as a host-directed therapeutic target.
Genomic analysis quantifies pyroptosis in the immune microenvironment of HBV-related hepatocellular carcinoma
Authors: Li Jiarui , Yu Jinghui , Zhang Ting , Pu Xingyu , Li Yilan , Wu Zhongjun
Published: July 2022

Pyroptosis, a way of pro-inflammatory death, plays a significant part in the tumor microenvironment (TME). A recent study has shown that the hepatitis C virus changes the TME by inducing pyroptosis against hepatocellular carcinoma (HCC). However, compared to TME in hepatitis C virus-infected HCC, the exploration of immune characteristics and response to immunotherapy associated with the pyroptosis phenotype is still insufficient in hepatitis B virus-related HCC (HBV-HCC). Our study constructed pyroptosis-score (PYS) via principal-component analysis (PCA) to unveil the link between pyroptosis and tumor immunity in 369 HBV-HCC patients. Compared with the low-PYS group, subjects with higher PYS were associated with poor prognosis but were more susceptible to anti-PD-L1 treatment. In addition, we found that PYS can serve independently as a prognostic factor for HBV-HCC, making it possible for us to identify specific small molecule drugs with a potential value in inhibiting tumors via targeting pyroptosis. Also, the target genes predicted by the Weighted gene co-expression network analysis (WGCNA) and pharmacophore model were enriched in the HIF-1 signaling pathway and NF-kB transcription factor activity, which were related to the mechanism of inflammation-driven cancer. The PYS is extremely important in predicting prognosis and responses to immunotherapy. New treatment strategies for inflammation-driven cancers may be found by targeting pyroptosis.
Increased frequency of TIGIT+ CD4 T Cell subset in autoantibody-positive first-degree relatives of patients with rheumatoid arthritis
Authors: Anaparti Vidyanand , Tanner Stacy , Zhang Christine , O’Neil Liam , Smolik Irene , Meng Xiaobo , Marshall Aaron J. , El-Gabalawy Hani
Published: July 2022

Background

Despite immune cell dysregulation being an important event preceding the onset of rheumatoid arthritis (RA), the phenotype of T and B cells in preclinical RA is less understood. The aim of this study was to characterize T and B cell populations in RA patients and their autoantibody (aAb) negative and positive first-degree relatives (FDR).

Methods

Cryopreserved peripheral blood mononuclear cells (PBMCs) collected at scheduled visits from aAb-(n=25), and aAb+ FDR (n=10) and RA patients (n=13) were thawed and stained using optimized antibody cocktails as per a specific 13-color T or B cell panel. Immunophenotyping was performed using a Cytoflex LX (Beckman-Coulter) flow cytometer and FlowJo software was used for analyzing the frequency of immune cell populations.

Results

Multicolor flow cytometry experiments identified an increased TIGIT expression in circulating lymphocytes of aAb+ FDR and RA patients, relative to aAb- FDR (P<0.01). These TIGIT+ T cells exhibited a memory phenotype and expressed high levels of PD-1, ICOS, HLA-DR, CXCR3 and CXCR5. Moreover, increased TIGIT+ CD4 T cell frequency correlated with the frequency of PD-1+ CD4 T cells (r = 0.4705: P = 0.0043) and circulating levels of ACPA and RF. We also identified a decreased frequency of CD27+IgD- switched memory B cells in RA patients (P < 0.01), while increased frequency of TIGIT+ CD4 T cells in FDR correlated with the frequency of PD1+PTEN+ B cells (r = 0.6838, P = 0.0004) and autoantibody positivity (P = 0.01).

Conclusion

We demonstrate TIGIT as a distinct CD4 T cell marker for differentiating aAb- FDR from aAb+FDR and might play a critical role in regulating T and B cell crosstalk in preclinical RA.
Integrative lipidomic features identify plasma lipid signatures in chronic urticaria
Authors: Li Jie , Li Liqiao , Liu Runqiu , Zhu Lei , Zhou Bingjing , Xiao Yi , Hou Guixue , Lin Liang , Chen Xiang , Peng Cong
Published: July 2022

Chronic urticaria (CU) is a chronic inflammatory skin disease mainly mediated by mast cells. Lipids exert essential functions in biological processes; however, the role of lipids in CU remains unclear. Nontargeted lipidomics was performed to investigate the differential lipid profiles between CU patients and healthy control (HC) subjects. Functional validation studies were performed in vitro and in vivo including β-hexosaminidase release examination from mast cells and passive cutaneous anaphylaxis (PCA) mouse model. We detected dramatically altered glycerophospholipids in CU patients compared with HCs. Phosphatidylserine (PS), phosphatidylethanolamine (PE), and phosphatidylglycerol (PG) were increased, while phosphatidylcholine (PC) was reduced in CU patients. The reduction in PC was related to a high weekly urticaria activity score (UAS7), while PS was positively associated with the dermatology life quality index (DLQI). We also identified the differential lipid profiles between chronic spontaneous urticaria (CSU), symptomatic dermographism (SD), and CSU coexist with SD. CU patients were classified into two subtypes (subtype 1 and subtype 2) based on consensus clustering of lipid profiling. Compared with patients in subtype 2, patients in subtype 1 had elevated levels of PC (18:0e/18:2) and PE (38:2), and lower urticaria control test (UCT) scores indicated worse clinical efficiency of secondary generation H1 antihistamines treatment. Importantly, we found that supplementation with PC could attenuate IgE-induced immune responses in mast cells. In general, We described the landscape of plasma lipid alterations in CU patients and provided novel insights into the role of PC in mast cells.
Antibody response following the third and fourth SARS-CoV-2 vaccine dose in individuals with common variable immunodeficiency
Authors: Nielsen Bibi Uhre , Drabe Camilla Heldbjerg , Barnkob Mike Bogetofte , Johansen Isik Somuncu , Hansen Anne Kirstine Kronborg , Nilsson Anna Christine , Rasmussen Line Dahlerup
Published: July 2022

Background

The antibody response after vaccination is impaired in common variable immunodeficiency (CVID).

Objective

We aimed to study the spike receptor-binding domain IgG antibody (anti-S-RBD) levels during a four-dose SARS-CoV-2 vaccination strategy and after monoclonal antibody (mAB) treatment in CVID. Moreover, we assessed the anti-S-RBD levels in immunoglobulin replacement therapy (IgRT) products.

Methods

In an observational study, we examined anti-S-RBD levels after the second, third, and fourth dose of mRNA SARS-CoV-2 vaccines. Moreover, we measured anti-S-RBD after treatment with mAB. Finally, anti-S-RBD was assessed in common IgRT products. Antibody non-responders (anti-S-RBD < 7.1) were compared by McNemar’s test and anti-S-RBD levels were compared with paired and non-paired Wilcoxon signed rank tests as well as Kruskal–Wallis tests.

Results

Among 33 individuals with CVID, anti-S-RBD levels increased after the third vaccine dose (165 BAU/ml [95% confidence interval: 85; 2280 BAU/ml], p = 0.006) and tended to increase after the fourth dose (193 BAU/ml, [−22; 569 BAU/ml], p = 0.080) compared to the previous dose. With increasing number of vaccinations, the proportion of patients who seroconverted (anti-S-RBD ≥ 7.1) increased non-significantly. mAB treatment resulted in a large increase in anti-S-RBD and a higher median level than gained after the fourth dose of vaccine (p = 0.009). IgRT products had varying concentrations of anti-S-RBD (p < 0.001), but none of the products seemed to affect the overall antibody levels (p = 0.460).

Conclusion

Multiple SARS-CoV-2 vaccine doses in CVID seem to provide additional protection, as antibody levels increased after the third and fourth vaccine dose. However, anti-S-RBD levels from mAB outperform the levels mounted after vaccination.

Clinical Implications

Boosting with SARS-CoV-2 vaccines seems to improve the antibody response in CVID patients.

Capsule summary

The third and possibly also the fourth dose of mRNA SARS-CoV-2 vaccine in CVID improve the antibody response as well as stimulate seroconversion in most non-responders.
Research progress on the role of PKM2 in the immune response
Authors: Liu Chunyan , Liu Chenchen , Fu Rong
Published: July 2022

Pyruvate kinase (PK) is a key enzyme that catalyzes the dephosphorylation of phosphoenolpyruvate (PEP) into pyruvate, and is responsible for the production of ATP during glycolysis. As another important isozyme of PK, pyruvate kinase M2 (PKM2) exists in cells with high levels of nucleic acid synthesis, such as normal proliferating cells (e.g., lymphocytes and intestinal epithelial cells), embryonic cells, adult stem cells, and tumor cells. With further research, PKM2, as an important regulator of cellular pathophysiological activity, has attracted increasing attention in the process of autoimmune response and inflammatory. In this re]view, we examine the contribution of PKM2 to the human immune response. Further studies on the immune mechanisms of PKM2 are expected to provide more new ideas and drug targets for immunotherapy of inflammatory and autoimmune diseases, guiding drug development and disease treatment.
Immune escape mechanisms of severe fever with thrombocytopenia syndrome virus
Authors: Wang Tong , Xu Ling , Zhu Bin , Wang Junzhong , Zheng Xin
Published: July 2022

Severe fever with thrombocytopenia syndrome (SFTS), which is caused by SFTS virus (SFTSV), poses a serious threat to global public health, with high fatalities and an increasing prevalence. As effective therapies and prevention strategies are limited, there is an urgent need to elucidate the pathogenesis of SFTS. SFTSV has evolved several mechanisms to escape from host immunity. In this review, we summarize the mechanisms through which SFTSV escapes host immune responses, including the inhibition of innate immunity and evasion of adaptive immunity. Understanding the pathogenesis of SFTS will aid in the development of new strategies for the treatment of this disease.
Identification of pyroptosis-related subtypes and establishment of prognostic model and immune characteristics in asthma
Authors: Yang Fan , Wang Tieshan , Yan Peizheng , Li Wanyang , Kong Jingwei , Zong Yuhan , Chao Xiang , Li Weijie , Zhao Xiaoshan , Wang Ji
Published: July 2022

Background

Although studies have shown that cell pyroptosis is involved in the progression of asthma, a systematic analysis of the clinical significance of pyroptosis-related genes (PRGs) cooperating with immune cells in asthma patients is still lacking.

Methods

Transcriptome sequencing datasets from patients with different disease courses were used to screen pyroptosis-related differentially expressed genes and perform biological function analysis. Clustering based on K-means unsupervised clustering method is performed to identify pyroptosis-related subtypes in asthma and explore biological functional characteristics of poorly controlled subtypes. Diagnostic markers between subtypes were screened and validated using an asthma mouse model. The infiltration of immune cells in airway epithelium was evaluated based on CIBERSORT, and the correlation between diagnostic markers and immune cells was analyzed. Finally, a risk prediction model was established and experimentally verified using differentially expressed genes between pyroptosis subtypes in combination with asthma control. The cMAP database and molecular docking were utilized to predict potential therapeutic drugs.

Results

Nineteen differentially expressed PRGs and two subtypes were identified between patients with mild-to-moderate and severe asthma conditions. Significant differences were observed in asthma control and FEV1 reversibility between the two subtypes. Poor control subtypes were closely related to glucocorticoid resistance and airway remodeling. BNIP3 was identified as a diagnostic marker and associated with immune cell infiltration such as, M2 macrophages. The risk prediction model containing four genes has accurate classification efficiency and prediction value. Small molecules obtained from the cMAP database that may have therapeutic effects on asthma are mainly DPP4 inhibitors.

Conclusion

Pyroptosis and its mediated immune phenotype are crucial in the occurrence, development, and prognosis of asthma. The predictive models and drugs developed on the basis of PRGs may provide new solutions for the management of asthma.
The expression pattern of Immune checkpoints after chemo/radiotherapy in the tumor microenvironment
Authors: Hassanian Hamidreza , Asadzadeh Zahra , Baghbanzadeh Amir , Derakhshani Afshin , Dufour Antoine , Rostami Khosroshahi Nazanin , Najafi Souzan , Brunetti Oronzo , Silvestris Nicola , Baradaran Behzad
Published: July 2022

As a disease with the highest disease-associated burden worldwide, cancer has been the main subject of a considerable proportion of medical research in recent years, intending to find more effective therapeutic approaches with fewer side effects. Combining conventional methods with newer biologically based treatments such as immunotherapy can be a promising approach to treating different tumors. The concept of “cancer immunoediting” that occurs in the field of the tumor microenvironment (TME) is the aspect of cancer therapy that has not been at the center of attention. One group of the role players of the so-called immunoediting process are the immune checkpoint molecules that exert either co-stimulatory or co-inhibitory effects in the anti-tumor immunity of the host. It involves alterations in a wide variety of immunologic pathways. Recent studies have proven that conventional cancer therapies, such as chemotherapy, radiotherapy, or a combination of them, i.e., chemoradiotherapy, alter the “immune compartment” of the TME. The mentioned changes encompass a wide range of variations, including the changes in the density and immunologic type of the tumor-infiltrating lymphocytes (TILs) and the alterations in the expression patterns of the different immune checkpoints. These rearrangements can have either anti-tumor immunity empowering or immune attenuating sequels. Thus, recognizing the consequences of various chemo(radio)therapeutic regimens in the TME seems to be of great significance in the evolution of therapeutic approaches. Therefore, the present review intends to summarize how chemo(radio)therapy affects the TME and specifically some of the most important, well-known immune checkpoints’ expressions according to the recent studies in this field.
GAS6/TAM signaling pathway controls MICA expression in multiple myeloma cells
Authors: Kosta Andrea , Mekhloufi Abdelilah , Lucantonio Lorenzo , Zingoni Alessandra , Soriani Alessandra , Cippitelli Marco , Gismondi Angela , Fazio Francesca , Petrucci Maria Teresa , Santoni Angela , Stabile Helena , Fionda Cinzia
Published: July 2022

NKG2D ligands play a relevant role in Natural Killer (NK) cell -mediated immune surveillance of multiple myeloma (MM). Different levels of regulation control the expression of these molecules at cell surface. A number of oncogenic proteins and miRNAs act as negative regulators of NKG2D ligand transcription and translation, but the molecular mechanisms sustaining their basal expression in MM cells remain poorly understood. Here, we evaluated the role of the growth arrest specific 6 (GAS6)/TAM signaling pathway in the regulation of NKG2D ligand expression and MM recognition by NK cells. Our data showed that GAS6 as well as MERTK and AXL depletion in MM cells results in MICA downregulation and inhibition of NKG2D-mediated NK cell degranulation. Noteworthy, GAS6 derived from bone marrow stromal cells (BMSCs) also increases MICA expression at both protein and mRNA level in human MM cell lines and in primary malignant plasma cells. NF-kB activation is required for these regulatory mechanisms since deletion of a site responsive for this transcription factor compromises the induction of mica promoter by BMSCs. Accordingly, knockdown of GAS6 reduces the capability of BMSCs to activate NF-kB pathway as well as to enhance MICA expression in MM cells. Taken together, these results shed light on molecular mechanism underlying NKG2D ligand regulation and identify GAS6 protein as a novel autocrine and paracrine regulator of basal expression of MICA in human MM cells.
The adenosinergic signaling in the pathogenesis and treatment of multiple sclerosis
Authors: Duarte-Silva Eduardo , Ulrich Henning , Oliveira-Giacomelli Ágatha , Hartung Hans-Peter , Meuth Sven G. , Peixoto Christina Alves
Published: July 2022

Multiple sclerosis (MS) is a highly disabling, progressive neurodegenerative disease with no curative treatment available. Although significant progress has been made in understanding how MS develops, there remain aspects of disease pathogenesis that are yet to be fully elucidated. In this regard, studies have shown that dysfunctional adenosinergic signaling plays a pivotal role, as patients with MS have altered levels adenosine (ADO), adenosine receptors and proteins involved in the generation and termination of ADO signaling, such as CD39 and adenosine deaminase (ADA). We have therefore performed a literature review regarding the involvement of the adenosinergic system in the development of MS and propose mechanisms by which the modulation of this system can support drug development and repurposing.
Left ventricle- and skeletal muscle-derived fibroblasts exhibit a differential inflammatory and metabolic responsiveness to interleukin-6
Authors: Matz Isabell , Pappritz Kathleen , Springer Jochen , Van Linthout Sophie
Published: July 2022

Interleukin-6 (IL-6) is an important player in chronic inflammation associated with heart failure and tumor-induced cachexia. Fibroblasts are salient mediators of both inflammation and fibrosis. Whereas the general outcome of IL-6 on the heart’s function and muscle wasting has been intensively studied, the influence of IL-6 on fibroblasts of the heart and skeletal muscle (SM) has not been analyzed so far. We illustrate that SM-derived fibroblasts exhibit higher basal mRNA expression of α-SMA, extracellular matrix molecules (collagen1a1/3a1/5a1), and chemokines (CCL2, CCL7, and CX3CL1) as compared to the left ventricle (LV)-derived fibroblasts. IL-6 drives the transdifferentiation of fibroblasts into myofibroblasts as indicated by an increase in α-SMA expression and upregulates NLRP3 inflammasome activity in both LV- and SM-derived fibroblasts. IL-6 increases the release of CCL7 to CX3CL1 in the supernatant of SM-derived fibroblasts associated with the attraction of more pro(Ly6Chi) versus anti(Ly6Clo) inflammatory monocytes as compared to unstimulated fibroblasts. IL-6-stimulated LV-derived fibroblasts attract less Ly6Chi to Ly6Clo monocytes compared to IL-6-stimulated SM-derived fibroblasts. In addition, SM-derived fibroblasts have a higher mitochondrial energy turnover and lower glycolytic activity versus LV-derived fibroblasts under basal and IL-6 conditions. In conclusion, IL-6 modulates the inflammatory and metabolic phenotype of LV- and SM-originated fibroblasts.
Immunosuppressive landscape in hepatocellular carcinoma revealed by single-cell sequencing
Authors: Bai Yi , Chen Dapeng , Cheng Chuanliang , Li Zhongmin , Chi Hao , Zhang Yuliang , Zhang Xiaoyu , Tang Shaohai , Zhao Qiang , Ang Bing , Zhang Yamin
Published: July 2022

Background/Aims

Hepatocellular carcinoma (HCC), accounting for 75-85% of primary liver cancer cases, is the third leading cause of cancer-related death worldwide. The purpose of this research was to examine the tumor immune microenvironment (TIME) in HCC.

Methods

We investigated the HCC TIME by integrated analysis of single-cell and bulk-tissue sequencing data to reveal the landscape of major immune cell types.

Results

Regulatory T(Treg) cells were found to be specifically distributed in the TIME of HCC. Several immune checkpoints, including TNFRSF4, TIGIT and CTLA4, were found to be uniquely overexpressed in Treg cells, and the glycolysis/gluconeogenesis pathway was enriched in Treg cells. We also discovered the presence of two NK-cell subsets with different cytotoxic capacities, one in an activated state with antitumor effects and another with an exhausted status. In addition, memory B cells in HCC were found to exist in a unique state, with high proliferation, low differentiation, and low activity, which was induced by overexpression of PRAP1 and activation of the MIF-CD74 axis.

Conclusions

We revealed the TIME landscape in HCC, highlighting the heterogeneity of major immune cell types and their potential mechanisms in the formation of an immunosuppressive environment. Hence, blocking the formation of the TIME could be a useful therapeutic strategy for HCC.
Distinct host immune responses in recurrent vulvovaginal candidiasis and vulvovaginal candidiasis
Authors: Ge Gai , Yang Zhiya , Li Dongmei , Zhang Ning , Chen Biao , Shi Dongmei
Published: July 2022

Recurrent vulvovaginal candidiasis (RVVC) and vulvovaginal candidiasis (RVVC) are one of the most common gynecological infections, primarily caused by Candida species. Although risk factors of RVVC and VVC have been identified in many studies, antifungal immunological mechanisms are still not fully understood. We performed a 1-year prospective study in a local hospital to monitor 98 patients clinically diagnosed with gynecological Candida infection. The results showed that 20.41% (20/98) are with RVVC, and 79.59% (78/98) patients have VVC. C. albicans accounts for 90% and 96.1% of all strains isolated collected from RVVC and VVC patients, respectively. Antifungal susceptibility testing showed no significant difference in Candida species between RVVC and VVC patients. However, the serum levels of IFN-γ, TNF-α, and IL-17F in the RVVC group were significantly lower than those of the VVC group, while IL-4, IL-6, and IL-10 were higher in the RVVC patients than VVC patients. IL-17A and IL-2 levels were comparable between the two groups. Taken together, our results suggest that the host-immune responses, especially Th1/2 immunity, may play important roles in prognosis of RVVC and VVC.
An integrated model of acinar to ductal metaplasia-related N7-methyladenosine regulators predicts prognosis and immunotherapy in pancreatic carcinoma based on digital spatial profiling
Authors: Yang Hao , Messina-Pacheco Julia , Corredor Andrea Liliam Gomez , Gregorieff Alex , Liu Jun-li , Nehme Ali , Najafabadi Hamed S. , Riazalhosseini Yasser , Gao Bo , Gao Zu-hua
Published: July 2022

Acinar-to-ductal metaplasia (ADM) is a recently recognized, yet less well-studied, precursor lesion of pancreatic ductal adenocarcinoma (PDAC) developed in the setting of chronic pancreatitis. Through digital spatial mRNA profiling, we compared ADM and adjacent PDAC tissues from patient samples to unveil the bridging genes during the malignant transformation of pancreatitis. By comparing the bridging genes with the 7-methylguanosine (m7G)-seq dataset, we screened 19 m7G methylation genes for a subsequent large sample analysis. We constructed the “m7G score” model based on the RNA-seq data for pancreatic cancer in The Cancer Genome Atlas (TCGA) database and The Gene Expression Omnibus (GEO) database. Tumors with a high m7G score were characterized by increased immune cell infiltration, increased genomic instability, higher response rate to combined immune checkpoint inhibitors (ICIs), and overall poor survival. These findings indicate that the m7G score is associated with tumor invasiveness, immune cell infiltration, ICI treatment response, and overall patients’ survival. We also identified FN1 and ITGB1 as core genes in the m7Gscore model, which affect immune cell infiltration and genomic instability not only in pancreatic cancer but also in pan-cancer. FN1 and ITGB1 can inhibit immune T cell activition by upregulation of macrophages and neutrophils, thereby leading to immune escape of pancreatic cancer cells and reducing the response rate of ICI treatment.
Microsporidia: a promising vector control tool for residual malaria transmission
Authors: Bukhari Tullu , Pevsner Roland , Herren Jeremy Keith.
Published: July 2022

Long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) have resulted in a major decrease in malaria transmission. However, it has become apparent that malaria can be effectively transmitted despite high coverage of LLINs/IRS. Residual transmission can occur due toPlasmodium-carryingAnophelesmosquitoes that are insecticide resistant and have feeding and resting behavior that reduces their chance of encountering the currently deployed indoor malaria control tools. Residual malaria transmission is likely to be the most significant hurdle to achieving the goal of malaria eradication and research and development towards new tools and strategies that can control residual malaria transmission is therefore critical. One of the most promising strategies involves biological agents that are part of the mosquito microbiome and influence the ability ofAnophelesto transmitPlasmodium.These differ from biological agents previously used for vector control in that their primary effect is on vectoral capacity rather than the longevity and fitness ofAnopheles(which may or may not be affected). An example of this type of biological agent isMicrosporidia MB, which was identified in field collectedAnopheles arabiensisand caused complete inhibition ofPlasmodium falciparumtransmission without effecting the longevity and fitness of the host.Microsporidia MBbelongs to a unique group of rapidly adapting and evolving intracellular parasites and symbionts called microsporidia. In this review we discuss the general biology of microsporidians and the inherent characteristics that make some of them particularly suitable for malaria control. We then discuss the research priorities for developing a transmission blocking strategy for the currently leading microsporidian candidateMicrosporidia MBfor malaria control.
Opportunistic gillnet depredation by common bottlenose dolphins in the southwestern Gulf of Mexico: Testing the relationship with ecological, trophic, and nutritional characteristics of their prey
Authors: Chávez-Martínez Karina , Morteo Eduardo , Hernández-Candelario Isabel , Herzka Sharon Z. , Delfín-Alfonso Chrstian A.
Published: July 2022

Competition between fisheries and bottlenose dolphins is a globally relevant conflict given its socioeconomic and ecological implications. Understanding the factors driving the interactions between dolphins and fishery activities is key to the development of appropriate mitigation strategies. Our study aimed to assess whether these interactions are related to the ecological, trophic, and nutritional characteristics of the catch. We used 117 gillnet sets from 48 fishing trips during 2009 – 2010 and 2015 – 2019, which were classified based on the presence or absence of dolphin interactions. These interactions occurred year-round and were documented in 46.1% of the sets, with 14.5% of those showing signs of depredation. The passive acoustic predatory hypothesis, which states that fish species that generate sound are subject to a higher predation intensity by dolphins, was not supported by our data. Also, with the exception of species diversity, ecological parameters such as richness, biomass and CPUE were slightly higher, although not significant in sets with dolphin interaction. Furthermore, during 2015 – 2016, we sampled 123 organisms of 25 representative fish species in the catches and determined the whole fish isotopic composition (δ13C and δ15N), and estimated the nutritional value (i.e., lipid, protein, and energy content) of each species. Isotopic values showed no differences between net settings (with and without interaction), fish habitat, or prey type (potential prey,n= 11 species,vs. non-potential prey,n= 14). However, a preference towards fish from a certain range of thropic levels was evident. All the fish (N= 123) showed significantly higher protein values during the Rainy period, which may be attributed to their reproductive cycles and higher primary productivity. Interestingly, energy contents of the dolphins’ potential prey were also significantly higher during this period. Unexpectedly, protein and energy contents were significantly higher in the fishes caught in the sets without dolphin interaction, but only during the Dry and Windy periods, respectively. Opportunistic feeding habits are well known for bottlenose dolphins, and our results showed that “easy access” to prey will likely prompt interaction with gillnets, regardless of the species composition, biomass, seasonality, preferred habitat, sound production capacity, or nutritional value of the captured fish.
A new genetic lineage of Asparagopsis taxiformis (Rhodophyta) in the Mediterranean Sea: As the DNA barcoding indicates a recent Lessepsian introduction
Authors: Nahor Omri , Luzzatto-Knaan Tal , Israel Álvaro
Published: July 2022

Asparagopsis taxiformis(Delile) Trevisan is a red marine macroalga (Bonnemaisoniales, Rhodophyta) with high invasive potential and broad worldwide distribution. In the Mediterranean Sea,A. taxiformiswas reported before the opening of the Suez Canal and is comprised of two different cryptic lineages, named L2 and L3. As for the Israeli Mediterranean Sea (IMS),A. taxiformisbenthic populations have seemingly expanded with several large seasonal blooms recorded in recent years. However, neither ecology nor molecular substantial studies have been conducted for this particular geographical area. Increasing sampling intensity and geographical coverage may reveal new lineages or indicate human-mediated spread routes not only forA. taxiformisbut for macroalgae in general. This approach is particularly important in areas such as the eastern Mediterranean Sea, which experiences intense biological invasion on a global scale. In this study, randomly samples specimens (n = 30) ofA. taxiformisand preserved herbarium samples (n = 4) collected from the IMS in the past, were all barcoded and taxonomically identified using three molecular genetic markers (LSU,cox2-3 spacer, andrbcL). We found a cryptic lineage 4 (L4) ofA. taxiformisfirst reported here for the Mediterranean Sea, and previously described for the western Indo-Pacific and Hawaii. Herbarium samples confirmed the presence of L4 as early as 2013. Comparative assessment ofcox2-3 spacer marker indicates 100% similarity to sequenced L4 samples from Egypt in the Red Sea. The IMScox2-3 spacer sequences differed from previously sequenced samples from the Mediterranean Sea by 2.3% and 3.9% bp, compared to L3 and L2 Mediterranean populations, respectively. Morphological inspections indicate monoecious L4 gametophytes which are larger than the L4 population reported previously from Hawaii. Altogether, our results strongly indicate a Lessepsian migration route forA. taxiformisL4 with yet unknown consequences for the local marine ecosystems.
Identification of a Novel Species, Cladonema digitatum sp. nov. (Cnidaria: Hydrozoa: Cladonematidae), Using DNA Barcoding and Life Cycle Analyses
Authors: Fang Xinyu , Lin Shen , Zhang Yuting , Wang Zonghua , Zhou Konglin , Chen Jianming
Published: July 2022

In this study, a new Cladonema species was identified in a laboratory aquarium in Fuzhou, China, and named Cladonema digitatum sp. nov. based on its morphological characteristics and DNA barcoding. It is distinct from other Cladonema medusae in having a manubrium with finger-like protuberances, radial canals with Y-shaped bifurcations, tentacles with 3–11 adhesive branches, and 3–7 stinging branches growing from the main branch as side branches. The validity of C. digitatum sp. nov. was supported by molecular phylogenetic analyses based on both mitochondrial cytochrome oxidase and mitochondrial 16S rRNA sequences. Similar to other Cladonema medusae, the adhesive and stinging branches of each tentacle, oral tentacle, manubrium, and gonads in C. digitatum displayed considerable phenotypic plasticity, thus making species identification based solely on morphology difficult. Although diagnostic characters such as filiform tentacles and medusa buds of hydroids and nematocysts are also useful for species identification in the genus Cladonema, related information is missing in some Cladonema species. Thus, information on the life cycle and DNA barcoding should be updated to describe new or cryptic species and to improve the taxonomy of the genus Cladonema.
Tidal variation shaped microplastic enrichment patterns in mangrove blue carbon ecosystem of northern Beibu Gulf, China
Authors: Zhang Li , Wang Shujia , Jian Qiying , Zhang Peng , Lu Yejin , Liu Haoqi
Published: July 2022

Mangroves are considered to be a sink for microplastics (MPs) due to their unique characteristics. Previous studies mainly focused on the spatial distribution of MPs, but few researchers have addressed the influence of tidal variation on this distribution, especially since the MP total number in mangroves was unknown. In this study, surface sediment samples were collected in mangroves from the Beibu Gulf, South China Sea, and the abundance, composition, and number of MPs were investigated. The results showed that MPs were widely present in all mangrove sediment samples, with abundances ranging from 26.67 ± 9.43 to 239.94 ± 37.80 items/kg. The distribution of MPs was heterogeneous among different sampling sites, with the highest levels in the Shankou (SK) area. The MP abundance in the same mangrove forest gradually increased from the low tidal zone to the high tidal zone, with the enrichment factor ranging from 1.50 to 4.00. The MP abundance was significantly correlated with particulate organic carbon (POC) (n = 12, R = 0.664, p < 0.05). Results showed that mangroves had an interception effect on MPs and factors affecting MP distribution in mangrove sediments included not only tides but also human activities, such as aquaculture, agriculture, and residential life. Finally, this paper estimated the MP total number in mangroves at different sampling areas and tidal zones, and the middle tidal zone was considered to be more accurate for MP pollution assessment in mangroves.
Vertical patterns of chlorophyll a in the euphotic layer are related to mesoscale eddies in the South China Sea
Authors: Wu Mei-Lin , Wang You-Shao , Wang Yu-Tu , Sun Fu-Lin , Li Xiaomei , Gu Fang-Fang , Xiang Jing-Chang
Published: July 2022

Phytoplankton closely connects with the hydrodynamics and biogeochemical environment of the ocean. While research focusing on both the physiochemical factors and hydrodynamics regulating phytoplankton has already been conducted, the coupling mechanism between mesoscale eddies and the vertical distribution of phyto plankton in the South China Sea (SCS) is still not well understood. Here, phytoplankton was studied under one weak-cold and two warm eddies along the 18°N transect in the SCS. The results show that the vertical distribution of chlorophyll (chl-a) presented a similar pattern at all four sampling stations. The mixed layer is less than 50 m. It is the same as the meridional salinity gradients that may be distinguished above a depth of 60 m. The subsurface chlorophyll maximum at the edge of a warm (WI) and cold eddy (CI) at E413 and E411 was shallower than that at the edge of a warm eddy (WII) at E407 and E409, indicating that temperature and salinity may be the important driving factors. On the whole, mesoscale eddies had a significant influence on the vertical pattern of chl-a in the SCS during the study period.
Qi no tu i baba ni qwali (living down by the river): Impacts of flooding and mining on ecosystems and livelihoods
Authors: Varea Rufino , Varea Renata , Kant Romitesh , Farrelly Trisia
Published: July 2022

A vast ocean rich with resources to maintain a sustainable livelihood surround Pacific Island Countries and Territories. In Fiji, coastal resources are a primary source of food, medicine, income and other necessities for livelihood security. Human-induced climate change places growing pressure on the quality of coastal resources due to the increased intensity and frequency of natural disasters like coastal erosion and flooding. Anthropogenic activities like coastal mining of earth minerals further threatens livelihood security with cumulative pressure on the coastal environment and its resources. This paper discusses the compounding impacts of mining in the flood-prone community of Vanua Votua in Ba (Fiji). They currently witness the degradation of their coastal environment and its resources (iqoliqoli). The people of Vanua Votua have a cultural and spiritual attachment to their coastal ecosystem as indigenous custodians. However, they are limited in their ability to conserve and protect their iqoliqoli due to an unfair legal duality of national coastal governance structures and processes between the state and indigenous custodians. We found that a central issue of coastal mining, governance, and the people’s livelihood vulnerabilities, is Fiji’s Mining Act [Cap 146] and associated environmental legislations and policies that consolidate much of the coastal governance authority with the state. The Fiji Mining Act is currently under review. This paper provides a timely case study using the Sustainable Livelihood Approach and the Vanua Research Framework, outlining the need for current and future legislation to be nuanced and sensitive to the realities of the local context.