bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and Functional Prediction of Circular RNAs Related to Growth Traits and Skeletal Muscle Development in Duroc pigs
Authors: Ma Lixia , Chen Wei , Li Shiyin , Qin Ming , Zeng Yongqing
Published: September 2022

Porcine skeletal muscle is a highly heterogeneous tissue type, and the Longissimus Dorsi muscle (LDM), as the most economical and physiologically metabolized skeletal muscle in pigs, has always been the focus of research and improvement in pig molecular breeding. Circular RNA, as an important new member of regulatory non-coding RNA after microRNA, has become a frontier hot spot in life science research. This study aims to explore candidate circRNAs related to growth, meat quality, and skeletal muscle development among Duroc pigs with different average daily gain (ADG). Eight pigs were selected and divided into two groups: H group (high-ADG) and L group (low-ADG), followed by RNA-Seq analysis to identify circRNAs. The results showed that backfat at 6-7 rib (BF) and Intramuscular fat (IMF) content in the H group was significantly lower than L group, but ribeye area (REA) in the H group was higher than in the L group. In RNA-seq, 296 Differentially expressed (DE) circRNAs (157 upregulated and 139 downregulated) were identified and exons flanking long introns are easier to circularize to produce circRNAs. Most of the DE circRNAs were enriched in Quantitative trait locus (QTL) regions related to meat quality and growth traits. In addition, a gene can produce one or more circRNA transcripts. It was also found that the source genes of DE circRNAs were enriched in MAPK, FoXO, mTOR, PI3K-Akt, and Wnt signaling pathways. The results showed that different ADG, carcass, and meat quality traits among half-sibling Duroc pigs with the same diet may be due to the DE circRNAs related to skeletal muscle growth and development.
Genetic instability-related lncRNAs predict prognosis and influence the immune microenvironment in breast cancer
Authors: Lv Zhenyi , Wang Qiang , Liu Xuxu , Du Zhiwei , Liang Wenping , Liu Tianming , Zheng Yi , Ma Biao , Xue Dongbo
Published: September 2022

Genome instability is a hallmark of cancer, and the function of lncRNAs in regulating genomic stability has been gradually characterized. However, the prognostic value of lncRNAs related to genetic instability has not been found in breast cancer. Here we constructed a genetic instability-related lncRNA model including U62317.4, SEMA3B-AS1, MAPT-AS1, AC115837.2, LINC01269, AL645608.7, and GACAT2. This model can evaluate the risk and predict the survival outcomes of patients. Further analysis showed that the differentially expressed genes between the high- and low-risk groups were enriched in immunity and cornified envelope formation pathways. In addition, M2 macrophages infiltrated more obviously in the high-risk group. In summary, lncRNAs related to genetic instability may influence the development of breast cancer through immune infiltration and keratinization. This study provides a wider insight into breast cancer development and treatment.
The diagnostic and prognostic value of the miR-17-92 cluster in hepatocellular carcinoma: A meta-analysis
Authors: Lu Fang , Zhao Xianghong , Zhang Zhongqiu , Xiong Mengqiu , Wang Ying , Sun Yalan , He Bangshun , Zhu Junrong
Published: September 2022

Previous studies demonstrated that microRNAs (miRNAs) could serve as biomarkers in various cancers. This meta-analysis aimed to determine the roles of a miR-17-92 cluster in hepatocellular carcinoma (HCC). Here, eligible included studies were searched through PubMed, Embase, and Wan Fang databases up to 1st February 2022. Relevant data were extracted from each eligible study to evaluate the relationship between miRNA-17-92 cluster miRNA expression and the diagnosis and prognosis of HCC. Finally, a total of 21 studies were pooled and included in the meta-analysis, of which four articles were used for diagnostic meta-analysis and eight articles were used for prognostic meta-analysis. The pooled sensitivity, specificity, and diagnostic odds ratios (DOR) of the miR17-92 cluster for diagnosis of HCC were 0.75 [95% confidence interval (CI): 0.64–0.83], 0.73 (95% CI: 0.65–0.79), and 7.87 (95% CI: 5.36–11.54), respectively. Also, the area under the curve (AUC) for the miR-17-92 cluster when diagnosing HCC was 0.79 (95% CI: 0.76–0.83). For prognostic analysis, hazard ratios (HRs) with 95% CIs were extracted from the included studies and pooled HRs were determined to assess the associations. Patients with increased expression of miR17-92 cluster miRNA were associated with poor overall survival (OS) and recurrence-free survival (RFS) (HR=1.86, 95% CI: 1.04–3.33; HR = 4.18, 95% CI: 3.02–5.77, respectively), but not progression-free survival (PFS) (HR = 0.43, 95% CI: 0.25–0.73), while no association of the miR-17-92 cluster high-expression was detected with disease-free survival (DFS) (HR: 0.95, 95% CI: 0.21–4.34). In short, current pieces of evidence suggested that the miR-17-92 cluster may serve as a novel diagnostic and prognostic biomarker for HCC. However, given the limited study number, larger-size, multi-center, and higher-quality studies are indispensable in the future.
Genome-wide identification and expression analysis of the GRAS transcription in eggplant (Solanum melongena L.)
Authors: Yang Ting , Li Cheng , Zhang Hui , Wang Jingyu , Xie Xiaofang , Wen Yongxian
Published: September 2022

GRAS proteins are plant-specific transcription factors and play important roles in plant growth, development, and stress responses. In this study, a total of 48 GRAS genes in the eggplant (S. melongena) genome were identified. These genes were distributed on 11 chromosomes unevenly, with amino acid lengths ranging from 417 to 841 aa. A total of 48 GRAS proteins were divided into 13 subgroups based on the maximum likelihood (ML) model. The gene structure showed that 60.42% (29/48) of SmGRASs did not contain any introns. Nine pairs of SmGRAS appeared to have a collinear relationship, and all of them belonged to segmental duplication. Four types of cis-acting elements, namely, light response, growth and development, hormone response, and stress response, were identified by a cis-acting element predictive analysis. The expression pattern analysis based on the RNA-seq data of eggplant indicated that SmGRASs were expressed differently in various tissues and responded specifically to cold stress. In addition, five out of ten selected SmGRASs (SmGRAS2/28/32/41/44) were upregulated under cold stress. These results provided a theoretical basis for further functional study of GRAS genes in eggplant.
INHBB is a novel prognostic biomarker and correlated with immune infiltrates in gastric cancer
Authors: Yu Weifeng , He Guihua , Zhang Wang , Ye Zhenhao , Zhong Zishao , Huang Suiping
Published: September 2022

Inhibin subunit beta B (INHBB) is a potential prognostic biomarker for a variety of cancers. However, its role in gastric cancer (GC) remains elusive. The differential expression data of INHBB in tumor and normal tissues were extracted from several databases and genetic alterations of INHBB were assessed by cBioPortal. Kaplan-Meier analysis was used to evaluate the survival rate of patients with GC with INHBB and association with clinical features in GC. Cox regression analysis was used to explore the prognostic value of clinical indicators and INHBB in GC, and a nomogram prognostic model was established. In addition, the predictive validity of the nomogram model was assessed by time-depended receiver operating characteristic (ROC) and calibration curves. Functional enrichment analyses were conducted to functionally annotate INHBB. Notably, we found that the quantitative assessment of immune cell subpopulation infiltration correlated with INHBB expression. INHBB expression is upregulated in GC and is correlated with several clinical features including prognostic indicators and a histological type. Genetic alterations were observed in INHBB, its DNA methylation level was negatively correlated with INHBB expression. High INHBB expression is associated with a poor prognosis and is an independent risk factor for prognosis in GC, along with age and residual tumor. The nomogram model showed a good prediction ability and was validated by time-depended ROC and calibration curves. Functional enrichment analysis indicated that INHBB-associated genes were enriched in tumor microenvironment Gene Ontology (GO) terms and were correlated with tumor-associated pathways. INHBB has a regulatory function in immune cell infiltration, especially macrophage infiltration in GC. Specifically, patients with GC with high INHBB expression and high macrophage infiltration have a worse prognosis. INHBB expression was negatively correlated with the expression of chemokines/chemokine receptors and plays a regulatory role in immunoinhibitor/immunostimulator-involved pathways. INHBB is a potential prognostic biomarker for GC and may drive the abnormal activity of critical cancer-associated pathways, potentially contributing to immune cell infiltration to promote GC development.
Association of genetic variants in ULK4 with the age of first onset of type B aortic dissection
Authors: Huang Lihong , Tang Jiaqi , Lin Lijuan , Wang Ruihan , Chen Feng , Wei Yongyue , Si Yi , Fu Weiguo
Published: September 2022

Background: The association between autophagy, structural alterations of the aortic wall, and endothelial dysfunction in humans has yet to be fully elucidated. The family of ULK (UNC51-like) enzymes plays critical roles in autophagy and development. This study aimed to evaluate the association between ULK gene family members and patient age of first type B aortic dissection (TBAD) onset.

Methods: The genotype data in a TBAD cohort from China and the related summary-level datasets were analyzed. We applied the sequence kernel association test (SKAT) to test the association between single-nucleotide polymorphisms (SNPs) and age of first onset of TBAD controlling for gender, hypertension, and renal function. Next, we performed a 2-sample Mendelian randomization (MR) to explore the potential causal relationship between ULK4 and early onset of TBAD at the level of gene expression coupled with DNA methylation with genetic variants as instrumental variables.

Results: A total of 159 TBAD patients with 1,180,097 SNPs were included. Concerning the association between the ULK gene family and the age of first onset of the TBAD, only ULK4 was found to be significant according to SKAT analysis (q-FDR = 0.0088). From 2-sample MR, the high level of ULK4 gene expression was related to a later age of first onset of TBAD (β = 4.58, p = 0.0214).

Conclusion: This is the first study of the ULK gene family in TBAD, regarding the association with the first onset age. We demonstrated that the ULK4 gene is associated with the time of onset of TBAD based on both the SKAT and 2-sample MR analyses.
Case report: Exotropia in waardenburg syndrome with novel variations
Authors: Huang Lijuan , Guo Maosheng , Li Ningdong
Published: September 2022

Background: Waardenburg syndrome (WS) is a rare genetic disorder characterized by congenital sensorineural hearing loss and pigmentary abnormalities of the hair, skin and eyes. However, exotropia is rarely reported. The purpose of this study is to describe the clinical characteristics of three sporadic patients with WS and congenital exotropia and to investigate the disease-causing genes for them.

Methods: Patients underwent detailed physical and ocular examinations. Ocular alignment and binocular status were evaluated. DNA was extracted and whole exome sequencing was performed to detect the pathogenic variations in the disease-causing genes for WS. Cloning sequencing was carried out for those indel variations.

Results: Three unrelated patients were diagnosed with Waardenburg syndrome and congenital exotropia. Four novel variants, including c.136delA (p.I46Sfs*64) and c.668G>T (p.R223L) in PAX3, c.709dupC (p.Q237Pfs*119) in COL11A2, c.426G>A (p.W142X) in SOX10 gene, were detected in this study.

Conclusion: Simultaneous presence of congenital exotropia and WS in our patients is suggested that WS could be involved in malfunction in the multiple nerve systems. Our genetic study will expand the mutation spectrum of PAX3, COL11A2 and SOX10 genes, and is helpful for further study on the molecular pathogenesis of WS.
Identification and expression analysis of sex biased miRNAs in chinese hook snout carp Opsariichthys bidens
Authors: Tang Rongkang , Xu Cong , Zhu Yefei , Yan Jinpeng , Yao Ziliang , Zhou Wenzong , Gui Lang , Li Mingyou
Published: September 2022

As an economically important fish, Opsariichthys bidens has obvious sexual dimorphism and strong reproductive capacity, but no epigenetics study can well explain its phenotypic variations. In recent years, many microRNAs involved in the regulation of reproductive development have been explored. In this study, the small RNA libraries of O. bidens on the testis and ovary were constructed and sequenced. A total of 295 known miRNAs were obtained and 100 novel miRNAs were predicted. By comparing testis and ovary libraries, 115 differentially expressed (DE) miRNAs were selected, of which 53 were up-regulated and 62 were down-regulated. A total of 64 GO items (padj < 0.01) and 206 KEGG pathways (padj < 0.01) were enriched in the target gene of miRNA. After that, the expression levels of nine DE miRNAs, including let-7a, miR-146b, miR-18c, miR-202-5p, miR-135c, miR-9-5p, miR-34c-3p, miR-460-5p and miR-338 were verified by qRT-PCR. Furthermore, bidirectional prediction of DE miRNAs and sex-related genes was carried out and the targeting correlation between miR-9-5p and nanos1 was verified by Dual-Luciferase reporter assay. Our findings identified the differentially expressed miRNA and paved the way to new possibilities for the follow-up study on the mechanism of miRNA-mRNA interaction in the gonads of O. bidens.
Cancer stemness-associated LINC02475 serves as a novel biomarker for diagnosis and prognosis prediction of hepatocellular carcinoma
Authors: Lin Xian , Luo Lianxiang , Zou Yujiao , Chen Jian
Published: September 2022

Purpose: Hepatocellular carcinoma (HCC) is a severe malignant tumor with high incidence and mortality. LncRNAs present broad clinical application prospects. Herein, we aim to identify a cancer stemness associated lncRNA and reveal its role in HCC diagnosis, prognosis evaluation, and progression.

Methods: The cancer stemness-associated LINC02475 in HCC samples were identified using bioinformatics analysis. Cellular and molecular experiments were conducted to elucidate the role of LINC02475 in HCC.

Results: The firm links between LINC02475 and HCC stemness and prognosis were demonstrated by bioinformatics analysis of public cancer datasets. LINC02475 expression was elevated in HCC, performed well in the diagnosis, and independently predicts poor overall survival (hazard ratio = 1.389, 95% confidence interval = 1.047–1.843, p = 0.023), as well as progression-free survival (hazard ratio = 1.396, 95% confidence interval = 1.016–1.917, p = 0.040) of HCC patients. Moreover, LINC02475 enhanced the tumorigenic pathways necessary for cell stemness, DNA replication required for cell proliferation, epithelial-mesenchymal transition involved in metastasis, and DNA damage repair pathways that drove cell radioresistance and cisplatin resistance, thus promoting HCC progression.

Conclusion: Cancer stemness-associated LINC02475 independently predicted a poor prognosis and promoted HCC progression by enhancing stemness, proliferation, metastasis, radioresistance, and chemoresistance. Our study lays a foundation for the clinical application of LINC02475 as a novel biomarker and target for the diagnosis, prognosis evaluation, as well as treatment of HCC.
Targeting inflammation and immune activation to improve CTLA4-Ig-based modulation of transplant rejection
Authors: Iglesias Marcos , Brennan Daniel C. , Larsen Christian P. , Raimondi Giorgio
Published: September 2022

For the last few decades, Calcineurin inhibitors (CNI)-based therapy has been the pillar of immunosuppression for prevention of organ transplant rejection. However, despite exerting effective control of acute rejection in the first year post-transplant, prolonged CNI use is associated with significant side effects and is not well suited for long term allograft survival. The implementation of Costimulation Blockade (CoB) therapies, based on the interruption of T cell costimulatory signals as strategy to control allo-responses, has proven potential for better management of transplant recipients compared to CNI-based therapies. The use of the biologic cytotoxic T-lymphocyte associated protein 4 (CTLA4)-Ig is the most successful approach to date in this arena. Following evaluation of the BENEFIT trials, Belatacept, a high-affinity version of CTLA4-Ig, has been FDA approved for use in kidney transplant recipients. Despite its benefits, the use of CTLA4-Ig as a monotherapy has proved to be insufficient to induce long-term allograft acceptance in several settings. Multiple studies have demonstrated that events that induce an acute inflammatory response with the consequent release of proinflammatory cytokines, and an abundance of allograft-reactive memory cells in the recipient, can prevent the induction of or break established immunomodulation induced with CoB regimens. This review highlights advances in our understanding of the factors and mechanisms that limit CoB regimens efficacy. We also discuss recent successes in experimentally designing complementary therapies that favor CTLA4-Ig effect, affording a better control of transplant rejection and supporting their clinical applicability.
Integrated multi-omics reveals the activated retinal microglia with intracellular metabolic reprogramming contributes to inflammation in STZ-induced early diabetic retinopathy
Authors: Lv Kangjia , Ying Hui , Hu Guangyi , Hu Jing , Jian Qizhi , Zhang Fang
Published: September 2022

Diabetic retinopathy (DR) is the leading cause of visual impairment and blindness among working-age people. Inflammation is recognized as a critical driver of the DR process. However, the main retina-specific cell type producing pro-inflammatory cytokines and its mechanism underlying DR are still unclear. Here, we used single-cell sequencing to identify microglia with metabolic pathway alterations that were the main source of IL-1β in STZ-induced DR mice. To profile the full extent of local metabolic shifts in activated microglia and to reveal the metabolic microenvironment contributing to immune mechanisms, we performed integrated metabolomics, lipidomics, and RNA profiling analyses in microglia cell line samples representative of the DR microenvironment. The results showed that activated microglia with IL-1β increase exhibited a metabolic bias favoring glycolysis, purine metabolism, and triacylglycerol synthesis, but less Tricarboxylic acid (TCA). In addition, some of these especially glycolysis was necessary to facilitate their pro-inflammation. These findings suggest that activated microglia with intracellular metabolic reprogramming in retina may contribute to pro-inflammation in the early DR.
The Th1/Tfh-like biased responses elicited by the rASP-1 innate adjuvant are dependent on TRIF and Type I IFN receptor pathways
Authors: George Parakkal Jovvian , Marches Radu , Nehar-Belaid Djamel , Banchereau Jacques , Lustigman Sara
Published: September 2022

Ov-ASP-1 (rASP-1), a parasite-derived protein secreted by the helminth Onchocerca volvulus, is an adjuvant which enhances the potency of the influenza trivalent vaccine (IIV3), even when used with 40-fold less IIV3. This study is aimed to provide a deeper insight into the molecular networks that underline the adjuvanticity of rASP-1. Here we show that rASP-1 stimulates mouse CD11c+ bone marrow-derived dendritic (BMDCs) to secrete elevated levels of IL-12p40, TNF-α, IP-10 and IFN-β in a TRIF-dependent but MyD88-independent manner. rASP-1-activated BMDCs promoted the differentiation of naïve CD4+ T cells into Th1 cells (IFN-γ+) that was TRIF- and type I interferon receptor (IFNAR)-dependent, and into Tfh-like cells (IL21+) and Tfh1 (IFN-γ+ IL21+) that were TRIF-, MyD88- and IFNAR-dependent. rASP-1-activated BMDCs promoted the differentiation of naïve CD4+ T cells into Th17 (IL-17+) cells only when the MyD88 pathway was inhibited. Importantly, rASP-1-activated human blood cDCs expressed upregulated genes that are associated with DC maturation, type I IFN and type II IFN signaling, as well as TLR4-TRIF dependent signaling. These activated cDCs promoted the differentiation of naïve human CD4+ T cells into Th1, Tfh-like and Th17 cells. Our data thus confirms that the rASP-1 is a potent innate adjuvant that polarizes the adaptive T cell responses to Th1/Tfh1 in both mouse and human DCs. Notably, the rASP-1-adjuvanted IIV3 vaccine elicited protection of mice from a lethal H1N1 infection that is also dependent on the TLR4-TRIF axis and IFNAR signaling pathway, as well as on its ability to induce anti-IIV3 antibody production.
Ion channel Piezo1 activation promotes aerobic glycolysis in macrophages
Authors: Leng Shaoqiu , Zhang Xiaoyu , Wang Shuwen , Qin Jing , Liu Qiang , Liu Anli , Sheng Zi , Feng Qi , Hu Xiang , Peng Jun
Published: September 2022

Altered microenvironmental stiffness is a hallmark of inflammation. It is sensed by the mechanically activated cation channel Piezo1 in macrophages to induce subsequent immune responses. However, the mechanism by which the mechanosensitive signals shape the metabolic status of macrophages and tune immune responses remains unclear. We revealed that Piezo1-deficient macrophages exhibit reduced aerobic glycolysis in resting or liposaccharide (LPS)-stimulated macrophages with impaired LPS-induced secretion of inflammatory cytokinesin vitro. Additionally, pretreatment with the Piezo1 agonist, Yoda1, or cyclical hydrostatic pressure (CHP) upregulated glycolytic activity and enhanced LPS-induced secretion of inflammatory cytokines. Piezo1-deficient mice were less susceptible to dextran sulfate sodium (DSS)-induced colitis, whereas Yoda1 treatment aggravated colitis. Mechanistically, we found that Piezo1 activation promotes aerobic glycolysis through the Ca2+-induced CaMKII-HIF1α axis. Therefore, our study revealed that Piezo1-mediated mechanosensitive signals Piezo1 can enhance aerobic glycolysis and promote the LPS-induced immune response in macrophages.
Characterization and comparison of novel adjuvants for a prefusion clamped MERS vaccine
Authors: O’Donnell Jake S. , Isaacs Ariel , Jakob Virginie , Lebas Celia , Barnes James B. , Reading Patrick C. , Young Paul R. , Watterson Daniel , Dubois Patrice M. , Collin Nicolas , Chappell Keith J.
Published: September 2022

Various chemical adjuvants are available to augment immune responses to non-replicative, subunit vaccines. Optimized adjuvant selection can ensure that vaccine-induced immune responses protect against the diversity of pathogen-associated infection routes, mechanisms of infectious spread, and pathways of immune evasion. In this study, we compare the immune response of mice to a subunit vaccine of Middle Eastern respiratory syndrome coronavirus (MERS-CoV) spike protein, stabilized in its prefusion conformation by a proprietary molecular clamp (MERS SClamp) alone or formulated with one of six adjuvants: either (i) aluminium hydroxide, (ii) SWE, a squalene-in-water emulsion, (iii) SQ, a squalene-in-water emulsion containing QS21 saponin, (iv) SMQ, a squalene-in-water emulsion containing QS21 and a synthetic toll-like receptor 4 (TLR4) agonist 3D-6-acyl Phosphorylated HexaAcyl Disaccharide (3D6AP); (v) LQ, neutral liposomes containing cholesterol, 1.2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and QS21, (vi) or LMQ, neutral liposomes containing cholesterol, DOPC, QS21, and 3D6AP. All adjuvanted formulations induced elevated antibody titers which where greatest for QS21-containing formulations. These had elevated neutralization capacity and induced higher frequencies of IFNƔ and IL-2-producing CD4+ and CD8+ T cells. Additionally, LMQ-containing formulations skewed the antibody response towards IgG2b/c isotypes, allowing for antibody-dependent cellular cytotoxicity. This study highlights the utility of side-by-side adjuvant comparisons in vaccine development.
Tumor accomplice: T cell exhaustion induced by chronic inflammation
Authors: Fang Liguang , Liu Kunjing , Liu Cun , Wang Xiaomin , Ma Wenzhe , Xu Wenhua , Wu Jibiao , Sun Changgang
Published: September 2022

The development and response to treatment of tumor are modulated by inflammation, and chronic inflammation promotes tumor progression and therapy resistance. This article summarizes the dynamic evolution of inflammation from acute to chronic in the process of tumor development, and its effect on T cells from activation to the promotion of exhaustion. We review the mechanisms by which inflammatory cells and inflammatory cytokines regulate T cell exhaustion and methods for targeting chronic inflammation to improve the efficacy of immunotherapy. It is great significance to refer to the specific state of inflammation and T cells at different stages of tumor development for accurate clinical decision-making of immunotherapy and improving the efficiency of tumor immunotherapy.
Roles and therapeutic potential of CD1d-Restricted NKT cells in inflammatory skin diseases
Authors: Lee Sung Won , Park Hyun Jung , Van Kaer Luc , Hong Seokmann
Published: September 2022

Natural killer T (NKT) cells are innate-like T lymphocytes that recognize glycolipid antigens rather than peptides. Due to their immunoregulatory properties, extensive work has been done to elucidate the immune functions of NKT cells in various immune contexts such as autoimmunity for more than two decades. In addition, as research on barrier immunity such as the mucosa-associated lymphoid tissue has flourished in recent years, the role of NKT cells to immunity in the skin has attracted substantial attention. Here, we review the contributions of NKT cells to regulating skin inflammation and discuss the factors that can modulate the functions of NKT cells in inflammatory skin diseases such as atopic dermatitis. This mini-review article will mainly focus on CD1d-dependent NKT cells and their therapeutic potential in skin-related immune diseases.
Colivelin, a synthetic derivative of humanin, ameliorates endothelial injury and glycocalyx shedding after sepsis in mice
Authors: Urban Catherine , Hayes Hannah V. , Piraino Giovanna , Wolfe Vivian , Lahni Patrick , O’Connor Michael , Phares Ciara , Zingarelli Basilia
Published: September 2022

Endothelial dysfunction plays a central role in the pathogenesis of sepsis-mediated multiple organ failure. Several clinical and experimental studies have suggested that the glycocalyx is an early target of endothelial injury during an infection. Colivelin, a synthetic derivative of the mitochondrial peptide humanin, has displayed cytoprotective effects in oxidative conditions. In the current study, we aimed to determine the potential therapeutic effects of colivelin in endothelial dysfunction and outcomes of sepsis in vivo. Male C57BL/6 mice were subjected to a clinically relevant model of polymicrobial sepsis by cecal ligation and puncture (CLP) and were treated with vehicle or colivelin (100-200 µg/kg) intraperitoneally at 1 h after CLP. We observed that vehicle-treated mice had early elevation of plasma levels of the adhesion molecules ICAM-1 and P-selectin, the angiogenetic factor endoglin and the glycocalyx syndecan-1 at 6 h after CLP when compared to control mice, while levels of angiopoietin-2, a mediator of microvascular disintegration, and the proprotein convertase subtilisin/kexin type 9, an enzyme implicated in clearance of endotoxins, raised at 18 h after CLP. The early elevation of these endothelial and glycocalyx damage biomarkers coincided with lung histological injury and neutrophil inflammation in lung, liver, and kidneys. At transmission electron microscopy analysis, thoracic aortas of septic mice showed increased glycocalyx breakdown and shedding, and damaged mitochondria in endothelial and smooth muscle cells. Treatment with colivelin ameliorated lung architecture, reduced organ neutrophil infiltration, and attenuated plasma levels of syndecan-1, tumor necrosis factor-α, macrophage inflammatory protein-1α and interleukin-10. These therapeutic effects of colivelin were associated with amelioration of glycocalyx density and mitochondrial structure in the aorta. At molecular analysis, colivelin treatment was associated with inhibition of the signal transducer and activator of transcription 3 and activation of the AMP-activated protein kinase in the aorta and lung. In long-term outcomes studies up to 7 days, co-treatment of colivelin with antimicrobial agents significantly reduced the disease severity score when compared to treatment with antibiotics alone. In conclusion, our data support that damage of the glycocalyx is an early pathogenetic event during sepsis and that colivelin may have therapeutic potential for the treatment of sepsis-associated endothelial dysfunction.
The evolution of humoral immune responses to past and novel influenza virus strains gives evidence for antigenic seniority
Authors: Sicca Federica , Sakorafa Eleni , de Jonge Anouk , de Vries-Idema Jacqueline , Zhou Fan , Cox Rebecca Jane , Huckriede Anke
Published: September 2022

The high genetic and antigenic variability of influenza virus and the repeated exposures of individuals to the virus over time account for the human immune responses toward this pathogen to continuously evolve during the lifespan of an individual. Influenza-specific immune memory to past strains has been shown to affect the immune responses to subsequent influenza strains and in turn to be changed itself through the new virus encounter. However, exactly how and to what extent this happens remains unclear. Here we studied pre-existing immunity against influenza A virus (IAV) by assessing IAV binding (IgG), neutralizing, and neuraminidase-specific antibodies to 5 different IAV strains in 180 subjects from 3 different age cohorts, adolescents, adults, and elderly, over a 5-year time span. In each age cohort, the highest neutralizing antibody titers were seen for a virus strain that circulated early in their life but the highest increase in titer was found for the most recent virus strains. In contrast, the highest IgG titers were seen against recent virus strains but the biggest increase in titer occurred against older strains. Significant increases in neutralizing antibody titers against a newly encountered virus strain were observed in all age cohorts demonstrating that pre-existing immunity did not hamper antibody induction. Our results indicate that the evolution of influenza-specific humoral immunity differs for rather cross-reactive virus-binding antibodies and more strain-specific neutralizing antibodies. Nevertheless, in general, our observations lend support to the antigenic seniority theory according to which the antibody response to influenza is broadened with each virus encounter, with the earliest encountered strain taking in the most senior and thus dominant position.
Prognostic value of PD-1, PD-L1 and PD-L2 deserves attention in head and neck cancer
Authors: Jiang Siqing , Li Xin , Huang Lihua , Xu Zhensheng , Lin Jinguan
Published: September 2022

Head and neck cancer has high heterogeneity with poor prognosis, and emerging researches have been focusing on the prognostic markers of head and neck cancer. PD-L1 expression is an important basis for strategies of immunosuppressive treatment, but whether it has prognostic value is still controversial. Although meta-analysis on PD-L1 expression versus head and neck cancer prognosis has been performed, the conclusions are controversial. Since PD-L1 and PD-L2 are two receptors for PD-1, here we summarize and analyze the different prognostic values of PD-1, PD-L1, and PD-L2 in head and neck cancer in the context of different cell types, tissue localization and protein forms. We propose that for head and neck cancer, the risk warning value of PD-1/PD-L1 expression in precancerous lesions is worthy of attention, and the prognostic value of PD-L1 expression at different subcellular levels as well as the judgment convenience of prognostic value of PD-1, PD-L1, PD-L2 should be fully considered. The PD-L1 evaluation systems established based on immune checkpoint inhibitors (ICIs) are not fully suitable for the evaluation of PD-L1 prognosis in head and neck cancer. It is necessary to establish a new PD-L1 evaluation system based on the prognosis for further explorations. The prognostic value of PD-L1, PD-L2 expression in head and neck cancer may be different for early-stage and late-stage samples, and further stratification is required.
A versatile toolkit for overcoming AAV immunity
Authors: Li Xuefeng , Wei Xiaoli , Lin Jinduan , Ou Li
Published: September 2022

Recombinant adeno-associated virus (AAV) is a promising delivery vehicle for in vivo gene therapy and has been widely used in >200 clinical trials globally. There are already several approved gene therapy products, e.g., Luxturna and Zolgensma, highlighting the remarkable potential of AAV delivery. In the past, AAV has been seen as a relatively non-immunogenic vector associated with low risk of toxicity. However, an increasing number of recent studies indicate that immune responses against AAV and transgene products could be the bottleneck of AAV gene therapy. In clinical studies, pre-existing antibodies against AAV capsids exclude many patients from receiving the treatment as there is high prevalence of antibodies among humans. Moreover, immune response could lead to loss of efficacy over time and severe toxicity, manifested as liver enzyme elevations, kidney injury, and thrombocytopenia, resulting in deaths of non-human primates and patients. Therefore, extensive efforts have been attempted to address these issues, including capsid engineering, plasmapheresis, IgG proteases, CpG depletion, empty capsid decoy, exosome encapsulation, capsid variant switch, induction of regulatory T cells, and immunosuppressants. This review will discuss these methods in detail and highlight important milestones along the way.
Immunomodulatory effects of regorafenib: Enhancing the efficacy of anti-PD-1/PD-L1 therapy
Authors: Liu Junjie , Tao Haisu , Yuan Tong , Li Jiang , Li Jian , Liang Huifang , Huang Zhiyong , Zhang Erlei
Published: September 2022

Anti-PD-1/PD-L1 therapy has shown significant benefits in the treatment of a variety of malignancies. However, not all cancer patients can benefit from this strategy due to drug resistance. Therefore, there is an urgent need for methods that can effectively improve the efficacy of anti-PD-1/PD-L1 therapy. Combining anti-PD-1/PD-L1 therapy with regorafenib has been demonstrated as an effective method to enhance its therapeutic effect in several clinical studies. In this review, we describe common mechanisms of resistance to anti-PD-1/PD-L1 therapy, including lack of tumor immunogenicity, T cell dysfunction, and abnormal expression of PD-L1. Then, we illustrate the role of regorafenib in modifying the tumor microenvironment (TME) from multiple aspects, which is different from other tyrosine kinase inhibitors. Regorafenib not only has immunomodulatory effects on various immune cells, but can also regulate PD-L1 and MHC-I on tumor cells and promote normalization of abnormal blood vessels. Therefore, studies on the synergetic mechanism of the combination therapy may usher in a new era for cancer treatment and help us identify the most appropriate individuals for more precise treatment.
ICOS-Fc as innovative immunomodulatory approach to counteract inflammation and organ injury in sepsis
Authors: Alves Gustavo Ferreira , Stoppa Ian , Aimaretti Eleonora , Monge Chiara , Mastrocola Raffaella , Porchietto Elisa , Einaudi Giacomo , Collotta Debora , Bertocchi Ilaria , Boggio Elena , Gigliotti Casimiro Luca , Clemente Nausicaa , Aragno Manuela , Fernandes Daniel , Cifani Carlo , Thiemermann Christoph , Dianzani Chiara , Dianzani Umberto , Collino Massimo
Published: September 2022

Inducible T cell co-stimulator (ICOS), an immune checkpoint protein expressed on activated T cells and its unique ligand, ICOSL, which is expressed on antigen-presenting cells and non-hematopoietic cells, have been extensively investigated in the immune response. Recent findings showed that a soluble recombinant form of ICOS (ICOS-Fc) can act as an innovative immunomodulatory drug as both antagonist of ICOS and agonist of ICOSL, modulating cytokine release and cell migration to inflamed tissues. Although the ICOS-ICOSL pathway has been poorly investigated in the septic context, a few studies have reported that septic patients have reduced ICOS expression in whole blood and increased serum levels of osteopontin (OPN), that is another ligand of ICOSL. Thus, we investigated the pathological role of the ICOS-ICOSL axis in the context of sepsis and the potential protective effects of its immunomodulation by administering ICOS-Fc in a murine model of sepsis. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in five-month-old male wild-type (WT) C57BL/6, ICOS-/-, ICOSL-/- and OPN-/- mice. One hour after the surgical procedure, either CLP or Sham (control) mice were randomly assigned to receive once ICOS-Fc, F119SICOS-Fc, a mutated form uncapable to bind ICOSL, or vehicle intravenously. Organs and plasma were collected 24 h after surgery for analyses. When compared to Sham mice, WT mice that underwent CLP developed within 24 h a higher clinical severity score, a reduced body temperature, an increase in plasma cytokines (TNF-α, IL-1β, IL-6, IFN-γ and IL-10), liver injury (AST and ALT) and kidney (creatinine and urea) dysfunction. Administration of ICOS-Fc to WT CLP mice reduced all of these abnormalities caused by sepsis. Similar beneficial effects were not seen in CLP-mice treated with F119SICOS-Fc. Treatment of CLP-mice with ICOS-Fc also attenuated the sepsis-induced local activation of FAK, P38 MAPK and NLRP3 inflammasome. ICOS-Fc seemed to act at both sides of the ICOS-ICOSL interaction, as the protective effect was lost in septic knockout mice for the ICOS or ICOSL genes, whereas it was maintained in OPN knockout mice. Collectively, our data show the beneficial effects of pharmacological modulation of the ICOS-ICOSL pathway in counteracting the sepsis-induced inflammation and organ dysfunction.
Comparative analysis of four types of mesoscale eddies in the north pacific subtropical countercurrent region – part I spatial characteristics
Authors: An Mengxuan , Liu Jie , Liu Jishan , Sun Wenjin , Yang Jingsong , Tan Wei , Liu Yu , Sian Kenny T. C. Lim Kam , Ji Jinlin , Dong Changming
Published: September 2022

The North Pacific Subtropical Countercurrent (STCC) region has high mesoscale eddy activities due to its complex circulation structure. This study divides these mesoscale eddies into four types: cyclonic cold-core eddy (CCE), anticyclonic warm-core eddy (AWE), cyclonic warm-core eddy (CWE), and anticyclonic cold-core eddy (ACE) according to the rotation direction of the eddy flow field and the sign of average temperature anomaly within the eddy after spatial high-pass filtering. CCE and ACE are called normal eddies, while CWE and ACE are named abnormal eddies. Using eddy-resolving model data (OFES), this work finds that the abnormal eddy phenomenon mainly occurs in the ocean’s upper layer. The eddy number proportion for CCEs, AWEs, CWEs, and ACEs at the sea surface is 35.60, 32.08, 12.95, and 19.37%. The corresponding average radius is 79.14 ± 3.7, 83.34 ± 3.75, 73.74 ± 4.14, and 79.46 ± 3.89 km, respectively. Each type of eddy’s average amplitude is about 3 cm. Regarding the eddy average eccentricity, the four types of eddies have very close eccentricities, with a range of 0.73 ~ 0.76. If the types of eddies are not distinguished, the eddies generated north of 21°N tend to move southward, while eddies generated south of that latitude tend to move northward. The depth of CCEs, AWEs, CWEs, and ACEs with average eddy nonlinearity larger than one is concentrated in the ocean’s upper layer at 109.0, 116.0, 159.0, and 52.0 m, respectively. This study deepens the understanding of the spatial distribution characteristics of mesoscale eddies in the STCC region.
Seabird vulnerability to oil: Exposure potential, sensitivity, and uncertainty in the northern Gulf of Mexico
Authors: Michael Pamela E. , Hixson Kathy M. , Haney J. Christopher , Satgé Yvan G. , Gleason Jeffrey S. , Jodice Patrick G. R.
Published: September 2022

The northern Gulf of Mexico (nGoM) is a globally important region for oil extraction and supports a diverse assemblage of marine birds. Due to their frequent contact with surface waters, diverse foraging strategies, and the ease with which oil adheres to feathers, seabirds are particularly susceptible to hydrocarbon contamination. Given the chronic and acute exposure of seabirds to oiling and a lack of studies that focus on the exposure of seabirds to oiling in sub-tropical and tropical regions, a greater understanding of the vulnerability of seabirds to oil in the nGoM appears warranted. We present an oil vulnerability index for seabirds in the nGoM tailored to the current state of knowledge using new, spatiotemporally expensive vessel-based seabird observations. We use information on the exposure and sensitivity of seabirds to oil to rank seabird vulnerability. Exposure variables characterized the potential to encounter oil and gas (O&G). Sensitivity variables characterized the potential impact of seabirds interacting with O&G and are related to life history and productivity. We also incorporated uncertainty in each variable, identifying data gaps. We found that the percent of seabirds’ habitat defined as highly suitable within 10 km of an O&G platform ranged from 0%-65% among 24 species. Though O&G platforms only overlap with 15% of highly suitable seabird habitat, overlap occurs in areas of moderate to high vulnerability of seabirds, particularly along the shelf-slope. Productivity-associated sensitivity variables were primarily responsible for creating the gradient in vulnerability scores and had greater uncertainty than exposure variables. Highly vulnerable species (e.g., Northern gannet (Morus bassanus)) tended to have high exposure to the water surface via foraging behaviors (e.g., plunge-diving), older age at first breeding, and an extended incubating and fledging period compared to less vulnerable species (e.g., Pomarine jaeger (Stercorarius pomarinus)). Uncertainty related to productivity could be reduced through at-colony monitoring. Strategic seabird satellite tagging could help target monitoring efforts to colonies known to use the nGoM, and continued vessel-based observations could improve habitat characterization. As offshore energy development in the nGoM continues, managers and researchers could use these vulnerability ranks to identify information gaps to prioritize research and focal species.
Acclimation of marine invertebrate osmolyte systems to low salinity: A systematic review & meta-analysis
Authors: Podbielski Imke , Schmittmann Lara , Sanders Trystan , Melzner Frank
Published: September 2022

Salinity is a major environmental factor shaping the distribution and abundance of marine organisms. Climate change is predicted to alter salinity in many coastal regions due to sea level rise, evaporation, and changes in freshwater input. This exerts significant physiological stress on coastal invertebrates whose body fluid osmolality follows that of seawater (‘osmoconformers’). In this study, we conducted a systematic review and meta-analysis of osmolytes (both organic and inorganic) utilized by osmoconforming marine invertebrates during a >14-day acclimation to reduced salinity. Of the 2,389 studies screened, a total of 56 fulfilled the search criteria. Thirty-eight studies reported tissue osmolyte. Following acclimation to reduced salinity, tissue concentrations of six organic compounds and sodium were consistently reduced across phyla. This suggests that intracellular inorganic ions are not only utilized as a rapid response system during acute exposure to low salinity stress but also, in concert with reductions in organic osmolyte concentrations, during longer-term acclimation. Our systematic review demonstrates that only a few studies (n = 13) have quantified salinity-induced long-term changes in intracellular ion concentrations. In addition, no study has compiled a complete intracellular osmolyte budget. Alanine, betaine, glycine, and taurine are the major organic osmolytes that are universally employed across five phyla. The characterization of organic osmolytes was heavily weighted towards free amino acids (FAAs) and derivatives—neglecting methylamines and methylsulfonium compounds, which can be as important as FAAs in modulating intracellular osmolality. As a consequence, we suggest best-practice guidelines to streamline experimental designs and protocols in osmoregulation research in order to better understand the conserved mechanisms that define the limits of salinity acclimation in marine invertebrates. To our best knowledge, this is the first systematic review and meta-analysis on osmolyte concentrations in osmoconformers acclimated to low salinity. It creates a valuable baseline for future research and reveals large research gaps. Our meta-analysis suggests that there are common osmolyte actors employed across phyla but no uniform concept since osmolyte pool composition and proportions were taxon-specific. In light of future salinity changes and their potential consequences, it becomes more important to understand salinity tolerance capacities and limits.
Reporting the accuracy of small-scale fishing data by simply applying Benford’s law
Authors: Noleto-Filho Eurico Mesquita , Carvalho Adriana Rosa , Thomé-Souza Mario J. F. , Angelini Ronaldo
Published: September 2022

Small-scale fisheries (SSFs) play essential economic, social, and cultural roles for many fleets in the Atlantic region. The basis of fisheries assessment and management is the landings reported by observers or fishers. Even though the information from the landings is essential, it can be subject to a fisher’s bias, such as the tendency to inflate catches and the refusal to fill the logs. The feasibility for managers using field surveys to validate these datasets is held up by the high costs, shortage in monitoring, and the lack of prior information. Alternatively, Benford analysis overcomes those limitations since it can be applied directly on the logbook data. This method is growing in popularity, underlining its suitability to many economic and biological fields. Hence, in this study, we inspected small-scale fisheries data by the Benford’s distribution, aiming to validate fish landing data from 27 points in Brazil’s northeastern region over 3 years. Our results suggest that 20% of landings data are considered highly imprecise (misinformation), especially from non-motorized canoes. Also, harbors in remote locations provide poorer quality data, specifically monthly catch values reported by several boats. The way we mine our data affects the sensitivity of the analysis, with monthly data being less prone to be accessed by this method than daily information. As the results match our prior knowledge on the location, we endorse the suitability of the method and reliability for assessing accuracy in fishing data. Hence, we recommend that it ought to be used as an audit tool for SSF landing data aiming to enlighten data reliance and support managers for planning management actions.