bluuebunny/crossref_metadata_2025 huggingface dataset:
Allostasis revisited: A perception, variation, and risk framework
Authors: Word Karen R. , Austin Suzanne H. , Wingfield John C.
Published: September 2022

The framework of allostasis, allostatic load and overload (i.e., stability through change) attempts to combine homeostasis processes in day-to-day responses of physiology and behavior. These include predictive changes in environment such as seasons, and facultative responses to perturbations. The latter can be severe, occur at any time, and may present considerable additional challenges to homeostasis. Hormonal cascades, such as the hypothalamo-pituitary-adrenal cortex (HPA) axis, play a key role in responses to perturbations across vertebrate taxa. Glucocorticoids have been implicated in these processes in relation to energy balance that plays a role in determining responses to energetic demand (allostatic load) and influencing subsequent physiology and behavior associated with coping. Circulating glucocorticoid levels are likely regulated in part based on an individual’s proximity to energetic crisis, identified as the perturbation resistance potential (PRP). In the model of allostatic load, PRP is quantified as the difference between available resources and all energetic costs of allostatic load such as daily routines, life history stages (breeding, migration, molt and so on), and the impact of environmental perturbations. PRP can change gradually or abruptly and may be reflected by spikes in blood hormone levels. The pattern of individual responsiveness to PRP may vary and has specific implications for the activation of mineralocorticoid vs glucocorticoid-type receptors, hormone metabolizing enzymes and other downstream factors in target tissues. However, PRP is a difficult metric to measure. Here, we examine the variety of cues that animals may use to inform them about the status of their PRP and probability of energetic crisis. We consider (1) elevation in glucocorticoids as an endocrine “decision,” and (2) error management strategies in evaluating responsiveness to cues that may reflect or predict an impending energetic crisis. The potential for differential receptor activation as well as further integrative “decisions” to determine the diverse and sometimes contradictory effects of receptor activation and its downstream actions are important to the consideration of error management. This perspective offers insight into the basis of intra- and inter-individual variability in responsiveness and opens an avenue toward improving compatibility of the allostasis model with more classical views on “stress”.
Transmembrane and coiled-coil domains 3 is a diagnostic biomarker for predicting immune checkpoint blockade efficacy in hepatocellular carcinoma
Authors: Hu Xinyao , Zhu Hua , Feng Shi , Wang Chaoqun , Ye Yingze , Xiong Xiaoxing
Published: September 2022

Liver hepatocellular carcinoma (LIHC) is a malignancy with a high mortality and morbidity rate worldwide. However, the pathogenesis of LIHC has still not been thoroughly studied. Transmembrane and coiled-coil domains 3 (TMCO3) encodes a monovalent cation, a member of the proton transducer 2 (CPA2) family of transporter proteins. In the present study, TMCO3 expression and its relationship with cancer prognosis, as well as its immunological role in LIHC were studied by bioinformatic analysis. We found the significant overexpression of TMCO3 in LIHC in the TCGA, HCCDB, and GEO databases. In LIHC patients, high TMCO3 expression was related to poorer overall survival (OS) and TMCO3 had good predictive accuracy for prognosis. Moreover, TMCO3 was linked to the infiltrates of certain immune cells in LIHC. The correlation of TMCO3 with immune checkpoints was also revealed. Moreover, patients with LIHC with low TMCO3 expression showed a better response to immune checkpoint blockade (ICB) than those with LIHC with high TMCO3 expression. GO and KEGG enrichment analyses indicated that TMCO3 was probably involved in the microtubule cytoskeleton organization involved in mitosis, small GTPase mediated signal transduction, and TGF-β pathway. In conclusion, TMCO3 may be a potential biomarker for LIHC prognosis and immunotherapy.
Identification and validation of a prognostic model of necroptosis-related lncRNAs in hepatocellular carcinoma
Authors: Chen Min , Wu Guang-Bo , Hua Shan , Zhao Zhi-Feng , Li Hong-Jie , Luo Meng
Published: September 2022

Background: The study focused on establishing a prognostic survival model with six necroptosis-related lncRNAs to predict overall survival (OS) in patients with hepatocellular carcinoma (HCC).

Methods: The data of gene expression and clinical information of HCC patients were obtained from The Cancer Genome Atlas (TCGA). Cox regression with LASSO was used for constructing a necroptosis-related lncRNA survival model, which we further validated with qRT-PCR in vitro. The relative bioinformatics analysis and consensus cluster analysis were performed based on six differentially expressed lncRNAs.

Results: The survival prognostic model was constructed by using data from TCGA. Receiver operating characteristic (ROC) curves showed a good survival prediction by this model. GSEA showed that several signaling pathways were related to HCC progression. Immune-related functional analysis showed that aDCs, macrophages, Th2 cells, and Tregs have stronger correlation with the high-risk group. The consensus cluster analysis further validated the 6-lncRNA prognostic model.

Conclusion: A novel 6-lncRNA (AL606489.1, NRAV, LINC02870, DUXAP8, “ZFPM2-AS1,” and AL031985.3) prognostic model had an accurately predictive power in HCC prognosis, which might be worthy of clinical application.
Diverse selection pressures shaping the genetic architecture of behçet disease susceptibility
Authors: Sezgin Efe , Kaplan Elif
Published: September 2022

Behçet disease (BD) is a polygenic, multifactorial, multisystem inflammatory condition with unknown etiology. Global distribution of BD is geographically structured, highest prevalence observed among East Asian, Middle Eastern, and Mediterranean populations. Although adaptive selection on a few BD susceptibility loci is speculated, a thorough evolutionary analysis on the genetic architecture of BD is lacking. We aimed to understand whether increased BD risk in the human populations with high prevalence is due to past selection on BD associated genes. We performed population genetics analyses with East Asian (high BD prevalence), European (low/very low BD prevalence), and African (very low/no BD prevalence) populations. Comparison of ancestral and derived alleles’ frequencies versus their reported susceptible or protective effect on BD showed both derived and ancestral alleles are associated with increased BD risk. Variants showing higher risk to and more significant association with BD had smaller allele frequency differences, and showed less population differentiation compared to variants that showed smaller risk and less significant association with BD. Results suggest BD alleles are not unique to East Asians but are also found in other world populations at appreciable frequencies, and argue against selection favoring these variants only in populations with high BD prevalence. BD associated gene analyses showed similar evolutionary histories driven by neutral processes for many genes or balancing selection for HLA (Human Leukocyte Antigen) genes in all three populations studied. However, nucleotide diversity in several HLA region genes was much higher in East Asians suggesting selection for high nucleotide and haplotype diversity in East Asians. Recent selective sweep for genes involved in antigen recognition, peptide processing, immune and cellular differentiation regulation was observed only in East Asians. We conclude that the evolutionary processes shaping the genetic diversity in BD risk genes are diverse, and elucidating the underlying specific selection mechanisms is complex. Several of the genes examined in this study are risk factors (such as ERAP1, IL23R, HLA-G) for other inflammatory diseases. Thus, our conclusions are not only limited to BD but may have broader implications for other inflammatory diseases.
Exploring the casual association between coffee intake and bladder cancer risk using Mendelian Randomization
Authors: Deng Yuqing , Wu Tingting , Luo Gang , Chen Lin
Published: September 2022

Objective: Several observational studies have suggested that coffee consumption is associated with a lower risk of bladder cancer. However, observational studies are susceptible to confounding factors and reverse causality. We used a two-sample Mendelian randomization (MR) method to assess the causal nature of this association.

Methods: At the genome-wide significance level (p < 5 × 10−8), 12 single nucleotide polymorphisms (SNPs) strongly associated with coffee consumption were used as instrumental variables (IVs). Summary-level data on genetic variation in bladder cancer were obtained from the United Kingdom biobank (420,838 samples) and FinnGen consortium (175,121 samples). Multiple MR methods were used. Heterogeneity and horizontal pleiotropy were detected using Cochran’s Q test and MR-Egger.

Results: Twelve SNPs were included in the primary analysis. After excluding 8 SNPs with potential secondary phenotypes, the remaining 4 SNPs were included in the sensitivity analysis. In all analyses, Cochran’s Q statistic indicated that there was no heterogeneity among SNPs, and the MR-Egger analysis did not reveal the existence of horizontal pleiotropy (p > 0.05). In the United Kingdom Biobank, the odds ratio (OR) for bladder cancer was 1.022 (95% confidence interval (CI), 0.679–1.537) for per 50% increase in coffee consumption. Consistent results were obtained in the FinnGen consortium (OR = 0.890, 95% CI, 0.467–1.697). Sensitivity analysis showed consistent results with primary analysis.

Conclusion This study does not support a causal association between habitual coffee consumption and bladder cancer risk.
HTRA1 rs11528744, BCRA1 rs9928736, and B3GLCT rs4381465 are associated with age-related macular degeneration in a Chinese population
Authors: Huang Guo , Li Huan , Lai Shuang , Xiao Jialing , Wang Liang , Xu Huijuan , Lei Chuntao , Zhang Jinglan , Yu Man , Shuai Ping , Liu Yuping , Shi Yi , Wang Kaijie , Gong Bo
Published: September 2022

Purpose: Age-related macular degeneration (AMD) is a leading cause of vision loss. A Previous study based on the co-localization analysis of the genome-wide association study (GWAS) and eQTL genetic signals have reported that single nucleotide polymorphisms (SNPs), including rs760975, rs11528744, rs3761159, rs7212510, rs6965458, rs7559693, rs56108400, rs28495773, rs9928736, rs11777697, rs4381465 are associated with AMD in Americans. The aim of this study was to investigate the association of these SNPs in a Han Chinese population.

Methods: There were 576 patients with wet AMD and 572 healthy controls collected in this study. All SNPs were genotyped by flight mass spectrum. Hardy–Weinberg equilibrium was applied to evaluate allele distributions for both AMD and control groups. The genotype and allele frequencies were evaluated using the χ2 tests. Odds ratio (OR) and 95% confidence intervals (95% CI) were calculated for the risk of genotype and allele.

Results: Three of the 11 SNPs (rs11528744 in HTRA1, rs9928736 in BCRA1 and rs4381465 in B3GLCT) were found to be significantly associated with AMD in the allelic model (corrected p = 0.001, OR = 1.391, 95%CI = 1.179–1.640 for rs11528744; corrected p = 0.004, OR = 0.695, 95%CI = 0.544–0.888 for rs9928736; corrected p = 0.002, OR = 0.614, 95%CI = 0.448–0.841 for rs4381465). There were no differences for the remaining eight SNPs between AMD cases and healthy controls.

Conclusion: Our results showed that HTRA1 rs11528744, BCRA1 rs9928736, and B3GLCT rs4381465 were associated with wet AMD, suggesting that HTRA1, BCRA1, and B3GLCT genes may be involved in the development of AMD.
A boy with amblyopia and familial exudative vitreoretinopathy harboring a new mutation of LRP5 and OPA1: A case report
Authors: Chen Chunli , Guo Sitong , Zhao Rui , Liu Shoubin , Wu Jingjing , Xiao Yuanyuan , Hou Simeng , Jiang Libin
Published: September 2022

Background: The study aimed to report a boy with familial exudative vitreoretinopathy and amblyopia harboring a new mutation of the LRP5 and OPA1 gene abnormality.

Case presentation: A 9-year-old boy presented with a 2-year history of deteriorating visual acuity in the right eye. His best-corrected visual acuity was −7.00/−1.75 × 100 = 0.3 in the right eye and −2.50/−1.50 × 170 = 0.8 in the left eye. Two autosomal dominant gene mutation sites were identified in the patient: LRP5 (c.2551C > T, p.His851Tyr) from his father and OPA1 (c.565G > A, p.Glu189Lys) from his mother. Interestingly, his fraternal twin brother harbored no abnormal gene mutations, and his eye tests were normal.

Conclusion: This case expands the spectrum of LRP5 gene mutations among Chinese patients with familial exudative vitreoretinopathy, and it is the first time to report a patient harboring both LRP5 and OPA1 gene mutations having anisometropic amblyopia and strabismus as the primary manifestations. These four family members exhibited individual heterogeneity of phenotypes and genotypes associated with hereditary ophthalmopathy. A comprehensive analysis of clinical phenotypes and genotypes provides clinical clues for improving the level of clinical and genetic diagnoses and a deeper understanding of the disease.
Identification and validation of a 17-gene signature to improve the survival prediction of gliomas
Authors: Tong Shiao , Xia Minqi , Xu Yang , Sun Qian , Ye Liguo , Cai Jiayang , Ye Zhang , Tian Daofeng
Published: September 2022

Gliomas are one of the most frequent types of nervous system tumours and have significant morbidity and mortality rates. As a result, it is critical to fully comprehend the molecular mechanism of glioma to predict prognosis and target gene therapy. The goal of this research was to discover the hub genes of glioma and investigate their prognostic and diagnostic usefulness. In this study, we collected mRNA expression profiles and clinical information from glioma patients in the TCGA, GTEx, GSE68848, and GSE4920 databases. WGCNA and differential expression analysis identified 170 DEGs in the collected datasets. GO and KEGG pathway analyses revealed that DEGs were mainly enriched in gliogenesis and extracellular matrix. LASSO was performed to construct prognostic signatures in the TCGA cohort, and 17 genes were used to build risk models and were validated in the CGGA database. The ROC curve confirmed the accuracy of the prognostic signature. Univariate and multivariate Cox regression analyses showed that all independent risk factors for glioma except gender. Next, we performed ssGSEA to demonstrate a high correlation between risk score and immunity. Subsequently, 7 hub genes were identified by the PPI network and found to have great drug targeting potential. Finally, RPL39, as one of the hub genes, was found to be closely related to the prognosis of glioma patients. Knockdown of RPL39 in vitro significantly inhibited the proliferation and migration of glioma cells, whereas overexpression of RPL39 had the opposite effect. And we found that knockdown of RPL39 inhibited the polarization and infiltration of M2 phenotype macrophages. In conclusion, our new prognosis-related model provides more potential therapeutic strategies for glioma patients.
In ovo model in cancer research and tumor immunology
Authors: Miebach Lea , Berner Julia , Bekeschus Sander
Published: September 2022

Considering cancer not only as malignant cells on their own but as a complex disease in which tumor cells interact and communicate with their microenvironment has motivated the establishment of clinically relevant 3D models in past years. Technological advances gave rise to novel bioengineered models, improved organoid systems, and microfabrication approaches, increasing scientific importance in preclinical research. Notwithstanding, mammalianin vivomodels remain closest to mimic the patient’s situation but are limited by cost, time, and ethical constraints. Herein, thein ovomodel bridges the gap as an advanced model for basic and translational cancer research without the need for ethical approval. With the avian embryo being a naturally immunodeficient host, tumor cells and primary tissues can be engrafted on the vascularized chorioallantoic membrane (CAM) with high efficiencies regardless of species-specific restrictions. The extraembryonic membranes are connected to the embryo through a continuous circulatory system, readily accessible for manipulation or longitudinal monitoring of tumor growth, metastasis, angiogenesis, and matrix remodeling. However, its applicability in immunoncological research is largely underexplored. Dual engrafting of malignant and immune cells could provide a platform to study tumor-immune cell interactions in a complex, heterogenic and dynamic microenvironment with high reproducibility. With some caveats to keep in mind, versatile methods forinandex ovomonitoring of cellular and molecular dynamics already establishedin ovoare applicable alike. In this view, the present review aims to emphasize and discuss opportunities and limitations of the chicken embryo model for pre-clinical research in cancer and cancer immunology.
Acute stress induces an inflammation dominated by innate immunity represented by neutrophils in mice
Authors: Tang Lanjing , Cai Nannan , Zhou Yao , Liu Yi , Hu Jingxia , Li Yalin , Yi Shuying , Song Wengang , Kang Li , He Hao
Published: September 2022

It is well known that psychological stress could affect the immune system and then regulate the disease process. Previous studies mostly focused on the effects of chronic stress on diseases and immune cells. How acute stress affects the immune system remains poorly understood. In this study, after 6 hours of restraint stress or no stress, RNA was extracted from mouse peripheral blood followed by sequencing. Through bioinformatics analysis, we found that when compared with the control group, differentially expressed genes in the stress group mainly displayed up-regulated expression. Gene set enrichment analysis results showed that the enriched gene terms were mainly related to inflammatory response, defense response, wounding response, wound healing, complement activation and pro-inflammatory cytokine production. In terms of cell activation, differentiation and chemotaxis, the enriched gene terms were related to a variety of immune cells, among which neutrophils seemed more active in stress response. The results of gene set variation analysis showed that under acute stress, the inflammatory reaction dominated by innate immunity was forming. Additionally, the concentration of serum IL-1β and IL-6 increased significantly after acute stress, indicating that the body was in an inflammatory state. Importantly, we found that acute stress led to a significant increase in the number of neutrophils in peripheral blood, while the number of T cells and B cells decreased significantly through flow cytometric analysis. Through protein-protein interaction network analysis, we screened 10 hub genes, which mainly related to inflammation and neutrophils. We also found acute stress led to an up-regulation of Ccr1, Ccr2, Xcr1 and Cxcr2 genes, which were involved in cell migration and chemotaxis. Our data suggested that immune cells were ready to infiltrate into tissues in emergency through blood vessels under acute stress. This hypothesis was supported in LPS-induced acute inflammatory models. After 48 hours of LPS treatment, flow cytometric analysis showed that the lungs of mice with acute stress were characterized by increased neutrophil infiltration, decreased T cell and B cell infiltration. Immunohistochemical analysis also showed that acute stress led to more severe lung inflammation. If mice received repeat acute stress and LPS stimulation, the survival rate was significantly lower than that of mice only stimulated by LPS. Altogether, acute stress led to rapid mobilization of the immune system, and the body presented an inflammatory state dominated by innate immune response represented by neutrophils.
Blood DNA methylation marks discriminate Chagas cardiomyopathy disease clinical forms
Authors: Brochet Pauline , Ianni Barbara , Nunes João P. S. , Frade Amanda F. , Teixeira Priscila C. , Mady Charles , Ferreira Ludmila R. P. , Kuramoto Andreia , Pissetti Cristina W. , Saba Bruno , Cândido Darlan D. S. , Dias Fabrício , Sampaio Marcelo , Marin-Neto José A. , Fragata Abílio , Zaniratto Ricardo C .F. , Siqueira Sergio , Peixoto Giselle D. L. , Rigaud Vagner O. C. , Buck Paula , Almeida Rafael R. , Lin-Wang Hui Tzu , Schmidt André , Martinelli Martino , Hirata Mario H. , Donadi Eduardo , Rodrigues Junior Virmondes , Pereira Alexandre C. , Kalil Jorge , Spinelli Lionel , Cunha-Neto Edecio , Chevillard Christophe
Published: September 2022

Chagas disease is a parasitic disease from South America, affecting around 7 million people worldwide. Decades after the infection, 30% of people develop chronic forms, including Chronic Chagas Cardiomyopathy (CCC), for which no treatment exists. Two stages characterized this form: the moderate form, characterized by a heart ejection fraction (EF) ≥ 0.4, and the severe form, associated to an EF < 0.4. We propose two sets of DNA methylation biomarkers which can predict in blood CCC occurrence, and CCC stage. This analysis, based on machine learning algorithms, makes predictions with more than 95% accuracy in a test cohort. Beyond their predictive capacity, these CpGs are located near genes involved in the immune response, the nervous system, ion transport or ATP synthesis, pathways known to be deregulated in CCCs. Among these genes, some are also differentially expressed in heart tissues. Interestingly, the CpGs of interest are tagged to genes mainly involved in nervous and ionic processes. Given the close link between methylation and gene expression, these lists of CpGs promise to be not only good biomarkers, but also good indicators of key elements in the development of this pathology.
Downregulation of long noncoding RNA HCP5/miR-216a-5p/ZEB1 axis inhibits the malignant biological function of laryngeal squamous cell carcinoma cells
Authors: Zhang Sen , Huangfu Hui , Zhao Qinli , Li Yujun , Wu Lina
Published: September 2022

Previous studies find that long noncoding RNA human leukocyte antigen complex P5 (HCP5) is regarded as an oncogene via accelerating cancer cell growth, invasion, metastasis, vascularization, and drug resistance in renal cell carcinoma, gastric cancer, and colorectal cancer. Nevertheless, the effect and regulatory mechanism of HCP5 in laryngeal squamous cell carcinoma (LSCC) remains unknown. In this study, HCP5 expression levels were confirmed to be prominently raised in LSCC cell lines. HCP5 knockdown reduced cell proliferation and migration and invasive ability of LSCC cell lines. Furthermore, miR-216a-5p was confirmed to sponge HCP5, and its expression was prominently downregulated in LSCC cell lines and upregulated in HCP5-silenced LSCC cell lines. miR-216a-5p overexpression downregulated the cell proliferation and migration and invasive ability of LSCC cells. Additionally, the protein level of zinc finger E-box binding homeobox 1 (ZEB1), one target gene of miR-216a-5p, was highly expressed in LSCC cell lines, and its expression level was downregulated by HCP5 knockdown and miR-216a-5p overexpression. An miR-216a-5p inhibitor reversed the effect of HCP5 knockdown on the proliferation and migration and invasive ability of LSCC cells. In conclusion, knocking down HCP5 may be a strategy to suppress the malignant biological function via regulating miR-216a-5p/ZEB1. Therefore, HCP5 may become a prospective therapeutic target for LSCC.
Mycobacterial acyl carrier protein suppresses TFEB activation and upregulates miR-155 to inhibit host defense
Authors: Paik Seungwha , Kim Kyeong Tae , Kim In Soo , Kim Young Jae , Kim Hyeon Ji , Choi Seunga , Kim Hwa-Jung , Jo Eun-Kyeong
Published: September 2022

Mycobacterial acyl carrier protein (AcpM; Rv2244), a key protein involved in Mycobacterium tuberculosis (Mtb) mycolic acid production, has been shown to suppress host cell death during mycobacterial infection. This study reports that mycobacterial AcpM works as an effector to subvert host defense and promote bacterial growth by increasing microRNA (miRNA)-155-5p expression. In murine bone marrow-derived macrophages (BMDMs), AcpM protein prevented transcription factor EB (TFEB) from translocating to the nucleus in BMDMs, which likely inhibited transcriptional activation of several autophagy and lysosomal genes. Although AcpM did not suppress autophagic flux in BMDMs, AcpM reduced Mtb and LAMP1 co-localization indicating that AcpM inhibits phagolysosomal fusion during Mtb infection. Mechanistically, AcpM boosted the Akt-mTOR pathway in BMDMs by upregulating miRNA-155-5p, a SHIP1-targeting miRNA. When miRNA-155-5p expression was inhibited in BMDMs, AcpM-induced increased intracellular survival of Mtb was suppressed. In addition, AcpM overexpression significantly reduced mycobacterial clearance in C3HeB/FeJ mice infected with recombinant M. smegmatis strains. Collectively, our findings point to AcpM as a novel mycobacterial effector to regulate antimicrobial host defense and a potential new therapeutic target for Mtb infection.
Neutrophil depletion in the pre-implantation phase impairs pregnancy index, placenta and fetus development
Authors: Hebeda Cristina Bichels , Savioli Anna Carolina , Scharf Pablo , de Paula-Silva Marina , Gil Cristiane Damas , Farsky Sandra Helena Poliselli , Sandri Silvana
Published: September 2022

Maternal neutrophils cells are players in gestational tolerance and fetus delivery. Nonetheless, their actions in each phase of the pregnancy are unknown. We here investigated the role of maternal neutrophil depletion before the blastocyst implantation phase and outcomes in the pregnancy index, placenta, and fetus development. Neutrophils were pharmacologically depleted by i.p. injection of anti-Gr1 (anti-neutrophils; 200 µg) 24 hours after plug visualization in allogeneic-mated C57BL/6/BALB/c mice. Depletion of peripheral neutrophils lasted until 48 hours after anti-Gr1 injection (gestational day 1.5-3.5). On gestational day 5.5, neutrophil depletion impaired the blastocyst implantation, as 50% of pregnant mice presented reduced implantation sites. On gestational day 18.5, neutrophil depletion reduced the pregnancy rate and index, altered the placenta disposition in the uterine horns, and modified the structure of the placenta, detected by reduced junctional zone, associated with decreased numbers of giant trophoblast cells, spongiotrophoblast. Reduced number of placenta cells labeled for vascular endothelial growth factor (VEGF), platelet-endothelial cell adhesion molecule (PECAM-1), and intercellular cell adhesion molecule (ICAM-1), important markers of angiogenesis and adhesiveness, were detected in neutrophil depleted mice. Furthermore, neutrophil depletion promoted a higher frequency of monocytes, natural killers, and T regulatory cells, and lower frequency of cytotoxic T cells in the blood, and abnormal development of offspring. Associated data obtained herein highlight the pivotal role of neutrophils actions in the early stages of pregnancy, and address further investigations on the imbricating signaling evoked by neutrophils in the trophoblastic interaction with uterine epithelium.
Modulation of urelumab glycosylation separates immune stimulatory activity from organ toxicity
Authors: Reitinger Carmen , Ipsen-Escobedo Andrea , Hornung Chiara , Heger Lukas , Dudziak Diana , Lux Anja , Nimmerjahn Falk
Published: September 2022

Checkpoint control and immunomodulatory antibodies have become important tools for modulating tumor or self-reactive immune responses. A major issue preventing to make full use of the potential of these immunomodulatory antibodies are the severe side-effects, ranging from systemic cytokine release syndrome to organ-specific toxicities. The IgG Fc-portion has been demonstrated to contribute to both, the desired as well as the undesired antibody activities of checkpoint control and immunomodulatory antibodiesviabinding to cellular Fcγ-receptors (FcγR). Thus, choosing IgG subclasses, such as human IgG4, with a low ability to interact with FcγRs has been identified as a potential strategy to limit FcγR or complement pathway dependent side-effects. However, even immunomodulatory antibodies on the human IgG4 background may interact with cellular FcγRs and show dose limiting toxicities. By using a humanized mouse model allowing to study the immunomodulatory activity of human checkpoint control antibodiesin vivo, we demonstrate that deglycosylation of the CD137-specific IgG4 antibody urelumab results in an amelioration of liver toxicity, while maintaining T cell stimulatory activity. In addition, our results emphasize that antibody dosing impacts the separation of side-effects of urelumab from its therapeutic activityviaIgG deglycosylation. Thus, glycoengineering of human IgG4 antibodies may be a possible approach to limit collateral damage by immunomodulatory antibodies and allow for a greater therapeutic window of opportunity.
Comprehensive immune cell analysis of human menstrual-blood-derived stem cells therapy to concanavalin A hepatitis
Authors: Zhang Fen , Fan Linxiao , Liu Qiuhong , Tang Shima , Zhang Sainan , Xiao Lanlan , Zhang Lingjian , Li Qian , Maihemuti Nueraili , Li Lanjuan
Published: September 2022

Autoimmune hepatitis is an autoimmune disease with increasing occurrence worldwide. The most common and convenient mouse model is the concanavalin A (ConA) mouse model. Human menstrual-blood-derived stem cells (MenSCs) have shown great potential as a type of mesenchymal stem cell for treating various diseases. Time-of-flight mass cytometry was performed in phosphate-buffered saline control (NC) group and ConA injection with or without MenSCs treatment groups, and conventional flow cytometry was used for further validation. The serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and H&E staining depicted that MenSCs treatment could significantly alleviate ConA-induced hepatitis. The t-distributed stochastic neighbor embedding (t-SNE) analysis of nine liver samples displayed favorable cell clustering, and the NC group was significantly different from the other two groups. The proportions of CD69+T cells, NKT cells, and PD-L1+macrophages were notably increased by ConA injection, while MenSCs could decrease ConA-induced macrophage percentage and M1 polarization in the liver tissue. The analysis of proinflammatory factors carried out by cytometric bead array demonstrated that tumor necrosis factor alpha (TNF-α), interleukin (IL)-17A, IL-12p70, IL-6, IL-2, IL-1b, and interferon gamma (IFN-γ) were upregulated after ConA injection and then rapidly decreased at 12 h. MenSCs also played an important role in downregulating these cytokines. Here, we described the comprehensive changes in leukocytes in the liver tissue of ConA-induced hepatitis at 12 h after ConA injection and found that MenSCs rescued ConA-induced hepatitis mostly by inhibiting macrophages and M1 polarization in mouse liver.
Determinants of anti-S immune response at 6 months after COVID-19 vaccination in a multicentric European cohort of healthcare workers – ORCHESTRA project
Authors: Collatuzzo Giulia , Visci Giovanni , Violante Francesco S. , Porru Stefano , Spiteri Gianluca , Monaco Maria Grazia Lourdes , Larese Fillon Francesca , Negro Corrado , Janke Christian , Castelletti Noemi , De Palma Giuseppe , Sansone Emanuele , Mates Dana , Teodorescu Silvia , Fabiánová Eleonóra , Bérešová Jana , Vimercati Luigi , Tafuri Silvio , Abedini Mahsa , Ditano Giorgia , Asafo Shuffield S. , Boffetta Paolo ,   Orchestra WP5 Working Group
Published: September 2022

Background

The duration of immune response to COVID-19 vaccination is of major interest. Our aim was to analyze the determinants of anti-SARS-CoV-2 IgG titer at 6 months after 2-dose vaccination in an international cohort of vaccinated healthcare workers (HCWs).

Methods

We analyzed data on levels of anti-SARS-CoV-2 Spike antibodies and sociodemographic and clinical characteristics of 6,327 vaccinated HCWs from 8 centers from Germany, Italy, Romania and Slovakia. Time between 1st dose and serology ranged 150-210 days. Serological levels were log-transformed to account for the skewness of the distribution and normalized by dividing them by center-specific standard errors, obtaining standardized values. We fitted center-specific multivariate regression models to estimate the cohort-specific relative risks (RR) of an increase of 1 standard deviation of log antibody level and corresponding 95% confidence interval (CI), and finally combined them in random-effects meta-analyses.

Results

A 6-month serological response was detected in 99.6% of HCWs. Female sex (RR 1.10, 95%CI 1.00-1.21), past infection (RR 2.26, 95%CI 1.73-2.95) and two vaccine doses (RR 1.50, 95%CI 1.22-1.84) predicted higher IgG titer, contrary to interval since last dose (RR for 10-day increase 0.94, 95%CI 0.91-0.97) and age (RR for 10-year increase 0.87, 95%CI 0.83-0.92). M-RNA-based vaccines (p<0.001) and heterologous vaccination (RR 2.46, 95%CI 1.87-3.24, one cohort) were associated with increased antibody levels.

Conclusions

Female gender, young age, past infection, two vaccine doses, and m-RNA and heterologous vaccination predicted higher antibody level at 6 months. These results corroborate previous findings and offer valuable data for comparison with trends observed with longer follow-ups.
Early immunological responses to the mRNA SARS-CoV-2 vaccine in patients with neuromuscular disorders
Authors: Iwayama Hideyuki , Ishihara Naoko , Kawahara Kohei , Madokoro Yuta , Togawa Yasuko , Muramatsu Kanji , Murakami Ayuka , Kuru Satoshi , Kumagai Toshiyuki , Ohashi Wataru , Nanya Kengo , Hasegawa Shinji , Katsuno Masahisa , Okumura Akihisa
Published: September 2022

Backgrounds

Intramuscular injection of the SARS-CoV-2 vaccine has raised concerns about its use in patients with neuromuscular disorders (NMDs). We evaluated the response of patients with NMDs to the BNT162b2 vaccine.

Methods

Healthy subjects, patients with spinal muscular atrophy (SMA), and patients with Duchenne muscular dystrophy (DMD) were included. All participants received two BNT162b2 doses. SARS-CoV-2 antibody titers at baseline and 2 weeks after each vaccination were compared between groups. Residual muscle volume was evaluated in NMDs group. A questionnaire documented adverse reactions.

Results

Eleven patients with NMDs (9 with SMA, 2 with DMD; 7 males; aged 32.7 ± 19.3 years) and 346 healthy subjects (60 males, aged 40.0 ± 12.4 years) were included. Antibody titers (U/mL) were similar between groups (baseline: <0.40 vs. <0.40, first vaccination, 145 ± 258 vs. 103 ± 1192, and second vaccination, 1528 ± 1265 vs. 1429 ± 944; p = 1.000, 0.909, and 0.736, respectively). A negative correlation was found between antibody titers and residual muscle volume but was not significant (Mercuri scale, r = −0.429, p = 0.249; fat infiltration rate, r = −0.194, p = 0.618). The adverse reactions were comparable between groups.

Conclusion

The BNT162b2 vaccine is safe and effective in patients with NMDs.
Genetic association of leukocyte telomere length with Graves’ disease in Biobank Japan: A two-sample Mendelian randomization study
Authors: Ye Meijie , Wang Yu , Zhan Yiqiang
Published: September 2022

Background

Telomere length (TL) has been recognized to be fundamental to the risk of autoimmune disorders. However, the role of leukocyte TL in Graves’ disease has not yet been fully elucidated. In the study, we exploited the two-sample Mendelian randomization (MR) design to evaluate the causal effect of leukocyte TL on the risk of Graves’ disease.

Methods

Genome-wide association study (GWAS) data of leukocyte TL from the Singapore Chinese Health Study (SCHS) cohort and Graves’ disease from Biobank Japan (BBJ, 2176 cases and 210,277 controls) were analyzed. Nine single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) for TL. We used the inverse variance weighted (IVW) approach as the main estimator and MR-Egger regression, weighted median, simple mode, and weighed mode methods as complementary estimators. Horizontal pleiotropy was assessed using the intercept from MR-Egger.

Results

The analysis demonstrated that genetically predicted longer leukocyte TL was causally associated with a lower risk of Graves’ disease using the IVW method (odds ratio [OR]: 1.64, 95% confidence interval [CI]: 1.23-2.17, P=2.27e-04, and other complementary MR approaches achieved similar results. The intercept from the MR-Egger analysis provided no noticeable evidence of horizontal pleiotropy (β=0.02, P=0.641). MR-PRESSO method reported no outliers (P=0.266).

Conclusions

Our results provided evidence to support a genetic predisposition to shorter leukocyte TL with an increased risk of Graves’ disease. Further studies are warranted to explore the mechanism underlying the association.
Peripheral blood marker of residual acute leukemia after hematopoietic cell transplantation using multi-plex digital droplet PCR
Authors: Stanojevic M. , Grant M. , Vesely S. K. , Knoblach S. , Kanakry C. G. , Nazarian J. , Panditharatna E. , Panchapakesan K. , Gress R. E. , Holter-Chakrabarty J. , Williams Kirsten M.
Published: September 2022

Background

Relapse remains the primary cause of death after hematopoietic cell transplantation (HCT) for acute leukemia. The ability to identify minimal/measurable residual disease (MRD) via the blood could identify patients earlier when immunologic interventions may be more successful. We evaluated a new test that could quantify blood tumor mRNA as leukemia MRD surveillance using droplet digital PCR (ddPCR).

Methods

The multiplex ddPCR assay was developed using tumor cell lines positive for the tumor associated antigens (TAA: WT1, PRAME, BIRC5), with homeostatic ABL1. On IRB-approved protocols, RNA was isolated from mononuclear cells from acute leukemia patients after HCT (n = 31 subjects; n = 91 specimens) and healthy donors (n = 20). ddPCR simultaneously quantitated mRNA expression of WT1, PRAME, BIRC5, and ABL1 and the TAA/ABL1 blood ratio was measured in patients with and without active leukemia after HCT.

Results

Tumor cell lines confirmed quantitation of TAAs. In patients with active acute leukemia after HCT (MRD+ or relapse; n=19), the blood levels of WT1/ABL1, PRAME/ABL1, and BIRC5/ABL1 exceeded healthy donors (p<0.0001, p=0.0286, and p=0.0064 respectively). Active disease status was associated with TAA positivity (1+ TAA vs 0 TAA) with an odds ratio=10.67, (p=0.0070, 95% confidence interval 1.91 – 59.62). The area under the curve is 0.7544. Changes in ddPCR correlated with disease response captured on standard of care tests, accurately denoting positive or negative disease burden in 15/16 (95%). Of patients with MRD+ or relapsed leukemia after HCT, 84% were positive for at least one TAA/ABL1 in the peripheral blood. In summary, we have developed a new method for blood MRD monitoring of leukemia after HCT and present preliminary data that the TAA/ABL1 ratio may may serve as a novel surrogate biomarker for relapse of acute leukemia after HCT.
Spatial and temporal distribution of phytoplankton community in relation to environmental factors in the southern coastal waters of Korea
Authors: Sun Yanxu , Youn Seok-Hyun , Oh Hyun Joo , Joo Hui-Tae , Kim Yejin , Kang Jae Joong , Lee Dabin , Kim Kwanwoo , Jang Hyo Keun , Jo Naeun , Yun Mi Sun , Sun Linhe , Lee Sang Heon
Published: September 2022

The spatial and temporal environmental conditions in the southern coastal waters of Korea (SCWK) as a complex area, which is influenced by both ocean currents and anthropogenic nutrient inputs, are highly variable. The impacts of environmental factors on the distribution of phytoplankton community structure in the SCWK remain unclear. Based on high-performance liquid chromatography (HPLC) analysis of a variety of photosynthetic pigments, spatial and temporal variations in phytoplankton community compositions were investigated in the SCWK. Cluster analysis, correlation analysis, and generalized additive models (GAMs) were used to explore the major phytoplankton groups and their response patterns to temperature, salinity, depth, and macronutrients. The results indicated that diatoms were the absolute dominant groups in the SCWK for all seasons, especially in cold seasons. Diatoms mainly concentrated at 1% light depths, while high chlorophyll-a concentrations (>3 µg/L) occurred at 100% and 30% light depths with good light conditions. Both clustering and correlation analyses showed that diatoms had a strong positive correlation with macronutrients such as dissolved inorganic nitrogen (DIN), dissolved inorganic phosphate (DIP), and dissolved silica (DSi). The temperature and salinity discrepancy between surface and bottom layers in summer caused a strong water stratification resulting in blocking nutrient-rich bottom water upwelling and leading cyanobacteria to become the dominant groups at 100% and 30% light depths in summer. Consistently, the cyanobacteria were highly associated with high temperature and low salinity in the correlation analysis and GAM results. Compared with diatom-predominant sites, cryptophytes and diatom-dominated sites are characterized by higher average excess nitrate (ExN). Further research on the responses of small-sized prokaryotic phytoplankton especially cyanobacteria to environmental variations and their primary production contributions would warrant a better understanding of the SCWK ecosystem.
Dynamic effects of short-term exercise on muscle texture and gut flora in the hybrid (Megalobrama amblycephala♀ × Ancherythroculter nigrocauda♂)
Authors: Wei Huijie , Zhang Lang , Li Qing , Yu Yali , Sun Yanhong , Song Ziwei , Li Pei , Mao Tao , Chen Jian , He Li , Wang Guiying
Published: September 2022

Fillet texture plays a significant role in consumer acceptance, which heavily influenced by exercise according to previous studies. “Xianfeng No. 2”, a novel hybrid of Megalobrama amblycephala (M. amblycephala) (♀) and Ancherythroculter nigrocauda (A. nigrocauda) (♂), with characteristics of quick growth, good disease resistance, and anti-stress capability, is one of an important aquaculture fish species in China, however, the ways to improve fillet quality in this species remains unknown. In this study, a short-term exercise trial (0-16d), hematoxylin and eosin (H&E) staining, and texture analysis were carried out to determine the effects of exercise on muscle cellularity and texture. Furthermore, 16S rRNA analysis was performed to determine the impacts of exercise on the intestinal microbiota. Compared with non-exercised group (0d), exercised groups showed influences in muscle cellularity (decreased muscle fiber diameter and increased muscle fiber density) and improvements in muscle texture (increased hardness, cohesiveness, gumminess, and chewiness). In addition, 16S rRNA sequencing analysis exhibited that short-term exercise could significantly increase the community richness and diversity, as well as alter the composition of gut microflora in this hybrid species. At the level of phylum, the relative richness of Proteobacteria, Firmicutes, Bacteroidetes, and Fusobacteria changed remarkably after short-term exercise. At the level of genus, the relative richness of Pseudomonas, Acinetobacter, Stenotrophomonas, Alpinimonas, Rhodococcus, Shewanella, Brevundimonas changed significantly, suggested that short-term swimming exercise might increase intrinsic antimicrobial resistance and promote denitrification capacity of this hybrid species. Furthermore, a LEfSe analysis of intestinal microflora communities illustrated that Pseudomonas and MNG7 may be utilized to distinguish between exercised and non-exercised fish. Our research, collectively, found an effective way to improve fillet texture by exercise, revealed the impacts of exercise on the intestinal microbiota, further expanded our knowledge of fish under exercise.
Faint chemical traces of conspecifics delay settlement of barnacle larvae
Authors: Kitade Shiori , Endo Noriyuki , Nogata Yasuyuki , Matsumura Kiyotaka , Yasumoto Ko , Iguchi Akira , Yorisue Takefumi
Published: September 2022

Larval settlement drives population and community dynamics and evolution of marine invertebrates. While it is well known that larvae sense a variety of biological and environmental factors, there is limited information on how they react to specific factors so as to locate settlement sites. Proteinaceous Waterborne Settlement Pheromone (WSP) was purified from adult barnacles, Amphibalanus amphitrite, in a previous study, but it is unclear how WSP guides barnacle cyprids to the source. Here, a series of settlement assays were conducted to investigate the concentration dependence of recombinant WSP. We report that low concentrations of barnacle WSP decrease the probability of settlement of conspecific cyprids, whereas high concentrations have the opposite effect. We suggest that this is because weak WSP informs cyprids that suitable settlement sites with adult barnacles are distant, inducing them to extend the larval phase. The present study clearly shows that larvae use WSP concentration, rather than presence/absence information. In barnacles, several other conspecific chemical/visual cues also attract larvae. This study opens the door to future research to determine how these cues influence larval behavior in nature.
A systematic review of mangrove restoration studies in Southeast Asia: Challenges and opportunities for the United Nation’s Decade on Ecosystem Restoration
Authors: Gerona-Daga Maria Elisa B. , Salmo Severino G.
Published: September 2022

Mangroves provide valuable ecological and socio-economic services. The importance of mangroves is particularly evident in Southeast (SE) Asia where the most extensive and diverse forests are found. To recover degraded mangroves, several SE Asian countries have implemented restoration programs. However, to date, there has been no systematic and quantitative synthesis on mangrove restoration studies in the region. Here, we provide a bibliometric-based analysis of mangrove restoration to provide understanding on trends and future directions needed to meet biodiversity and restoration targets in the region. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol, we analyzed 335 articles (249 articles with ecological attributes; 86 articles with social attributes) published until February 2022 from Scopus and Web of Science databases. Mangrove restoration studies with ecological and social attributes started around the early 1990s mostly from Indonesia, Thailand, Malaysia, Vietnam, and the Philippines. Majority of SE Asian countries have stronger collaboration to western countries rather than within the region. Reasons for restoration vary per country, but mostly were intended to rehabilitate damaged mangroves. Direct planting was the most common restoration method used while hydrological rehabilitation was less practiced. Research on ecological attributes were dominated by biodiversity-related studies focused on flora and fauna, and less on other ecosystem services (e.g., coastal protection, fisheries production, etc.). Studies with social attributes only accounted for <30% of the publications, mostly on topics related to ecological economics. Although mangrove restoration studies are apparent, some thematic restoration foci are needed. We propose priority research topics to help achieve the biodiversity and restoration targets by 2030.