bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of scoparone on non-alcoholic fatty liver disease revealed by RNA sequencing
Authors: Huang Xiaoyan , Gao Ya , Cao Houkang , Li Jun , Mo Siyi , Li Ting , Wu Jianzhao , Guo Kai , Wei Riming , Zhang Kefeng
Published: September 2022

Scoparone (SCO) is known to have curative effect of alleviating liver injury. The purpose of this study was to observe the therapeutic effect and possible mechanism of SCO against high-fat diet (HFD) induced non-alcoholic liver disease (NAFLD) through in vivo experiments and RNA sequencing. Male Kunming mice were fed with HFD for 8 weeks to establish a mouse model of NAFLD, and SCO was used to treat NAFLD. Histopathology and biochemical indicators were used to evaluate the liver injury and the efficacy of SCO. RNA sequencing analysis was performed to elucidate the hepatoprotective mechanism of SCO. Finally, the differentially expressed genes of cholesterol synthesis and fatty acid (triglyceride) synthesis pathways were verified by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. The histopathological results showed that HFD could lead to significant steatosis in mice, while SCO could alleviate liver steatosis remarkably in NAFLD mice. The determination of biochemical indicators showed that SCO could inhibit the increased serum transaminase activity and liver lipid level induced by HFD. RNA sequencing analysis of liver tissues found that 2742 and 3663 genes were significantly changed by HFD and SCO, respectively. SCO reversed the most of genes involved in cholesterol synthesis and fatty acid (triglyceride) metabolism induced by HFD. the results of the validation experiment were mostly consistent with the RNA sequencing. SCO alleviated liver injury and steatosis in NAFLD mice, which may be closely related to the regulation of cholesterol and fatty acid (triglyceride) metabolism.
Relationship between physical performance and mild cognitive impairment in elderly hemodialysis patients is modified by the presence of diabetes: A multicenter cross-sectional study
Authors: Zhao Yinjiao , Song Peiyu , Zhu Chan , Zhang Lingyun , Chen Xiaoyu , Zhang Hui , Han Peipei , Ding Wei , Niu Jianying , Zhao Junli , Shao Xiang , Zhang Liming , Yu Chen , Xu Jia , Fang Chenghu , Guo Qi
Published: September 2022

Objective

The purpose of this study was to observe the relationship between physical performance and mild cognitive impairment (MCI) in the presence or absence of type 2 diabetes in elderly hemodialysis patients.

Methods

In this multicenter cross-sectional study, 396 clinically stable and aged ≥60 years hemodialysis patients (255 men; mean age: 68.3 ± 5.9 years) were included from seven dialysis units in Shanghai, China. The Chinese version of the Modified Mini-Mental State Examination (MMSE) and the Instrumental Activities of Daily Living (IADL) scale were utilized to assess MCI. The performance-based assessments consisted of three physical tests, grip strength (GS), Timed Up and Go Test (TUGT), and 4-m walking test, which respectively represent muscle strength, mobility, and walking speed (WS). Logistic regression and multivariate linear regression were used for analysis.

Results

Hemodialysis patients with diabetes had a high prevalence of MCI (20.6%). The odds ratio (OR) of MCI for the interacted items [(TUGT) * (diabetes) and (WS) * (diabetes)] was significant (p < 0.05). In diabetes patients, TUGT was positively associated with MCI, and WS was negatively associated with MCI after adjusting covariates [OR = 0.129; 95% confidence interval (CI) = 0.028–0.704, p = 0.021]. However, no significant association was found between physical performance and MCI in the non-diabetes hemodialysis patients (p > 0.05). Further analysis showed that TUGT was negatively associated with attention and calculation and language. WS was positively associated with recall and language in diabetic hemodialysis patients.

Conclusions

Physical performance was associated with MCI in diabetic hemodialysis patients rather than the non-diabetes group. Whether increasing mobility or WS can positively influence MCI in individuals with type 2 diabetes requires further study.
The value of ultrasound guided laser ablation in papillary thyroid recurrence carcinoma: A retrospective, single center study from China
Authors: Yong-ping Liang , Juan Zhang , Li Jing-wu , Qi Huai-hua , Liu Jing-ping , Zhao Yong-feng , Liu Wen-gang , Zhang Xing-hao , Zhou Ping
Published: September 2022

Objective

The efficacy and safety of ultrasound-guided percutaneous laser ablation (PLA) for treating recurrent papillary thyroid cancer nodules (RPTCNs).

Methods

A retrospective study was conducted in 43 patients with single recurrent thyroid cancer which was diagnosed by fine needle aspiration biopsy (FNAB). The extent of ablation was assessed by contrast-enhanced ultrasound (CEUS) 24h after PLA. At baseline (before ablation), 6, and 12 months, and every 6 months thereafter, the following were recorded: nodule maximum diameter, volume reduction rate (VRR), complications, and side effects.

Result

All 43 patients were successfully treated with PLA without serious complications. All patients underwent CEUS 24 hours after PLA treatment, and all achieved complete ablation. The success rate of single ablation was 100%. The average follow-up time was 23.47 ± 6.50 months, 12 ~ 36 months. At the last follow-up, 32 (74.4%) ablation lesions disappeared completely and 11 (25.6%) ablation lesions showed scar-like changes. No lymph node metastasis was found during follow-up. The maximum diameter and volume of nodules decreased from 5.1 ± 1.4 mm, 86.22 ± 20.46 mm3 before operation to 0.73 ± 1.1 mm, 1.02 ± 1.92 mm3 at the end of observation (P < 0.01). The average volume reduction rates (VRR) at 6, 12, 18, 24, 30 and 36 months after ablation were 11.92%, 60.64%, 82.26%, 90.96%, 93.7% and 97.79% respectively. No regrowth of treated nodule and distant metastases were detected. One patient (2.3%) had local recurrence and was treated with PLA again.

Conclusion

Ultrasound-guided PLA appears to be effective and safe for treating unifocal RPTCNs in selected patients who are ineligible for surgery, which is suitable for clinical application and promotion.
Temporal changes of the food web structure and function driven by changes in hydrological regimes and water quality in a large shallow lake
Authors: Yang Wei , Fu Xianting , Li Xiaoxiao , Yang Ying
Published: September 2022

Assessing food web structural properties and energy fluxes under changing hydrological regimes and water quality reveals the temporal patterns of ecosystem dynamics in shallow lakes. Here, we studied northern China’s largest shallow lake (Lake Baiyangdian) using quantitative food web models for five representative years (1958, 1980, 1993, 2009, and 2019). We analyzed the temporal patterns of food web structure and function by combining a Bayesian isotope mixing model with a food web energetics model. We further examined the temporal changes of unweighted and weighted food web topological attributes. Lake Baiyangdian changed from a detritus-based into a phytoplankton-based food web based on the relative contributions of basal food sources and energy flux distributions. The trophic position of fingerlings, large omnivorous fish, and carnivorous fish decreased with increasing eutrophication. The highest energy fluxes were from detritus to zooplankton and mollusks in 1958, from detritus and phytoplankton to zooplankton in 1980, 1993, and 2009, and from phytoplankton to zooplankton and detritus to mollusks in 2019. The highest total energy flux was in 1993, followed by 2019, with the lowest value in 1958. Unweighted food web metrics showed similar patterns. We observed more pronounced temporal variability in the node- and link-weighted food web metrics than in the unweighted metrics. In addition, hydrological factors (threshold, duration, reversals between high, and low water levels), eutrophication, and some water quality factors (chemical oxygen demand, dissolved oxygen, and pH) played important roles in the temporal changes of food web dynamics in Lake Baiyangdian. Our findings demonstrate the importance of integrating unweighted and weighted indicators to holistically comprehend how highly aggregated food webs respond to changing hydrological regimes and water quality, thereby improving management and restoration of shallow lake ecosystems.
Molecular mechanism of ferroptosis and its role in the occurrence and treatment of diabetes
Authors: Du Guanghui , Zhang Qi , Huang Xiaobo , Wang Yi
Published: September 2022

Ferroptosis is an iron-dependent programmed cell death, which is different from apoptosis, necrosis, and autophagy. Specifically, under the action of divalent iron or ester oxygenase, unsaturated fatty acids that are highly expressed on the cell membrane are catalyzed to produce lipid peroxidation, which induces cell death. In addition, the expression of the antioxidant system [glutathione (GSH) and glutathione peroxidase 4 (GPX4)] is decreased. Ferroptosis plays an important role in the development of diabetes mellitus and its complications. In this article, we review the molecular mechanism of ferroptosis in the development of diabetes mellitus and its complications. We also summarize the emerging questions in this particular area of research, some of which remain unanswered. Overall, this is a comprehensive review focusing on ferroptosis-mediated diabetes and providing novel insights in the treatment of diabetes from the perspective of ferroptosis.
Improving PARP inhibitor efficacy in high-grade serous ovarian carcinoma: A focus on the immune system
Authors: Bound Nirashaa T. , Vandenberg Cassandra J. , Kartikasari Apriliana E. R. , Plebanski Magdalena , Scott Clare L.
Published: September 2022

High-grade serous ovarian carcinoma (HGSOC) is a genomically unstable malignancy responsible for over 70% of all deaths due to ovarian cancer. With roughly 50% of all HGSOC harboring defects in the homologous recombination (HR) DNA repair pathway (e.g., BRCA1/2 mutations), the introduction of poly ADP-ribose polymerase inhibitors (PARPi) has dramatically improved outcomes for women with HR defective HGSOC. By blocking the repair of single-stranded DNA damage in cancer cells already lacking high-fidelity HR pathways, PARPi causes the accumulation of double-stranded DNA breaks, leading to cell death. Thus, this synthetic lethality results in PARPi selectively targeting cancer cells, resulting in impressive efficacy. Despite this, resistance to PARPi commonly develops through diverse mechanisms, such as the acquisition of secondary BRCA1/2 mutations. Perhaps less well documented is that PARPi can impact both the tumour microenvironment and the immune response, through upregulation of the stimulator of interferon genes (STING) pathway, upregulation of immune checkpoints such as PD-L1, and by stimulating the production of pro-inflammatory cytokines. Whilst targeted immunotherapies have not yet found their place in the clinic for HGSOC, the evidence above, as well as ongoing studies exploring the synergistic effects of PARPi with immune agents, including immune checkpoint inhibitors, suggests potential for targeting the immune response in HGSOC. Additionally, combining PARPi with epigenetic-modulating drugs may improve PARPi efficacy, by inducing a BRCA-defective phenotype to sensitise resistant cancer cells to PARPi. Finally, invigorating an immune response during PARPi therapy may engage anti-cancer immune responses that potentiate efficacy and mitigate the development of PARPi resistance. Here, we will review the emerging PARPi literature with a focus on PARPi effects on the immune response in HGSOC, as well as the potential of epigenetic combination therapies. We highlight the potential of transforming HGSOC from a lethal to a chronic disease and increasing the likelihood of cure.
Novel heterozygous mutation in COL4A4 responsible for Alport syndrome in a Chinese family
Authors: Du Ran , Liu Jishi , Hu Yiqiao , Peng Song , Fan Liangliang , Xiang Rong , Huang Hao
Published: September 2022

Background: Chronic kidney disease, a global public health problem, results in kidney damage or a gradual decline in the glomerular filtration rate. Alport syndrome is commonly characterized by chronic glomerulonephritis caused by a structural disorder in the glomerular basement membrane. Currently, three disease-causing genes, namely collagen type IV alpha 3–5 (COL4A3, COL4A4, and COL4A5), have been associated with the occurrence of Alport syndrome.

Methods: We enrolled a Chinese family where the affected individuals suffered from recurrent hematuria and proteinuria. The proband was selected for whole-exome sequencing to identify the pathogenic mutations in this family.

Results: After data filtering, a novel heterozygous COL4A4 variant (NM_000092: c.853G>A/p. G285A) was identified as the putative genetic lesion in the affected individuals. Further co-segregation analysis using Sanger sequencing confirmed that this novel COL4A4 mutation (c.853G>A/p. G285A) exists only in the affected individuals and is absent in other healthy family members as well as in the control cohort of 200 individuals from the same locality. According to American College of Medical Genetics and Genomics guidelines, the mutation was classified as ‘potentially pathogenic’. A bioinformatics-based prediction analysis revealed that this mutation is pathogenic and may disrupt the structure and function of type IV collagen. This variant is located at an evolutionarily conserved site of COL4A4.

Conclusion: In this study, we identified a novel heterozygous COL4A4 variant (c.853G>A) in a Chinese AS family and assisted to diagnose this AS proband as autosomal-dominant Alport syndrome (ADAS). Our study expands the spectrum of Alport syndrome mutations and contributes to the genetic counseling and diagnosis of patients with Alport syndrome.
Histone acetylation dynamics in repair of DNA double-strand breaks
Authors: Aricthota Shalini , Rana Paresh Priyadarshan , Haldar Devyani
Published: September 2022

Packaging of eukaryotic genome into chromatin is a major obstacle to cells encountering DNA damage caused by external or internal agents. For maintaining genomic integrity, the double-strand breaks (DSB) must be efficiently repaired, as these are the most deleterious type of DNA damage. The DNA breaks have to be detected in chromatin context, the DNA damage response (DDR) pathways have to be activated to repair breaks either by non‐ homologous end joining and homologous recombination repair. It is becoming clearer now that chromatin is not a mere hindrance to DDR, it plays active role in sensing, detection and repair of DNA damage. The repair of DSB is governed by the reorganization of the pre-existing chromatin, leading to recruitment of specific machineries, chromatin remodelling complexes, histone modifiers to bring about dynamic alterations in histone composition, nucleosome positioning, histone modifications. In response to DNA break, modulation of chromatin occurs via various mechanisms including post-translational modification of histones. DNA breaks induce many types of histone modifications, such as phosphorylation, acetylation, methylation and ubiquitylation on specific histone residues which are signal and context dependent. DNA break induced histone modifications have been reported to function in sensing the breaks, activating processing of breaks by specific pathways, and repairing damaged DNA to ensure integrity of the genome. Favourable environment for DSB repair is created by generating open and relaxed chromatin structure. Histone acetylation mediate de-condensation of chromatin and recruitment of DSB repair proteins to their site of action at the DSB to facilitate repair. In this review, we will discuss the current understanding on the critical role of histone acetylation in inducing changes both in chromatin organization and promoting recruitment of DSB repair proteins to sites of DNA damage. It consists of an overview of function and regulation of the deacetylase enzymes which remove these marks and the function of histone acetylation and regulators of acetylation in genome surveillance.
FOXP family DNA methylation correlates with immune infiltration and prognostic value in NSCLC
Authors: Hu Dong-Mei , Zhang Wen-Di , Shi Zhuang-E , Zhang Meng-Yu , Li Rui , Wang Qing-Xiang , Ji Xiu-Li , Qu Yi-Qing
Published: September 2022

Background: Forkhead box P (FOXP) family was introduced as a double-edged sword in tumorigenesis and influenced immunotherapy response by modulating host immunity. This study aimed to summarize the involvement of the FOXP family in non-small cell lung cancer (NSCLC).

Methods: The UALCAN, Gene Expression Profiling Interactive Analysis (GEPIA), and Reverse transcription-quantitative polymerase chain reaction (RT‒qPCR) were used to analyse the expression levels of the FOXP family in NSCLC. The prognostic impact was evaluated using Kaplan-Meier Plotter. MethSurv, UALCAN, and cBioPortal were applied to analyse the DNA methylation and mutation status of the FOXP family respectively. COEXPEDIA, STRING, and GeneMANIA were used to explore the interaction mechanism. Finally, TISIDB was used to investigate all of the immune-related characteristics regulated by the FOXP family.

Results: The expression levels of FOXP1/3/4 were dysregulated in NSCLC tissues than that in normal tissues. Groups with low expression levels of FOXP1/4 and high expression levels of FOXP2/3 were associated with poor prognosis in NSCLC. The transcriptional levels of FOXP2/3/4 were correlated with DNA methylation in NSCLC. FOXP1/3/4 DNA methylation were correlated with prognosis. Pathway enrichment analysis indicated the FOXP family was mainly related to immune-related pathways. After DNA methylation, the correlations between FOXP family and immune factors were opposite to that before alteration in NSCLC.

Conclusion: This study elucidated FOXP family could serve as vital diagnostic and prognostic biomarkers in NSCLC. Our study highlighted novel potential functions of FOXP family DNA methylation in regulation of immune-related signatures in NSCLC.
A novel mutation in SPINK5 gene underlies a case of atypical Netherton syndrome
Authors: Wang Yu , Song Hanqing , Yu Lingling , Wu Nan , Zheng Xiaodong , Liang Bo , Wang Peiguang
Published: September 2022

Netherton syndrome (NS, OMIM #256500) is a rare autosomal recessive disease characterized by a triad of congenital ichthyosiform erythroderma (CIE) or ichthyosis linearis circumflexa (ILC), trichorrhexis invaginata (TI), and atopic predisposition. The disease is caused by a mutation in the SPINK5 gene (serine protease inhibitor of Kazal type 5) encoding LEKTI (lymphoepithelial Kazal type-related inhibitor). We performed whole-exome sequencing on one Chinese NS family and made genotype–phenotype correlation analysis on the patients clinically diagnosed with NS or congenital ichthyosis erythroderma. We identified a novel frameshift mutation c.2474_2475del (p.Glu825Glyfs*2) in the SPINK5 gene. The N-terminal mutations of LEKTI cause a severer phenotype, while the C-terminal mutations of LEKT1 are related to a milder phenotype. Our findings suggest that Netherton syndrome may be underestimated clinically, and our findings further expand the reservoir of SPINK5 mutations in Netherton syndrome.
Genetic structure and differentiation from early bronze age in the mediterranean island of sicily: Insights from ancient mitochondrial genomes
Authors: Modi Alessandra , Vizzari Maria Teresa , Catalano Giulio , Boscolo Agostini Rajiv , Vai Stefania , Lari Martina , Vergata Chiara , Zaro Valentina , Liccioli Lucia , Fedi Mariaelena , Barone Serena , Nigro Lorenzo , Lancioni Hovirag , Achilli Alessandro , Sineo Luca , Caramelli David , Ghirotto Silvia
Published: September 2022

Sicily is one of the main islands of the Mediterranean Sea, and it is characterized by a variety of archaeological records, material culture and traditions, reflecting the history of migrations and populations’ interaction since its first colonization, during the Paleolithic. These deep and complex demographic and cultural dynamics should have affected the genomic landscape of Sicily at different levels; however, the relative impact of these migrations on the genomic structure and differentiation within the island remains largely unknown. The available Sicilian modern genetic data gave a picture of the current genetic structure, but the paucity of ancient data did not allow so far to make predictions about the level of historical variation. In this work, we sequenced and analyzed the complete mitochondrial genomes of 36 individuals from five different locations in Sicily, spanning from Early Bronze Age to Iron Age, and with different cultural backgrounds. The comparison with coeval groups from the Mediterranean Basin highlighted structured genetic variation in Sicily since Early Bronze Age, thus supporting a demic impact of the cultural transitions within the Island. Explicit model testing through Approximate Bayesian Computation allowed us to make predictions about the origin of Sicanians, one of the three indigenous peoples of Sicily, whose foreign origin from Spain, historically attributed, was not confirmed by our analysis of genetic data. Sicilian modern mitochondrial data show a different, more homogeneous, genetic composition, calling for a recent genetic replacement in the Island of pre-Iron Age populations, that should be further investigated.
Comprehensive analysis to identify GNG7 as a prognostic biomarker in lung adenocarcinoma correlating with immune infiltrates
Authors: Wei Qin , Miao Tianshu , Zhang Pengju , Jiang Baodong , Yan Hua
Published: September 2022

Background: G Protein Subunit Gamma 7 (GNG7), an important regulator of cell proliferation and cell apoptosis, has been reported to be downregulated in a variety of tumors including lung adenocarcinoma (LUAD). However, the correlation between low expression of GNG7 and prognosis of LUAD as well as the immune infiltrates of LUAD remains unclear.

Methods: The samples were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). R software was performed for statistical analysis. GNG7 expression and its prognostic value in LUAD were assessed through statistically analyzing the data from different databases. A nomogram was constructed to predict the impact of GNG7 on prognosis. Gene set enrichment analysis (GSEA) and single-sample gene set enrichment analyses GSEA (ssGSEA) were employed to determine the potential signal pathways and evaluated the immune cell infiltration regulated by GNG7. The prognostic significance of GNG7 expression associated with immune cell infiltration was investigated using the Tumor Immune Estimation Resource 2.0 (TIMER2.0) and the Kaplan-Meier plotter database. The UALCAN, cBio Cancer Genomics Portal (cBioPortal) and MethSurv database were used to analyze the correlation between the methylation of GNG7 and its mRNA expression as well as prognostic significance.

Results: GNG7 was demonstrated to be down-regulated in LUAD and its low expression was associated with poor prognosis. A clinical reliable prognostic-predictive model was constructed. Pathway enrichment showed that GNG7 was highly related to the B cell receptor signaling pathway. Further analysis showed that GNG7 was positively associated with B cell infiltration and low levels of B cell infiltration tended to associate with worse prognosis in patients with low GNG7 expression. Moreover, methylation analysis suggested hypermethylation may contribute to the low expression of GNG7 in LUAD.

Conclusion: Decreased expression of GNG7 at least partly caused by hypermethylation of the GNG7 promoter is closely associated with poor prognosis and tumor immune cell infiltration (especially B cells) in LUAD. These results suggest that GNG7 may be a promising prognostic biomarker and a potential immunotherapeutic target for LUAD, which provides new insights into immunotherapy for LUAD.
A specific immune signature for predicting the prognosis of glioma patients with IDH1-mutation and guiding immune checkpoint blockade therapy
Authors: Zeng Zhirui , Hu Chujiao , Ruan Wanyuan , Zhang Jinjuan , Lei Shan , Yang Yushi , Peng Pailan , Pan Feng , Chen Tengxiang
Published: September 2022

Isocitrate dehydrogenase (IDH1) is frequently mutated in glioma tissues, and this mutation mediates specific tumor-promoting mechanisms in glioma cells. We aimed to identify specific immune biomarkers for IDH1-mutation (IDH1mt) glioma. The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) were used to obtain RNA sequencing data and clinical characteristics of glioma tissues, while the stromal and immune scores of TCGA glioma tissues were determined using the ESTIMATE algorithm. Differentially expressed genes (DEGs), the protein–protein interaction(PPI) network, and least absolute shrinkage and selection operator (LASSO) and Cox regression analyses were used to select hub genes associated with stroma and immune scores and the prognoses of patients and to construct the risk model. The practicability and specificity of the risk model in both IDH1mt and IDH1-wildtype (wtIDH1) gliomas in TCGA and CGGA were evaluated. Molecular mechanisms, immunological characteristics and benefits of immune checkpoint blockade therapy in glioma tissues with IDH1mt were analyzed using GSEA, immunohistochemical staining, CIBERSORT, and T-cell dysfunction and exclusion (TIDE) analysis. The overall survival rate for IDH1mt-glioma patients with high stroma/immune scores was lower than that for those with low stroma/immune scores. A total of 222 DEGs were identified in IDH1mt glioma tissues with high stroma/immune scores. Among them, 72 genes had interactions in the PPI network, while three genes, HLA-DQA2, HOXA3, and SAA2, were selected as hub genes and used to construct risk models classifying patients into high- and low-risk score groups, followed by LASSO and Cox regression analyses. This risk model showed prognostic value in IDH1mt glioma in both TCGA and CCGA; nevertheless, the model was not suitable for wtIDH1 glioma. The risk model may act as an independent prognostic factor for IDH1mt glioma. IDH1mt glioma tissues from patients with high-risk scores showed more infiltration of M1 and CD8 T cells than those from patients with low-risk scores. Moreover, TIDE analysis showed that immune checkpoint blockade(ICB) therapy was highly beneficial for IDH1mt patients with high-risk scores. The risk model showed specific potential to predict the prognosis of IDH1mt-glioma patients, as well as guide ICB, contributing to the diagnosis and therapy of IDH1mt-glioma patients.
Bcl-3 regulates the function of Th17 cells through raptor mediated glycolysis metabolism
Authors: Liu Hui , Zeng Lin , Yang Yang , Huang Zhen , Guo Chunlei , Huang Liwenhui , Niu Xinqing , Zhang Chenguang , Wang Hui
Published: September 2022

Bcl-3 is an atypical IκB family member that regulates transcription in the nucleus by binding to the p50/p52 homologous dimer subunit. Although various studies illustrate the important role of Bcl-3 in physiological function, its role in metabolism is still unclear. We found that Bcl-3 has a metabolic regulatory effect on autoimmunity. Bcl-3-depleted mice are unable to develop experimental autoimmune encephalomyelitis. The disease resistance was linked to an increase in lactate levels in Th17 cells, and lactate could alleviate EAE development in WT mice. Bcl-3 deficient mice had more differentiated Th17 cells and an increased extracellular acidification rate in these cells. Concurrently, their ultimate respiration rate and respiratory reserve capacity were significantly lower than wild-type mice. However, adding GNE-140 (LADH inhibitor) to Bcl-3-deficient Th17 cells could reverse the phenomenon, and lactate supplementation could increase the glycolysis metabolism of Th17 cells in WT mice. Mechanically, Bcl-3 could interact with Raptor through ANK and RNC domains. Therefore, Bcl-3 regulates Th17 pathogenicity by promoting Raptor mediated energy metabolism, revealing a novel regulation of adaptive immunity.
Immune-related RNA signature predicts outcome of PD-1 inhibitor-combined GEMCIS therapy in advanced intrahepatic cholangiocarcinoma
Authors: Zeng Tian-mei , Pan Yu-fei , Yuan Zhen-gang , Chen Dong-sheng , Song Yun-jie , Gao Yong
Published: September 2022

Background

Immune checkpoint inhibitor (ICI)-combined chemotherapy in advanced intrahepatic cholangiocarcinoma has been proved to have more efficacy in a series of clinical trials. However, whether the tumor microenvironment (TME) plays a vital role in immune-combined therapy has not been rigorously evaluated.

Methods

Firstly, we assayed the immunogenic properties of GEM-based chemotherapy. Then, 12 ICC patients treated with PD-1 inhibitor (sintilimab) combined with gemcitabine and cisplatin (GemCis) from a phase 2 clinical trial (ChiCTR2000036652) were included and their immune-related gene expression profiles were analyzed using RNA from baseline tumor samples. Immune-related signature correlating with clinical outcome was identified according to the 12 ICC patients, and its predictive value was validated in an ICC cohort with 26 patients. Multiplexed immunofluorescence (mIF) and flow cytometry (FCM) analysis were performed to evaluate the immune-related molecules with therapeutic outcomes.

Results

GEM-based chemotherapy induced immunogenic cell death of cholangiocarcinoma cells, together with increased CD274 expression. In an ICC cohort, we found that upregulation of immune-checkpoint molecules and immune response-related pathways were significantly related to better clinical outcome. On the contrary, baseline immune-cell proportions in tumor tissues did not show any correlation with clinical benefit between responders and non-responders. Immune-related signature (including six genes) correlating with clinical outcome was identified according to the 12 ICC patients, and its predictive value was validated in a small ICC cohort with 26 patients.

Conclusion

Immune-related RNA signature predicts the outcome of PD-1 inhibitor-combined GEMCIS therapy in advanced intrahepatic cholangiocarcinoma, which could be tested as a biomarker for immune-chemotherapy in the future.
Visualization of macrophage subsets in the development of the fetal human inner ear
Authors: Steinacher Claudia , Chacko Lejo Johnson , Liu Wei , Rask-Andersen Helge , Bader Werner , Dudas Jozsef , Sergi Consolato M. , Dhanaseelan Tamilvendhan , Moreno Nadjeda , Glueckert Rudolf , Hoermann Romed , Schrott-Fischer Anneliese
Published: September 2022

Background

Human inner ear contains macrophages whose functional role in early development is yet unclear. Recent studies describe inner ear macrophages act as effector cells of the innate immune system and are often activated following acoustic trauma or exposure to ototoxic drugs. Few or limited literature describing the role of macrophages during inner ear development and organogenesis.

Material and Methods

We performed a study combining immunohistochemistry and immunofluorescence using antibodies against IBA1, CX3CL1, CD168, CD68, CD45 and CollagenIV. Immune staining and quantification was performed on human embryonic inner ear sections from gestational week 09 to 17.

Results

The study showed IBA1 and CD45 positive cells in the mesenchymal tissue at GW 09 to GW17. No IBA1 positive macrophages were detected in the sensory epithelium of the cochlea and vestibulum. Fractalkine (CX3CL1) signalling was initiated GW10 and parallel chemotactic attraction and migration of macrophages into the inner ear. Macrophages also migrated into the spiral ganglion, cochlear nerve, and peripheral nerve fibers and tissue-expressing CX3CL1. The mesenchymal tissue at all gestational weeks expressed CD163 and CD68.

Conclusion

Expressions of markers for resident and non-resident macrophages (IBA1, CD45, CD68, and CD163) were identified in the human fetal inner ear. We speculate that these cells play a role for the development of human inner ear tissue including shaping of the gracile structures.
Maturation of circulating Ly6ChiCCR2+ monocytes by mannan-MOG induces antigen-specific tolerance and reverses autoimmune encephalomyelitis
Authors: Dagkonaki Anastasia , Papalambrou Athina , Avloniti Maria , Gkika Areti , Evangelidou Maria , Androutsou Maria-Eleni , Tselios Theodore , Probert Lesley
Published: September 2022

Autoimmune diseases affecting the CNS not only overcome immune privilege mechanisms that protect neural tissues but also peripheral immune tolerance mechanisms towards self. Together with antigen-specific T cells, myeloid cells are main effector cells in CNS autoimmune diseases such as multiple sclerosis, but the relative contributions of blood-derived monocytes and the tissue resident macrophages to pathology and repair is incompletely understood. Through the study of oxidized mannan-conjugated myelin oligodendrocyte glycoprotein 35-55 (OM-MOG), we show that peripheral maturation of Ly6ChiCCR2+ monocytes to Ly6ChiMHCII+PD-L1+ cells is sufficient to reverse spinal cord inflammation and demyelination in MOG-induced autoimmune encephalomyelitis. Soluble intradermal OM-MOG drains directly to the skin draining lymph node to be sequestered by subcapsular sinus macrophages, activates Ly6ChiCCR2+ monocytes to produce MHC class II and PD-L1, prevents immune cell trafficking to spinal cord, and reverses established lesions. We previously showed that protection by OM-peptides is antigen specific. Here, using a neutralizing anti-PD-L1 antibody in vivo and dendritic cell-specific Pdl1 knockout mice, we further demonstrate that PD-L1 in non-dendritic cells is essential for the therapeutic effects of OM-MOG. These results show that maturation of circulating Ly6ChiCCR2+ monocytes by OM-myelin peptides represents a novel mechanism of immune tolerance that reverses autoimmune encephalomyelitis.
Differences in systemic and mucosal SARS-CoV-2 antibody prevalence in a prospective cohort of Dutch children
Authors: Keuning Maya W. , Grobben Marloes , Bijlsma Merijn W. , Anker Beau , Berman-de Jong Eveline P. , Cohen Sophie , Felderhof Mariet , de Groen Anne-Elise , de Groof Femke , Rijpert Maarten , van Eijk Hetty W. M. , Tejjani Khadija , van Rijswijk Jacqueline , Steenhuis Maurice , Rispens Theo , Plötz Frans B. , van Gils Marit J. , Pajkrt Dasja
Published: September 2022

Background

As SARS-CoV-2 will likely continue to circulate, low-impact methods become more relevant to monitor antibody-mediated immunity. Saliva sampling could provide a non-invasive method with reduced impact on children. Studies reporting on the differences between systemic and mucosal humoral immunity to SARS-CoV-2 are inconsistent in adults and scarce in children. These differences may be further unraveled by exploring associations to demographic and clinical variables.

Methods

To evaluate the use of saliva antibody assays, we performed a cross-sectional cohort study by collecting serum and saliva of 223 children attending medical services in the Netherlands (irrespective of SARS-CoV-2 exposure, symptoms or vaccination) from May to October 2021. With a Luminex and a Wantai assay, we measured prevalence of SARS-CoV-2 spike (S), receptor binding domain (RBD) and nucleocapsid-specific IgG and IgA in serum and saliva and explored associations with demographic variables.

Findings

The S-specific IgG prevalence was higher in serum 39% (95% CI 32 – 45%) than in saliva 30% (95% CI 24 – 36%) (P ≤ 0.003). Twenty-seven percent (55/205) of children were S-specific IgG positive in serum and saliva, 12% (25/205) were only positive in serum and 3% (6/205) only in saliva. Vaccinated children showed a higher concordance between serum and saliva than infected children. Odds for saliva S-specific IgG positivity were higher in girls compared to boys (aOR 2.63, P = 0.012). Moreover, immunocompromised children showed lower odds for S- and RBD-specific IgG in both serum and saliva compared to healthy children (aOR 0.23 – 0.25, P ≤ 0.050).

Conclusions

We showed that saliva-based antibody assays can be useful for identifying SARS-CoV-2 humoral immunity in a non-invasive manner, and that IgG prevalence may be affected by sex and immunocompromisation. Differences between infection and vaccination, between sexes and between immunocompromised and healthy children should be further investigated and considered when choosing systemic or mucosal antibody measurement.
Integrating peripheral blood and brain transcriptomics to identify immunological features associated with Alzheimer’s disease in mild cognitive impairment patients
Authors: Qian Xiao-hang , Liu Xiao-li , Chen Sheng-di , Tang Hui-dong
Published: September 2022

Background

Immune system dysfunction has been proven to be an important pathological event in Alzheimer’s disease (AD). Mild cognitive impairment (MCI), as a transitional stage between normal cognitive function and AD, was an important research object for the screening of early diagnostic markers and therapeutic targets for AD. However, systematic assessment of peripheral immune system changes in MCI patients and consistent analysis with that in the CNS were still lacking.

Methods

Peripheral blood transcriptome data from the AddNeuroMed Cohort (n = 711) was used as a training dataset to assess the abundance of 24 immune cells through ImmuCellAI and to identify MCI-related immune signaling pathways and hub genes. The expression level of the immune hub gene was validated in peripheral blood (n = 587) and brain tissue (78 entorhinal cortex, 140 hippocampi, 91 temporal cortex, and 232 frontal cortex) validation datasets. Finally, reliable immune hub genes were applied for Gene Set Enrichment Analysis and correlation analysis of AD pathological characteristics.

Results

MCI patients have early changes in the abundance of various types of immune cells in peripheral blood, accompanied by significant changes in NF-kB, TNF, JAK-STAT, and MAPK signaling pathways. Five hub immune-related differentially expressed genes (NFKBIA, CD4, RELA, CASP3, and HSP90AA1) were screened by the cytoHubba plugin in Cytoscape and the least absolute shrinkage and selection operator (LASSO) regression. Their expression levels were significantly correlated with infiltration score and the abundance of monocytes, natural killer cells, Th2 T cells, T follicular helper cells, and cytotoxic T cells. After validation with independent datasets derived from peripheral blood and brain, RELA and HSP90AA1 were identified as two reliable immune hub genes in MCI patients and had consistent changes in AD. The Gene Set Enrichment Analysis (GSEA) showed that their expression levels were closely associated with Alzheimer’s disease, JAK-STAT, calcium signaling pathway, etc. In addition, the expression level of RELA was positively correlated with β- and γ-secretase activity and Braak stage. The expression level of HSP90AA1 was negatively correlated with α- and β-secretase activity.

Conclusion

Immune system dysfunction was an early event in AD. It provides a new target for the early diagnosis and treatment of AD.
Andrographolide promote the growth and immunity of Litopenaeus vannamei, and protects shrimps against Vibrio alginolyticus by regulating inflammation and apoptosis via a ROS-JNK dependent pathway
Authors: Yin Xiaoli , Zhuang Xueqi , Luo Weitao , Liao Meiqiu , Huang Lin , Cui Qiqian , Huang Jiayi , Yan Chunxia , Jiang Zixiang , Liu Yuan , Wang Weina
Published: September 2022

Vibrio alginolyticus (V. alginolyticus) is one of the major pathogens causing mass mortality of shrimps worldwide, affecting energy metabolism, immune response and development of shrimps. In the context of the prohibition of antibiotics, it is necessary to develop a drug that can protect shrimp from V. alginolyticus. Andrographolide (hereinafter called Andr), a traditional drug used in Chinese medicine, which possesses diverse biological effects including anti-bacteria, antioxidant, immune regulation. In this study, we investigated the effect of Andr on growth, immunity, and resistance to V. alginolyticus infection of Litopenaeus vannamei (L. vannamei) and elucidate the underlying molecular mechanisms. Four diets were formulated by adding Andr at the dosage of 0 g/kg (Control), 0.5 g/kg, 1 g/kg, and 2 g/kg in the basal diet, respectively. Each diet was randomly fed to one group with three replicates of shrimps in a 4-week feeding trial. The results showed that dietary Andr improved the growth performance and non-specific immune function of shrimps. L. vannamei fed with Andr diets showed lower mortality after being challenged by V. alginolyticus. After 6 h of V. alginolyticus infection, reactive oxygen species (ROS) production, tissue injury, apoptosis, expression of inflammatory factors (IL-1 β and TNFα) and apoptosis-related genes (Bax, caspase3 and p53) were increased in hemocytes and hepatopancreas, while feeding diet with 0.5 g/kg Andr could inhibit the increase. Considering that JNK are important mediators of apoptosis, we examined the influence of Andr on JNK activity during V. alginolyticus infection. We found that Andr inhibited JNK activation induced by V. alginolyticus infection on L. vannamei. The ROS scavenger N-acetyl-l-cysteine (NAC) suppressed V. alginolyticus-induced inflammation and apoptosis, suggesting that ROS play an important role in V. alginolyticus-induced inflammation and apoptosis. Treated cells with JNK specific activator anisomycin, the inflammation and apoptosis inhibited by Andr were counteracted. Collectively, Andr promote the growth and immunity of L. vannamei, and protects shrimps against V. alginolyticus by regulating inflammation and apoptosis via a ROS-JNK dependent pathway. These results improve the understanding of the pathogenesis of V. alginolyticus infection and provide clues to the development of effective drugs against V. alginolyticus.
Advancing fishery-independent stock assessments for the Norway lobster (Nephrops norvegicus) with new monitoring technologies
Authors: Aguzzi Jacopo , Chatzievangelou Damianos , Robinson Nathan J. , Bahamon Nixon , Berry Alan , Carreras Marc , Company Joan Batista , Costa Corrado , del Rio Fernandez Joaquin , Falahzadeh Ahmad , Fifas Spyros , Flögel Sascha , Grinyó Jordi , Jónasson Jonas Pall , Jonsson Patrik , Lordan Colm , Lundy Mathieu , Marini Simone , Martinelli Michela , Masmitja Ivan , Mirimin Luca , Naseer Atif , Navarro Joan , Palomeras Narcis , Picardi Giacomo , Silva Cristina , Stefanni Sergio , Vigo Maria , Vila Yolanda , Weetman Adrian , Doyle Jennifer
Published: September 2022

The Norway lobster, Nephrops norvegicus, supports a key European fishery. Stock assessments for this species are mostly based on trawling and UnderWater TeleVision (UWTV) surveys. However, N. norvegicus are burrowing organisms and these survey methods are unable to sample or observe individuals in their burrows. To account for this, UWTV surveys generally assume that “1 burrow system = 1 animal”, due to the territorial behavior of N. norvegicus. Nevertheless, this assumption still requires in-situ validation. Here, we outline how to improve the accuracy of current stock assessments for N. norvegicus with novel ecological monitoring technologies, including: robotic fixed and mobile camera-platforms, telemetry, environmental DNA (eDNA), and Artificial Intelligence (AI). First, we outline the present status and threat for overexploitation in N. norvegicus stocks. Then, we discuss how the burrowing behavior of N. norvegicus biases current stock assessment methods. We propose that state-of-the-art stationary and mobile robotic platforms endowed with innovative sensors and complemented with AI tools could be used to count both animals and burrows systems in-situ, as well as to provide key insights into burrowing behavior. Next, we illustrate how multiparametric monitoring can be incorporated into assessments of physiology and burrowing behavior. Finally, we develop a flowchart for the appropriate treatment of multiparametric biological and environmental data required to improve current stock assessment methods.
Proposal for standardizing normal insulin ranges in Brazilian patients and a new classification of metabolic syndrome
Authors: Chocair Pedro Renato , de Menezes Neves Precil Diego Miranda , Sato Victor Augusto Hamamoto , Mohrbacher Sara , Oliveira Érico Souza , Pereira Leonardo Victor Barbosa , Bales Alessandra Martins , da Silva Fagner Pereira , Duley John A. , Cuvello-Neto Américo Lourenço
Published: September 2022

Background

Insulin resistance and/or hyperinsulinemia are closely linked to adiposity, metabolic syndrome (MetS) and prolonged inflammatory processes.

Methods

We retrospectively analyzed 1,018 adult individuals with a mean age of 46 years (74% male) and classified them as: Metabolically normal: without any of the five criteria of the International Diabetes Federation (IDF) used for the diagnosis of MetS, plus normal fasting insulin (Men < 8 mU/L, Women < 10 mU/L); Level 1 MetS: with one or two IDF criteria, plus hyperinsulinemia (Men: ≥ 8 mU/L), and Women: ≥ 10 mU/L); Level 2 MetS: with three or more IDF criteria, plus hyperinsulinemia.

Results

The mean values for fasting insulinemia in metabolically normal individuals was 4.6 ± 1.8 mU/L and 5.6 ± 2.3 mU/L, while their means for the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) were 1.0 and 1.2 for men and women, respectively. In addition, the mean values for insulin (and HOMA-IR) for individuals with two normal anthropometric parameters (body mass index and waist girth), or two normal anthropometric parameters plus no IDF criteria, were similar to the metabolically normal group. Based on the obtained mean + 2 SD, we established the following insulin (and HOMA-IR) values as diagnostic cut-offs for hyperinsulinemia: Men: ≥ 8 mU/L (≥ 1.5), and Women: ≥ 10 mU/L (≥ 2.0). The mean serum insulin was significantly higher for individuals with Level 1 MetS (approx. 9 mU/L for both genders) compared with metabolically normal individuals, as was the prevalence of hepatic steatosis, which was more evident in men. Thus, the presence of one or two abnormal IDF criteria, combined with hyperinsulinemia and/or raised HOMA-IR, suggests the presence of MetS and insulin resistance. Patients of both genders with Level 2 MetS had higher serum insulin and/or HOMA-IR values than Level 1, as well as a higher prevalence of hypertension and hepatic steatosis, being more pronounced among men. The process was progressive and proportional to the degree of hyperinsulinemia.

Conclusion

It is proposed that intervention against MetS progression should be started in individuals with Level 1 MetS, rather than waiting for more criteria for diagnostic confirmation, which this should help to reduce the occurrence of known complications such as type 2 diabetes, atherosclerosis, hypertension, and chronic kidney disease, among others.