bluuebunny/crossref_metadata_2025 huggingface dataset:
Promising Roles of Exosomal microRNAs in Systemic Lupus Erythematosus
Authors: Wang Wenqian , Yue Chenran , Gao Sheng , Li Shuting , Zhou Jianan , Chen Jiaqing , Fu Jiahong , Sun Weijian , Hua Chunyan
Published: December 2021

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the loss of immune tolerance. Lupus nephritis (LN) is still a major cause of the morbidity and mortality of SLE. In clinical practice, diagnosis, and therapy of SLE is complicated and challenging due to lack of ideal biomarkers. Exosomes could be detected from numerous kinds of biological fluids and their specific contents are considered as hallmarks of autoimmune diseases. The exosomal miRNA profiles of SLE/LN patients significantly differ from those of the healthy controls making them as attractive biomarkers for renal injury. Exosomes are considered as optimal delivery vehicles owing to their higher stable, minimal toxicity, lower immunogenicity features and specific target effects. Endogenous miRNAs can be functionally transferred by exosomes from donor cells to recipient cells, displaying their immunomodulatory effects. In addition, it has been confirmed that exosomal miRNAs could directly interact with Toll-like receptors (TLRs) signaling pathways to regulate NF-κB activation and the secretion of inflammatory cytokines. The present Review mainly focuses on the immunomodulatory effects of exosomal-miRNAs, the complex interplay between exosomes, miRNAs and TLR signaling pathways, and how the exosomal-miRNAs can become non-invasive diagnostic molecules and potential therapeutic strategies for the management of SLE.
Neutrophil Homeostasis and Emergency Granulopoiesis: The Example of Systemic Juvenile Idiopathic Arthritis
Authors: Malengier-Devlies Bert , Metzemaekers Mieke , Wouters Carine , Proost Paul , Matthys Patrick
Published: December 2021

Neutrophils are key pathogen exterminators of the innate immune system endowed with oxidative and non-oxidative defense mechanisms. More recently, a more complex role for neutrophils as decision shaping cells that instruct other leukocytes to fine-tune innate and adaptive immune responses has come into view. Under homeostatic conditions, neutrophils are short-lived cells that are continuously released from the bone marrow. Their development starts with undifferentiated hematopoietic stem cells that pass through different immature subtypes to eventually become fully equipped, mature neutrophils capable of launching fast and robust immune responses. During severe (systemic) inflammation, there is an increased need for neutrophils. The hematopoietic system rapidly adapts to this increased demand by switching from steady-state blood cell production to emergency granulopoiesis. During emergency granulopoiesis, thede novoproduction of neutrophils by the bone marrow and at extramedullary sites is augmented, while additional mature neutrophils are rapidly released from the marginated pools. Although neutrophils are indispensable for host protection against microorganisms, excessive activation causes tissue damage in neutrophil-rich diseases. Therefore, tight regulation of neutrophil homeostasis is imperative. In this review, we discuss the kinetics of neutrophil ontogenesis in homeostatic conditions and during emergency myelopoiesis and provide an overview of the different molecular players involved in this regulation. We substantiate this review with the example of an autoinflammatory disease,i.e.systemic juvenile idiopathic arthritis.
Donor NK and T Cells in the Periphery of Lung Transplant Recipients Contain High Frequencies of Killer Cell Immunoglobulin-Like Receptor-Positive Subsets
Authors: Hitz Anna-Maria , Bläsing Kim-Alina , Wiegmann Bettina , Bellmàs-Sanz Ramon , Chichelnitskiy Evgeny , Wandrer Franziska , Horn Lisa-Marie , Neudörfl Christine , Keil Jana , Beushausen Kerstin , Ius Fabio , Sommer Wiebke , Avsar Murat , Kühn Christian , Tudorache Igor , Salman Jawad , Siemeni Thierry , Haverich Axel , Warnecke Gregor , Falk Christine S. , Kühne Jenny F.
Published: December 2021

Introduction

For end-stage lung diseases, double lung transplantation (DLTx) is the ultimate curative treatment option. However, acute and chronic rejection and chronic dysfunction are major limitations in thoracic transplantation medicine. Thus, a better understanding of the contribution of immune responses early after DLTx is urgently needed. Passenger cells, derived from donor lungs and migrating into the recipient periphery, are comprised primarily by NK and T cells. Here, we aimed at characterizing the expression of killer cell immunoglobulin-like receptors (KIR) on donor and recipient NK and T cells in recipient blood after DLTx. Furthermore, we investigated the functional status and capacity of donor vs. recipient NK cells.

Methods

Peripheral blood samples of 51 DLTx recipients were analyzed pre Tx and at T0, T24 and 3wk post Tx for the presence of HLA-mismatched donor NK and T cells, their KIR repertoire as well as activation status using flow cytometry.

Results

Within the first 3 weeks after DLTx, donor NK and T cells were detected in all patients with a peak at T0. An increase of the KIR2DL/S1-positive subset was found within the donor NK cell repertoire. Moreover, donor NK cells showed significantly higher frequencies of KIR2DL/S1-positive cells (p<0.01) 3wk post DLTx compared to recipient NK cells. This effect was also observed in donor KIR+ T cells 3wk after DLTx with higher proportions of KIR2DL/S1 (p<0.05) and KIR3DL/S1 (p<0.01) positive T cells. Higher activation levels of donor NK and T cells (p<0.001) were detected compared to recipient cells via CD25 expression as well as a higher degranulation capacity upon activation by K562 target cells.

Conclusion

Higher frequencies of donor NK and T cells expressing KIR compared to recipient NK and T cells argue for their origin in the lung as a part of a highly specialized immunocompetent compartment. Despite KIR expression, higher activation levels of donor NK and T cells in the periphery of recipients suggest their pre-activation during the ex situ phase. Taken together, donor NK and T cells are likely to have a regulatory effect in the balance between tolerance and rejection and, hence, graft survival after DLTx.
Ocean Acidification Triggers Cell Signaling, Suppress Immune and Calcification in the Pacific Oyster Larvae
Authors: Dineshram Ramadoss , Xiao Shu , Ko Ginger Wai Kuen , Li Jun , Smrithi Kovilingal , Thiyagarajan Vengatesen , Zhang Yang , Yu Ziniu
Published: December 2021

Elevated carbon dioxide levels in ocean waters, an anthropogenic stressor, can alter the chemical equilibrium of seawater through a process called ocean acidification (OA). The resultant reduction of pH can be detrimental during the early developmental stages of the commercially important edible Pacific oyster Crassostrea gigas; the ability of larvae to join a population is likely to be compromised by declining ocean pH. Given this threat, it is important to study the molecular mechanisms that these organisms use to overcome OA stress at the gene expression level. Here, we performed transcriptome profiling in oyster larvae following exposure to ambient (8.1) and reduced (7.4) pH during the pre-settlement growth period (i.e., 18 d post fertilization) using RNA-seq with Illumina sequencing technology. In total, 1,808 differentially expressed genes (DEGs) were identified, 1,410 of which were matched by BLAST against the Swiss-Prot database. Gene ontology classification showed that most of these DEGs were related to ribosomal, calcium ion binding, cell adhesion and apoptotic processes. Pathway enrichment analysis revealed that low pH (7.4) enhanced energy production and organelle biogenesis but prominently suppressed several immune response pathways. Moreover, activation of the MAPK signaling pathway was observed along with inhibition of the Wnt, VEGF, and ErbB pathways, highlighting the fact that the initiation of stress responses is given priority over larval development or shell growth when the larvae cope with low pH. In conclusion, our study demonstrated a unique gene expression profiling approach in studying oyster larval responses to OA, which not only provides comprehensive insights into the mechanisms underlying oyster tolerance to CO2-driven decreases in ocean pH but also supplies a valuable genomic resource for further studies in this species.
Efficient Fitting of 3D Tessellations to Curved Polycrystalline Grain Boundaries
Authors: Petrich Lukas , Furat Orkun , Wang Mingyan , Krill III Carl E. , Schmidt Volker
Published: December 2021

The curvature of grain boundaries in polycrystalline materials is an important characteristic, since it plays a key role in phenomena like grain growth. However, most traditional tessellation models that are used for modeling the microstructure morphology of these materials, e.g., Voronoi or Laguerre tessellations, have flat faces and thus fail to incorporate the curvature of the latter. For this reason, we consider generalizations of Laguerre tessellations—variations of so-called generalized balanced power diagrams (GBPDs)—that exhibit non-convex cells. With as many as ten parameters for each cell, it is computationally demanding to fit GBPDs to three-dimensional image data containing hundreds of grains. We therefore propose a modification of the traditional definition of GBDPs that allows gradient-based optimization methods to be employed. The resulting reduction in runtime makes it feasible to find approximations to real experimental datasets. We demonstrate this on a three-dimensional x-ray diffraction (3DXRD) mapping of an AlCu alloy, but we also evaluate the modeling errors for simulated data. Furthermore, we investigate the effect of noisy image data and whether the smoothing of image data prior to the fitting step is advantageous.
Influence of Calcined Bauxite Aggregate on the Resistance of Cement Composites Subjected to Small Caliber Deformable Projectile Impact
Authors: Zhang Fengling , Zhong Rui
Published: December 2021

This paper presents an experimental investigation on the influence of calcined bauxite aggregate (CBA) on the resistance of cement composites subjected to small caliber deformable projectile impact at a designed velocity of 400 m/s. The deformable projectile was made from copper with a purity of 99.5% and a diameter of 8.0 mm. Compared to mixtures with conventional coarse granite aggregate and/or siliceous fine aggregate, the incorporation of either fine or coarse CBA or their combination is beneficial in reducing the depth of penetration (DOP), equivalent crater diameter (CD), and crater volume (CV) caused by deformable projectile impact. CBA is found to be more effective in controlling the DOP and CV in comparison to the CD. Replacing of conventional aggregate with CBA leads to more severe damage to the projectiles (e.g., projectile length reduction, diameter increase, and mass loss). Relative effective hardness is an effective indicator to the deformation potential and penetration capacity of a deformable projectile to impact cement composites incorporating CBA.
Relation of Serum Hepcidin Levels and Restless Legs Syndrome in Patients Undergoing Peritoneal Dialysis
Authors: Guo Yanhong , Sang Yuan , Pu Tian , Li Xiaodan , Wang Yulin , Yu Lu , Liang Yan , Wang Liuwei , Liu Peipei , Tang Lin
Published: December 2021

Introduction: Restless legs syndrome is a common and severe complication in patients undergoing peritoneal dialysis (PD), which seriously affects the life quality and prognosis of patients undergoing PD. Unfortunately, there are still no effective prevention and treatment measures. Serum hepcidin was demonstrated to be related to primary restless legs syndrome (RLS), whereas there are no studies on the relationship between serum hepcidin and RLS in patients undergoing PD. We aimed to evaluate the role and function of serum hepcidin in patients undergoing PD with RLS.

Methods: A total of 51 patients undergoing PD with RLS and 102 age-and gender-matched patients undergoing PD without RLS were included. We collected the clinical data including serum hepcidin of those patients undergoing PD. We scored the severity of RLS according to the International restless leg Syndrome Research Group rating scale (IRLS). We compared the clinical characteristics of the two groups and evaluated the determinant factors of RLS by Logistic regression analysis. In addition, we evaluated the diagnostic value of serum hepcidin in patients undergoing PD with RLS by receiver operating characteristic (ROC) curve. We also analyzed the influencing factors of IRLS by multivariate linear regression analysis.

Results: The duration of PD, serum hepcidin, and calcium were found to be significantly higher in patients undergoing PD with RLS than those patients undergoing PD without RLS (P < 0.001, P < 0.001, and P = 0.002, respectively). The level of hemoglobin, albumin, and RKF were significantly lower in patients undergoing PD with RLS (P = 0.002, P = 0.042, and P < 0.001, respectively). The duration of PD [odds ratio (OR) 1.038, 95% CI: 1.017, 1.060, P < 0.001], hemoglobulin level (OR 0.969, 95% CI: 0.944, 0.995, P = 0.019), calcium level (OR 9.224, 95% CI: 1.261, 67.450, P = 0.029), albumin level (OR 0.835, 95% CI: 0.757, 0.921, P < 0.001), hepcidin level (OR 1.023, 95% CI: 1.009, 1.038, P = 0.001), and RKF (OR 0.65, 95% CI: 0.495, 0.856, P = 0.002) are independent determinant factors of RLS in patients undergoing PD. Multivariate linear regression analysis revealed that, in addition to albumin, they were also independently associated with the severity of RLS.

Conclusion: A significant relation was detected between serum hepcidin level and RLS in patients undergoing PD.
Case Report: A Case of Perifoveal Exudative Vascular Anomalous Complex With a Good Prognosis
Authors: Fu Min , Hu Pan , Zhang Gang , Huang Ludonghan , Xu Huan , Huang Ju , Wu Meihui , Chen Yanli
Published: December 2021

Significance: Perifoveal exudative vascular anomalous complex (PEVAC) is a unique clinical lesion. It manifests as isolated lesions and is easily misdiagnosed. Thus far, few PEVAC case reports have been published. PEVAC is typically inconsistent with other reported macular lesions.

Purpose: To report our 24-month follow-up experience on the treatment of PEVAC with a micropulse laser (MPL).

Case Report: A 56-year-old Chinese woman with no history of other diseases complained of decreased vision in her left eye that had persisted for more than 1 year. Comprehensive ophthalmic examinations were performed, including a vision test, slit lamp fundus exam, optical coherence tomography (OCT), optical coherence tomography angiography (OCT-A), fluorescein fundus angiography (FFA) and indocyanine green angiography (ICGA). Intravitreal injection of ranibizumab was ineffective, and bleeding, exudation and visual acuity were not improved. After two rounds of micropulse laser (MPL) treatment, the patient was followed up, and the prognosis was good.

Conclusion: PEVAC is very rare, and early diagnosis is important, as the lesions readily cause irreversible damage. Our results indicate that an MPL can be used as an alternative treatment for PEVAC patients.
IDbSV: An Open-Access Repository for Monitoring SARS-CoV-2 Variations and Evolution
Authors: Essabbar Abdelmounim , Kartti Souad , Alouane Tarek , Hakmi Mohammed , Belyamani Lahcen , Ibrahimi Azeddine
Published: December 2021

Ending COVID-19 pandemic requires a collaborative understanding of SARS-CoV-2 and COVID-19 mechanisms. Yet, the evolving nature of coronaviruses results in a continuous emergence of new variants of the virus. Central to this is the need for a continuous monitoring system able to detect potentially harmful variants of the virus in real-time. In this manuscript, we present the International Database of SARS-CoV-2 Variations (IDbSV), the result of ongoing efforts in curating, analyzing, and sharing comprehensive interpretation of SARS-CoV-2's genetic variations and variants. Through user-friendly interactive data visualizations, we aim to provide a novel surveillance tool to the scientific and public health communities. The database is regularly updated with new records through a 4-step workflow (1—Quality control of curated sequences, 2—Call of variations, 3—Functional annotation, and 4—Metadata association). To the best of our knowledge, IDbSV provides access to the largest repository of SARS-CoV-2 variations and the largest analysis of SARS-CoV-2 genomes with over 60 thousand annotated variations curated from the 1,808,613 genomes alongside their functional annotations, first known appearance, and associated genetic lineages, enabling a robust interpretation tool for SARS-CoV-2 variations to help understanding SARS-CoV-2 dynamics across the world.
The Communication Between Intestinal Microbiota and Ulcerative Colitis: An Exploration of Pathogenesis, Animal Models, and Potential Therapeutic Strategies
Authors: Hu Yu , Ye Zhen , Wu Mingquan , She Yingqi , Li Linzhen , Xu Yujie , Qin Kaihua , Hu Zhipeng , Yang Maoyi , Lu Fating , Ye Qiaobo
Published: December 2021

Ulcerative Colitis (UC) is a chronic inflammatory bowel disease. The prolonged course of UC and the lack of effective treatment management make it difficult to cure, affecting the health and life safety of patients. Although UC has received more attention, the etiology and pathogenesis of UC are still unclear. Therefore, it is urgent to establish an updated and comprehensive understanding of UC and explore effective treatment strategies. Notably, sufficient evidence shows that the intestinal microbiota plays an important role in the pathogenesis of UC, and the treating method aimed at improving the balance of the intestinal microbiota exhibits a therapeutic potential for UC. This article reviews the relationship between the genetic, immunological and microbial risk factors with UC. At the same time, the UC animal models related to intestinal microbiota dysbiosis induced by chemical drugs were evaluated. Finally, the potential value of the therapeutic strategies for restoring intestinal microbial homeostasis and treating UC were also investigated. Comprehensively, this study may help to carry out preclinical research, treatment theory and methods, and health management strategy of UC, and provide some theoretical basis for TCM in the treatment of UC.
Optimization of Environmental Conditions for Microbial Stabilization of Uranium Tailings, and the Microbial Community Response
Authors: Lv Ying , Tang Chuiyun , Liu Xingyu , Zhang Mingjiang , Chen Bowei , Hu Xuewu , Chen Susu , Zhu Xuezhe
Published: December 2021

Uranium pollution in tailings and its decay products is a global environmental problem. It is of great significance to use economical and efficient technologies to remediate uranium-contaminated soil. In this study, the effects of pH, temperature, and inoculation volume on stabilization efficiency and microbial community response of uranium tailings were investigated by a single-factor batch experiment in the remediation process by mixed sulfate-reducing bacteria (SRB) and phosphate-solubilizing bacteria (PSB, Pantoea sp. grinm-12). The results showed that the optimal parameters of microbial stabilization by mixed SRB-PSB were pH of 5.0, temperature of 25°C, and inoculation volume of 10%. Under the optimal conditions, the uranium in uranium tailings presented a tendency to transform from the acid-soluble state to residual state. In addition, the introduction of exogenous SRB-PSB can significantly increase the richness and diversity of endogenous microorganisms, effectively maintain the reductive environment for the microbial stabilization system, and promote the growth of functional microorganisms, such as sulfate-reducing bacteria (Desulfosporosinus and Desulfovibrio) and iron-reducing bacteria (Geobacter and Sedimentibacter). Finally, PCoA and CCA analyses showed that temperature and inoculation volume had significant effects on microbial community structure, and the influence order of the three environmental factors is as follows: inoculation volume > temperature > pH. The outcomes of this study provide theoretical support for the control of uranium in uranium-contaminated sites.
Characterization of External Mucosal Microbiomes of Nile Tilapia and Grey Mullet Co-cultured in Semi-Intensive Pond Systems
Authors: Elsheshtawy Ahmed , Clokie Benjamin Gregory James , Albalat Amaya , Beveridge Allan , Hamza Ahmad , Ibrahim Abdelaziz , MacKenzie Simon
Published: December 2021

The external mucosal surfaces of the fish harbor complex microbial communities, which may play pivotal roles in the physiological, metabolic, and immunological status of the host. Currently, little is known about the composition and role of these communities, whether they are species and/or tissue specific and whether they reflect their surrounding environment. Co-culture of fish, a common practice in semi-intensive aquaculture, where different fish species cohabit in the same contained environment, is an easily accessible and informative model toward understanding such interactions. This study provides the first in-depth characterization of gill and skin microbiomes in co-cultured Nile tilapia (Oreochromis niloticus) and grey mullet (Mugil capito) in semi-intensive pond systems in Egypt using 16S rRNA gene-based amplicon sequencing. Results showed that the microbiome composition of the external surfaces of both species and pond water was dominated by the following bacterial phyla: Proteobacteria, Fusobacteriota, Firmicutes, Planctomycetota, Verrucomicrobiota, Bacteroidota, and Actinobacteriota. However, water microbial communities had the highest abundance and richness and significantly diverged from the external microbiome of both species; thus, the external autochthonous communities are not a passive reflection of their allochthonous communities. The autochthonous bacterial communities of the skin were distinct from those of the gill in both species, indicating that the external microbiome is likely organ specific. However, gill autochthonous communities were clearly species specific, whereas skin communities showed higher commonalities between both species. Core microbiome analysis identified the presence of shared core taxa between both species and pond water in addition to organ-specific taxa within and between the core community of each species. These core taxa included possibly beneficial genera such as Uncultured Pirellulaceae, Exiguobacterium, and Cetobacterium and opportunistic potential pathogens such as Aeromonas, Plesiomonas, and Vibrio. This study provides the first in-depth mapping of bacterial communities in this semi-intensive system that in turn provides a foundation for further studies toward enhancing the health and welfare of these cultured fish and ensuring sustainability.
Prophage Activation in the Intestine: Insights Into Functions and Possible Applications
Authors: Hu Jie , Ye Hao , Wang Shilan , Wang Junjun , Han Dandan
Published: December 2021

Prophage activation in intestinal environments has been frequently reported to affect host adaptability, pathogen virulence, gut bacterial community composition, and intestinal health. Prophage activation is mostly caused by various stimulators, such as diet, antibiotics, some bacterial metabolites, gastrointestinal transit, inflammatory environment, oxidative stress, and quorum sensing. Moreover, with advancements in biotechnology and the deepening cognition of prophages, prophage activation regulation therapy is currently applied to the treatment of some bacterial intestinal diseases such as Shiga toxin-producing Escherichia coli infection. This review aims to make headway on prophage induction in the intestine, in order to make a better understanding of dynamic changes of prophages, effects of prophage activation on physiological characteristics of bacteria and intestinal health, and subsequently provide guidance on prophage activation regulation therapy.
Fermented Alfalfa Meal Instead of “Grain-Type” Feedstuffs in the Diet Improves Intestinal Health Related Indexes in Weaned Pigs
Authors: Luo Yuheng , Liu Yang , Shen Yuqing , He Jun , Li Hua , Lan Cong , Li Jiayan , Chen Hong , Chen Daiwen , Ren Zhihua , Yu Bing , Huang Zhiqing , Zheng Ping , Mao Xiangbing , Yu Jie , Luo Junqiu , Yan Hui
Published: December 2021

Corn and soybean meal are the two main components in formula feed of farm animals, leading to a serious food competition between humans and livestock. An alternative may be to encourage the utilization of unconventional feedstuff in animal diet. In the current study, we evaluated the utilization of fermented alfalfa meal (FAM) in weaned pigs. Twenty weaned piglets (separately caged) were randomly divided into two groups. Pigs in the control group (CON) were fed corn-soybean meal diet, and part of corn and soya protein concentrate in the diet of another group was replaced by 8% FAM. After 40 days of feeding, the average feed intake of FAM pigs was increased (P > 0.05), and the villus height (VH) of jejunum and duodenum, crypt depth (CD), and VH/CD in FAM pigs was improved compared to the CON group (P < 0.05). The increase (P < 0.05) of goblet cells in the jejunum of FAM pigs was positively correlated with the expression of MUC-2 gene (R = 0.9150). The expression of genes related to immunity (IRAK4, NF-κB, and IL-10) and intestinal barrier (Occludin and MUC-2) in the jejunum, as well as the expression of ZO-1 and MUC-2 in the colon of these pigs, also showed increase (P < 0.05) compared to CON pigs, which was accompanied by the decrease (P < 0.05) of LPS concentration in the serum. The elevated proportion of CD3+ and CD8+ T-lymphocyte subsets in spleen (P < 0.05) confirmed the improvement of systemic immune function in FAM pigs. In addition, FAM pigs have a higher β-diversity of microbial community (P < 0.05) and promoted enrichment of probiotics such as Lactobacillus that positively was correlated with acetate concentration in the colon over CON pigs. In summary, partially replacement of expanded corn and soya protein concentrate with FAM (8%) may benefit the intestinal barrier and immune function of weaned pigs without affecting their growth. Our findings also provide evidence of the feasibility of FAM as a dietary component in pigs to reduce the consumption of grain.
Identification and Validation of ATF3 Serving as a Potential Biomarker and Correlating With Pharmacotherapy Response and Immune Infiltration Characteristics in Rheumatoid Arthritis
Authors: Hu Huan , Zhang Facai , Li Li , Liu Jun , Ao Qin , Li Ping , Zeng Jiashun , Li Long
Published: December 2021

Background: Although disease-modifying antirheumatic drugs (DMARDs) have significantly improved the prognosis of patients with rheumatoid arthritis (RA), approximately 40% of RA patients have limited response. Therefore, it was essential to explore new biomarkers to improve the therapeutic effects on RA. This study aimed to develop a new biomarker and validate it by an in vitro study.

Methods: The RNA-seq and the clinicopathologic data of RA patients were downloaded from Gene Expression Omnibus (GEO) databases. Differentially expressed genes were screened in the GPL96 and GPL570 databases. Then, weighted gene co-expression network analysis (WGCNA) was used to explore the most correlated gene modules to normal and RA synovium in the GPL96 and GPL570 databases. After that, the differentially expressed genes were intersected with the correlated gene modules to find the potential biomarkers. The CIBERSORT tool was applied to investigate the relationship between activated transcription factor 3 (ATF3) expression and the immune cell infiltration, and Gene Set Enrichment Analysis (GSEA) was used to investigate the related signaling pathways of differentially expressed genes in the high and low ATF3 groups. Furthermore, the relationships between ATF3 expression and clinical parameters were also explored in the GEO database. Finally, the role of ATF3 was verified by in vitro cell experiments.

Results: We intersected the differentially expressed genes and the most correlated gene modules in the GPL570 and GPL96 databases and identified that ATF3 is a significant potential biomarker and correlates with some clinical–pharmacological variables. Immune infiltration analysis showed that activated mast cells had a significant infiltration in the high ATF3 group in the two databases. GSEA showed that metabolism-associated pathways belonged to the high ATF3 groups and that inflammation and immunoregulation pathways were enriched in the low ATF3 group. Finally, we validated that ATF3 could promote the proliferation, migration, and invasion of RA fibroblast-like synoviocyte (FLS) and MH7A. Flow cytometry showed that ATF3 expression could decrease the proportion of apoptotic cells and increase the proportion of S and G2/M phase cells.

Conclusion: We successfully identified and validated that ATF3 could serve as a novel biomarker in RA, which correlated with pharmacotherapy response and immune cell infiltration.
Lipocalin-2 Regulates Hippocampal Microglial Activation in Poststroke Depression
Authors: Wei Li , Du Yupeng , Xie Yirui , Yu Xiaopeng , Chen Hui , Qiu Yunqing
Published: December 2021

Background and Purpose: Microglia play important role in poststroke depression (PSD), however, the exact mechanism was still unclear. The purpose of the study was to study the mechanism of microglial activation in PSD.

Methods: 24 rats were randomly divided into three groups: the PSD group (n = 10), the poststroke (PS) group (n = 7), and the sham group (n = 7). Primary hippocampal microglia were isolated and cultured, and recombined LCN2 protein was used to stimulate the cultured microglia. The protein expression of Iba1, P38 MAPK and PP38 MAPK was analyzed by western blotting; the LCN2 expression was measured by RT-qPCR, the serum LCN2 level and the NO level were analyzed by ELISA.

Results: Open field test scores (horizontal score, vertical score, and self-grooming score) and the serum LCN2 level were significantly decreased in the PSD group compared with the other two groups (P < 0.05). The serum LCN2 level was positively correlated with the horizontal score and negatively correlated with the self-grooming score in the open field test (P < 0.05). The relative protein level of Iba1 and the LCN2 mRNA level were significantly increased in the hippocampal region compared with other brain regions (P < 0.05), while the relative protein level of Iba1 and the LCN2 mRNA level were significantly increased in the PSD group compared with the other two groups (P < 0.05). The length, supernatant NO level, phagocytic ability and migration ability of LCN2-treated microglia were significantly increased compared with those of untreated microglia (P < 0.05). The relative protein levels of P38 MAPK and the PP38 MAPK significantly increased in hippocampal region in the PSD group and LCN2-treated hippocampal microglia (P < 0.05).

Conclusion: Hippocampal microglia are activated during PSD; LCN2 may regulate hippocampal microglial activation by the P38 MAPK pathway in the process of PSD.
Direct Endovascular Thrombectomy or With Prior Intravenous Thrombolysis for Acute Ischemic Stroke: A Meta-Analysis
Authors: Chen Jing , Wan Teng-Fei , Xu Tian-Ce , Chang Guo-Can , Chen Hui-Sheng , Liu Liang
Published: December 2021

Background and purpose: It is unclear whether endovascular thrombectomy alone compared with intravenous thrombolysis combination with endovascular thrombectomy can achieve similar neurological outcomes in patients with acute large vessel occlusion stroke. We aimed to perform a systematic review and meta-analysis of randomized controlled trials to compare endovascular thrombectomy alone or intravenous thrombolysis plus endovascular thrombectomy in this population.

Methods: We systematically searched PubMed, Embase, and ClinicalTrials.gov. We restricted our search to randomized clinical trials that examined the clinical outcomes of endovascular thrombectomy alone vs. intravenous thrombolysis plus endovascular thrombectomy. The Cochrane risk of bias tool was used to assess study quality. Random-effects meta-analyses were used for evaluating all outcomes.

Results: Total three randomized controlled trials with 1,092 individuals enrolled were included in the meta-analysis, including 543 (49.7%) who received endovascular thrombectomy alone and 549 (50.3%) who received intravenous thrombolysis plus endovascular thrombectomy. The primary outcome of 90-day functional independence (modified Rankin scale (mRS) score ≤ 2) was 44.6% (242/543) in the endovascular thrombectomy alone group vs. 42.8% (235/549) in the alteplase with endovascular thrombectomy group (odds ratio (OR), 1.08 [95% CI, 0.85–1.38]; P = 0.0539). Among pre-specified secondary outcomes, no significant between-group differences were found in excellent outcome (mRS score ≤ 1) (OR, 1.12 [95% CI, 0.85–1.47]; P = 0.418), mortality at 90 days (OR, 0.93 [95% CI, 0.68–1.29]; P = 0.673), successful reperfusion (thrombolysis in cerebral infarction 2b-3) (OR, 0.75 [95% CI, 0.54–1.05]; P = 0.099), and symptomatic intracranial hemorrhage (OR, 0.72 [95% CI, 0.45–1.15]; P = 0.171).

Conclusions: Among patients with acute ischemic stroke in the anterior circulation within 4.5 h from the onset, endovascular thrombectomy alone was non-inferior to combined intravenous thrombolysis and endovascular thrombectomy.
Enhancing Safety in Epilepsy Surgery (EASINESS): Study Protocol for a Retrospective, Multicenter, Open Registry
Authors: Drexler Richard , Ben-Haim Sharona , Bien Christian G. , Borger Valeri , Cardinale Francesco , Carpentier Alexandre , Cendes Fernando , Chandra Sarat , Clusmann Hans , Colon Albert , Curtis Marco de , Delev Daniel , Didato Giuseppe , Dührsen Lasse , Farah Jibril Osman , Guenot Marc , Ghatan Saadi , Haegelen Claire , Hamer Hajo , Hauptmann Jason S. , Jeffree Rosalind L. , Kalbhenn Thilo , Kegele Josua , Krayenbühl Niklaus , Lang Johannes , Mathon Bertrand , Naros Georgios , Onken Julia , Panov Fedor , Raftopoulos Christian , Ricklefs Franz L. , Rijkers Kim , Rizzi Michele , Rössler Karl , Schijns Olaf , Schneider Ulf C. , Spyrantis Andrea , Strzelczyk Adam , Stodieck Stefan , Tripathi Manjari , Vadera Sumeet , Alonso-Vanegas Mario A. , Vaz José Géraldo Ribero , Wellmer Jörg , Wehner Tim , Westphal Manfred , Sauvigny Thomas
Published: December 2021

Introduction: Optimizing patient safety and quality improvement is increasingly important in surgery. Benchmarks and clinical quality registries are being developed to assess the best achievable results for several surgical procedures and reduce unwarranted variation between different centers. However, there is no clinical database from international centers for establishing standardized reference values of patients undergoing surgery for mesial temporal lobe epilepsy.

Design: The Enhancing Safety in Epilepsy Surgery (EASINESS) study is a retrospectively conducted, multicenter, open registry. All patients undergoing mesial temporal lobe epilepsy surgery in participating centers between January 2015 and December 2019 are included in this study. The patient characteristics, preoperative diagnostic tools, surgical data, postoperative complications, and long-term seizure outcomes are recorded.

Outcomes: The collected data will be used for establishing standardized reference values (“benchmarks”) for this type of surgical procedure. The primary endpoints include seizure outcomes according to the International League Against Epilepsy (ILAE) classification and defined postoperative complications.

Discussion: The EASINESS will define robust and standardized outcome references after amygdalohippocampectomy for temporal lobe epilepsy. After the successful definition of benchmarks from an international cohort of renowned centers, these data will serve as reference values for the evaluation of novel surgical techniques and comparisons among centers for future clinical trials.

Clinical trial registration: This study is indexed at clinicaltrials.gov (NT 04952298).
Academic Performance of Children With Sickle Cell Disease in the United States: A Meta-Analysis
Authors: Heitzer Andrew M. , Hamilton Latacha , Stafford Claire , Gossett Jeffrey , Ouellette Lara , Trpchevska Ana , King Allison A. , Kang Guolian , Hankins Jane S.
Published: December 2021

Background: Students with sickle cell disease are at risk for poor academic performance due to the combined and/or interactive effects of environmental, psychosocial, and disease-specific factors. Poor academic performance has significant social and health consequences.

Objective: To study academic achievement and attainment in children with sickle cell disease in the United States.

Design: Medline, Embase, SCOPUS, CINAHL, ERIC, and PsycINFO were searched for peer-reviewed articles. Studies of children (ages 5–18) diagnosed with sickle cell disease of any genotype reporting academic achievement (standardized tests of reading, math, and spelling) or attainment (grade retention or special education) outcomes were included. Outcomes were analyzed using a random effects model. Achievement scores were compared to within study controls or normative expectations. Prevalence of special education services was compared to national (United States) estimates for Black students. Age at assessment and overall IQ were evaluated separately for association with reading and mathematics scores. Subgroup analyses of reading and math scores were analyzed by cerebral infarct status (no cerebrovascular accident, silent infarct, stroke).

Results: There were 44 eligible studies. Students with sickle cell disease scored 0.70, 0.87, and 0.80 (p < 0.001) SD below normative expectations on measures of reading, mathematics, and spelling, respectively. Compared to unaffected sibling and/or healthy controls (k = 8, n = 508), reading and math scores were 0.40 (p = 0.017) and 0.36 (p = 0.033) SD below expectations. Intellectual functioning explained 97.3 and 85.8% of the variance in reading and mathematics performance, respectively (p < 0.001). Subgroup analyses revealed significant differences in reading (p = 0.034) and mathematics (p < 0.001) based on infarct status, with lower performance associated with presence of a silent infarct or stroke.

Conclusion: Students with sickle cell disease demonstrate notable academic difficulties and are at high risk for grade retainment. Development of academic interventions and increased access to school support services are needed for this vulnerable population.

Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020179062.
The Value of Diffusion Kurtosis Imaging in Detecting Delayed Brain Development of Premature Infants
Authors: Zhao Xin , Zhang Chunxiang , Zhang Bohao , Yan Jiayue , Wang Kaiyu , Zhu Zitao , Zhang Xiaoan
Published: December 2021

Objective: Preterm infants are at high risk of the adverse neurodevelopmental outcomes. Our aim is to explore the value of diffusion kurtosis imaging (DKI) in diagnosing brain developmental disorders in premature infants.

Materials and Methods: A total of 52 subjects were included in this study, including 26 premature infants as the preterm group, and 26 full-term infants as the control group. Routine MRI and DKI examinations were performed. Mean kurtosis (MK), radial kurtosis (RK), fractional anisotropy (FA), and mean diffusivity (MD) values were measured in the brain regions including posterior limbs of the internal capsule (PLIC), anterior limb of internal capsule (ALIC), parietal white matter (PWM), frontal white matter (FWM), thalamus (TH), caudate nucleus (CN), and genu of the corpus callosum (GCC). The chi-squared test, t-test, Spearman's correlation analysis, and receiver operating characteristic curve were used for data analyses.

Results: In the premature infant group, the MK and RK values of PLIA, ALIC, and PWM were lower than those in the control group (p < 0.05). The FA values of PWM, FWM, and TH were also lower than those of the control group (p < 0.05). The area under curves of MK in PLIC and ALIC, MD in PWM, and FA in FWM were 0.813, 0.802, 0.842, and 0.867 (p < 0.05). In the thalamus and CN, the correlations between MK, RK values, and postmenstrual age (PMA) were higher than those between FA, MD values, and PMA.

Conclusion: Diffusion kurtosis imaging can be used as an effective tool in detecting brain developmental disorders in premature infants.
Gamma Oscillations in Alzheimer’s Disease and Their Potential Therapeutic Role
Authors: Traikapi Artemis , Konstantinou Nikos
Published: December 2021

Despite decades of research, Alzheimer’s Disease (AD) remains a lethal neurodegenerative disorder for which there are no effective treatments. This review examines the latest evidence of a novel and newly introduced perspective, which focuses on the restoration of gamma oscillations and investigates their potential role in the treatment of AD. Gamma brain activity (∼25–100 Hz) has been well-known for its role in cognitive function, including memory, and it is fundamental for healthy brain activity and intra-brain communication. Aberrant gamma oscillations have been observed in both mice AD models and human AD patients. A recent line of work demonstrated that gamma entrainment, through auditory and visual sensory stimulation, can effectively attenuate AD pathology and improve cognitive function in mice models of the disease. The first evidence from AD patients indicate that gamma entrainment therapy can reduce loss of functional connectivity and brain atrophy, improve cognitive function, and ameliorate several pathological markers of the disease. Even though research is still in its infancy, evidence suggests that gamma-based therapy may have a disease-modifying effect and has signified a new and promising era in AD research.
Cereus sinensis Polysaccharide Alleviates Antibiotic-Associated Diarrhea Based on Modulating the Gut Microbiota in C57BL/6 Mice
Authors: Cui Mingxiao , Wang Yu , Elango Jeevithan , Wu Junwen , Liu Kehai , Jin Yinzhe
Published: December 2021

The present study investigated whether the purified polysaccharide from Cereus sinensis (CSP-1) had beneficial effects on mice with antibiotic-associated diarrhea (AAD). The effects of CSP-1 on gut microbiota were evaluated by 16S rRNA high-throughput sequencing. Results showed that CSP-1 increased the diversity and richness of gut microbiota. CSP-1 enriched Phasecolarctobacterium, Bifidobacterium and reduced the abundance of Parabacteroides, Sutterella, Coprobacillus to near normal levels, modifying the gut microbial community. Microbial metabolites were further analyzed by gas chromatography-mass spectrometry (GC-MS). Results indicated CSP-1 promoted the production of various short-chain fatty acids (SCFAs) and significantly improved intestinal microflora dysfunction in AAD mice. In addition, enzyme linked immunosorbent assay and hematoxylin-eosin staining were used to assess the effects of CSP-1 on cytokine levels and intestinal tissue in AAD mice. Results demonstrated that CSP-1 inhibited the secretion of interleukin-2 (IL-2), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) and improved the intestinal barrier. Correspondingly, the daily records also showed that CSP-1 promoted recovery of diarrhea status score, water intake and body weight in mice with AAD. In short, CSP-1 helped alleviate AAD by regulating the inflammatory cytokines, altering the composition and richness of intestinal flora, promoting the production of SCFAs, improving the intestinal barrier as well as reversing the dysregulated microbiota function.
Texture Analysis of Fat-Suppressed T2-Weighted Magnetic Resonance Imaging and Use of Machine Learning to Discriminate Nasal and Paranasal Sinus Small Round Malignant Cell Tumors
Authors: Chen Chen , Qin Yuhui , Cheng Junying , Gao Fabao , Zhou Xiaoyue
Published: December 2021

Objective

We used texture analysis and machine learning (ML) to classify small round cell malignant tumors (SRCMTs) and Non-SRCMTs of nasal and paranasal sinus on fat-suppressed T2 weighted imaging (Fs-T2WI).

Materials

Preoperative MRI scans of 164 patients from 1 January 2018 to 1 January 2021 diagnosed with SRCMTs and Non-SRCMTs were included in this study. A total of 271 features were extracted from each regions of interest. Datasets were randomly divided into two sets, including a training set (∼70%) and a test set (∼30%). The Pearson correlation coefficient (PCC) and principal component analysis (PCA) methods were performed to reduce dimensions, and the Analysis of Variance (ANOVA), Kruskal-Wallis (KW), and Recursive Feature Elimination (RFE) and Relief were performed for feature selections. Classifications were performed using 10 ML classifiers. Results were evaluated using a leave one out cross-validation analysis.

Results

We compared the AUC of all pipelines on the validation dataset with FeAture Explorer (FAE) software. The pipeline using a PCC dimension reduction, relief feature selection, and gaussian process (GP) classifier yielded the highest area under the curve (AUC) using 15 features. When the “one-standard error” rule was used, FAE also produced a simpler model with 13 features, including S(5,-5)SumAverg, S(3,0)InvDfMom, Skewness, WavEnHL_s-3, Horzl_GlevNonU, Horzl_RLNonUni, 135dr_GlevNonU, WavEnLL_s-3, Teta4, Teta2, S(5,5)DifVarnc, Perc.01%, and WavEnLH_s-2. The AUCs of the training/validation/test datasets were 1.000/0.965/0.979, and the accuracies, sensitivities, and specificities were 0.890, 0.880, and 0.920, respectively. The best algorithm was GP whose AUCs of the training/validation/test datasets by the two-dimensional reduction methods and four feature selection methods were greater than approximately 0.800. Especially, the AUCs of different datasets were greater than approximately 0.900 using the PCC, RFE/Relief, and GP algorithms.

Conclusions

We demonstrated the feasibility of combining artificial intelligence and the radiomics from Fs-T2WI to differentially diagnose SRCMTs and Non-SRCMTs. This non-invasive approach could be very promising in clinical oncology.
PD-L1 Test-Based Strategy With Nivolumab as the Second-Line Treatment in Advanced NSCLC： A Cost-Effectiveness Analysis in China
Authors: Liu Qiao , Luo Xia , Zhou Zhen , Peng Liubao , Yi Lidan , Wan Xiaomin , Tan Chongqing , Zeng Xiaohui
Published: December 2021

Objective

Our previous economic assessment found that nivolumab was not cost-effective for Chinese patients with advanced non-small cell lung cancer (NSCLC) and without EGFR mutations or ALK translocations, when compared with the standard second-line drug docetaxel. However, a greater survival benefit with nivolumab was observed for patients with 1% or greater tumor programmed death ligand 1 (PD-L1) expression. In view of this, we designed the present analysis to explore whether it is cost-effective to use the PD-L1 test to guide second-line nivolumab treatment in China.

Material and Methods

A Markov model was established to project the lifetime costs and quality-adjusted life-years (QALYs) of three second-line treatment strategies: nivolumab and docetaxel (strategies without a PD-L1 test) and PD-L1 test-based strategy. Deterministic and probabilistic sensitivity analyses were performed to examine the robustness of our results. Additional price reduction and willingness-to-pay (WTP) threshold scenario analyses were performed to explore the impact of economic and health policies with Chinese characteristics on our results.

Results

The PD-L1 test-based strategy costs approximately CNY 194,607 (USD 28,210) or more and yielded an additional 0.27 QALYs compared to the docetaxel strategy without a PD-L1 test, equating an incremental cost-effectiveness ratio (ICER) of CNY 731,089 (USD 105,978)/QALY. Deterministic sensitivity analyses showed that the price of nivolumab was the strongest source of variation in the ICERs. Probability sensitivity analysis showed that the probability for the PD-L1 test-based strategy being cost-effective increases with the increase of WTP thresholds.

Conclusion

From the perspective of the Chinese healthcare system, using a PD-L1 test to guide second-line nivolumab treatment was not cost-effective. The National Healthcare Security Administration negotiation on the price reduction of nivolumab was found to be the most effective action to improve its cost-effectiveness in China.