bluuebunny/crossref_metadata_2025 huggingface dataset:
EKSPRESI IDEALIS PEMERAN UTAMA DALAM NOVEL TUHAN, IZINKAN AKU MENJADI PELACUR KARYA MUHIDIN M. DAHLAN
Authors: Muhsyanur Muhsyanur
Published: July 2022

Penelitian ini pada dasarnya bertujuan mendeskripsikan ekspresi idealis pemeran utama dalam novel Tuhan, Izinkan Aku Menjadi Pelacur karya Muhidin M. Dahlan. Penelitian ini termasuk penelitian kualitatif dengan menerapkan metode deskriptif. Sumber data penelitian yakni  novel Tuhan, Izinkan Aku Menjadi Pelacur karya Muhidin M. Dahlan, dengan data penelitian berupa kata, frasa, kalimat dan pernyataan yang ekspresi idealis. Data penelitian dikumpulkan dengan teknik baca secara intensif dan sistem penandaan. Teknik analisis yang digunakan dalam penelitian ini ialah teknik hermeneutika. Hasil penelitian ini menunjukkan bahwa ekspresi idealis pemeran utama dalam novel Tuhan, Izinkan Aku Menjadi Pelacur karya Muhidin M. Dahlan mencakup (1) ambisius, (2)  teguh pada pendirian, dan (3) optimisme. Penelitian ini dapat dimanfaatkan, baik secara teoretis maupun praktis. Secara teoretis, penelitian ini dapat mengembangkan teori-teori sastra khususnya sastra Indonesia. Secara praktis, penelitian ini dapat dimanfaatkan bagi peneliti, guru, dan mahasiswa sebagai referensi dan rujukan untuk penelitian selanjutnya.
KECERDASAN EMOSIONAL DITINJAU DARI PERILAKU ALTRUISME PADA MAHASISWA JURUSAN KEPERAWATAN DI UNIVERSITAS RATU SAMBAN
Authors: Zuraida Zuraida
Published: July 2022

Students majoring in nursing are prospective nurses whose job is to serve and assist in healing patients. So that prospective nurses must have high altruism behavior and be smart in understanding what other people feel which is called emotional intelligence. This study aims to examine the relationship between emotional intelligence and altruism behavior in nursing students. The variables of emotional intelligence and altruism behavior were measured using a scale. The subjects of this study amounted to 32 students majoring in nursing at Ratu Samban University. The sampling technique in this study used a probability sampling technique. The analytical technique used in this research is quantitative analysis using Karl Pearson's product moment with SPSS Version 20 for Windows. Based on the results of the study, it is known that emotional intelligence has a positive relationship with altruism behavior in nursing students at Ratu Samban University. There is a significant correlation (r0.893 with a significance <0.05) between the variable emotional intelligence and altruism behavior in nursing students, namely 0.000 and the significance value is below/smaller than 0.05, this means that the higher emotional intelligence, the higher the altruism behavior in students. students majoring in nursing on the contrary, the lower the emotional intelligence of students majoring in nursing, the lower the altruism behavior in students majoring in nursing. In nursing students, emotional intelligence has the most moderate level category with a contribution of 44% and altruism behavior has the most moderate level category with 53% contribution.
Identification of Potential Inhibitors From Urginea indica Metabolites Against Xanthomonas oryzae pv. oryzae and Magnaporthe oryzae Receptors
Authors: Mansoori Aadil , Dwivedi Anurag , Sharma Kapil , Dubey Sharad Kumar , Thakur Tarun K. , Kumar Anirudh
Published: July 2022

Synthetic pesticides are extensively used in agriculture to control pests and prevent yield loss. However, excessive use imposes a serious threat to human health, environment, and biodiversity; hence, certain pesticides have been abandoned from agricultural applications. Thus, there is a need to discover potential and eco-friendly pesticides for the effective management of phytopathogens. In current study, Urginea indica bulb extract was evaluated for potential antimicrobials and antioxidant phytochemicals. The methanol and aqueous extracts were prepared from the bulbs of Urginea indica and were evaluated for polyphenol contents, alkaloid, total antioxidant capacity, and iron chelating activity. Aqueous extract exhibited high phenol and flavonoid content, whereas the total antioxidant activity was higher in methanol extract. The iron chelating activity of both methanolic and aqueous extracts was approximately similar. The antioxidant activity of both methanolic and aqueous extracts was expressed in terms of IC50 values for 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis-3-ethylbenzotiazolin-6-sulfonic acid (ABTS), and nitric oxide (NO). The highest IC50 value was observed for DPPH and the lowest for NO in both the extract. Further, fourier transform infrared spectroscopy (FTIR) was performed, which indicated the presence of several functional groups in the extract. In addition, 75 metabolites were recorded through gas chromatography–mass spectrometry (GC-MS), of which 23 were predicted to have antimicrobial activities. Consequently, metabolites were docked with D-alanine-D-alanine ligase A (DdlA) and mitogen-activated protein kinase 1 (MAPK1) of Xanthomonas oryzae pv. oryzae (Xoo) and Magnaporthe oryzae (M.oryzae), respectively, to understand the possible mechanism of interaction between active metabolites and pathogen receptors. Docking study revealed that quinic acid, 3-caffeoyl has highest binding affinity for both DdlA and MAPK1 with respect to reference compound D-cycloserine and Trametinib. Thus, quinic acid, 3-caffeoyl could inhibit both DdlA and MAPK1-mediated signal transduction and, hence, could be used as a promising natural inhibitor of DdlA and MAPK1 receptors. The above results indicate that Urginea indica could be a potential source of bioactive compounds and could be used as a potential source of natural pesticides to suppress phytopathogens.
Enhancing Stem Cell-Based Therapeutic Potential by Combining Various Bioengineering Technologies
Authors: Hong In-Sun
Published: July 2022

Stem cell-based therapeutics have gained tremendous attention in recent years due to their wide range of applications in various degenerative diseases, injuries, and other health-related conditions. Therapeutically effective bone marrow stem cells, cord blood- or adipose tissue-derived mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and more recently, induced pluripotent stem cells (iPSCs) have been widely reported in many preclinical and clinical studies with some promising results. However, these stem cell-only transplantation strategies are hindered by the harsh microenvironment, limited cell viability, and poor retention of transplanted cells at the sites of injury. In fact, a number of studies have reported that less than 5% of the transplanted cells are retained at the site of injury on the first day after transplantation, suggesting extremely low (<1%) viability of transplanted cells. In this context, 3D porous or fibrous national polymers (collagen, fibrin, hyaluronic acid, and chitosan)-based scaffold with appropriate mechanical features and biocompatibility can be used to overcome various limitations of stem cell-only transplantation by supporting their adhesion, survival, proliferation, and differentiation as well as providing elegant 3-dimensional (3D) tissue microenvironment. Therefore, stem cell-based tissue engineering using natural or synthetic biomimetics provides novel clinical and therapeutic opportunities for a number of degenerative diseases or tissue injury. Here, we summarized recent studies involving various types of stem cell-based tissue-engineering strategies for different degenerative diseases. We also reviewed recent studies for preclinical and clinical use of stem cell-based scaffolds and various optimization strategies.
Emerging Roles of Long Noncoding RNAs in Breast Cancer Epigenetics and Epitranscriptomics
Authors: Wanowska Elżbieta , Samorowska Klaudia , Szcześniak Michał Wojciech
Published: July 2022

Breast carcinogenesis is a multistep process that involves both genetic and epigenetic changes. Epigenetics refers to reversible changes in gene expression that are not accompanied by changes in gene sequence. In breast cancer (BC), dysregulated epigenetic changes, such as DNA methylation and histone modifications, are accompanied by epitranscriptomic changes, in particular adenine to inosine modifications within RNA molecules. Factors that trigger these phenomena are largely unknown, but there is evidence for widespread participation of long noncoding RNAs (lncRNAs) that already have been linked to virtually any aspect of BC biology, making them promising biomarkers and therapeutic targets in BC patients. Here, we provide a systematic review of known and possible roles of lncRNAs in epigenetic and epitranscriptomic processes, along with methods and tools to study them, followed by a brief overview of current challenges regarding the use of lncRNAs in medical applications.
Automated Quantification of Human Osteoclasts Using Object Detection
Authors: Kohtala Sampsa , Nedal Tonje Marie Vikene , Kriesi Carlo , Moen Siv Helen , Ma Qianli , Ødegaard Kristin Sirnes , Standal Therese , Steinert Martin
Published: July 2022

A balanced skeletal remodeling process is paramount to staying healthy. The remodeling process can be studied by analyzing osteoclasts differentiated in vitro from mononuclear cells isolated from peripheral blood or from buffy coats. Osteoclasts are highly specialized, multinucleated cells that break down bone tissue. Identifying and correctly quantifying osteoclasts in culture are usually done by trained personnel using light microscopy, which is time-consuming and susceptible to operator biases. Using machine learning with 307 different well images from seven human PBMC donors containing a total of 94,974 marked osteoclasts, we present an efficient and reliable method to quantify human osteoclasts from microscopic images. An open-source, deep learning-based object detection framework called Darknet (YOLOv4) was used to train and test several models to analyze the applicability and generalizability of the proposed method. The trained model achieved a mean average precision of 85.26% with a correlation coefficient of 0.99 with human annotators on an independent test set and counted on average 2.1% more osteoclasts per culture than the humans. Additionally, the trained models agreed more than two independent human annotators, supporting a more reliable and less biased approach to quantifying osteoclasts while saving time and resources. We invite interested researchers to test their datasets on our models to further strengthen and validate the results.
Green Synthesis of Thiazolidine-2,4-dione Derivatives and Their Lipoxygenase Inhibition Activity With QSAR and Molecular Docking Studies
Authors: Lončarić Melita , Strelec Ivica , Pavić Valentina , Rastija Vesna , Karnaš Maja , Molnar Maja
Published: July 2022

Thiazolidinediones are five-membered, heterocyclic compounds that possess a number of pharmacological activities such as antihyperglycemic, antitumor, antiarthritic, anti-inflammatory, and antimicrobial. Conventional methods for their synthesis are often environmentally unacceptable due to the utilization of various catalysts and organic solvents. In this study, deep eutectic solvents were used in the synthesis of thiazolidinedione derivatives that acted as both solvents and catalysts. Initially, a screening of 20 choline chloride-based deep eutectic solvents for thiazolidinedione synthesis, via Knoevenagel condensation, was performed in order to find the most suitable solvent. Deep eutectic solvent, choline chloride, N-methylurea, was proven to be the best for further synthesis of 19 thiazolidinedione derivatives. Synthesized thiazolidinediones are obtained in yields from 21.49% to 90.90%. The synthesized compounds were tested for the inhibition of lipid peroxidation as well as for the inhibition of soy lipoxygenase enzyme activity. The antioxidant activity of the compounds was also determined by the ABTS and DPPH methods. Compounds showed lipoxygenase inhibition in the range from 7.7% to 76.3%. Quantitative structure–activity relationship model (R2 = 0.88; Q2loo = 0.77; F = 33.69) for the inhibition of soybean lipoxygenase was obtained with descriptors Mor29m, G2u, and MAXDP. The molecular docking confirms experimentally obtained results, finding the binding affinity and interactions with the active sites of soybean LOX-3.
CD169 (Siglec-1) as a Robust Human Cell Biomarker of Toll-Like Receptor 9 Agonist Immunotherapy
Authors: Lende Stine Sofie Frank , Pahus Marie Høst , Monrad Ida , Olesen Rikke , Mahr Anna R. , Vibholm Line K. , Østergaard Lars , Søgaard Ole Schmeltz , Andersen Anna Halling Folkmar , Denton Paul W. , Tolstrup Martin
Published: July 2022

Immunotherapy is a promising therapeutic area in cancer and chronic viral infections. An important component of immunotherapy in these contexts is the activation of innate immunity. Here we investigate the potential for CD169 (Siglec 1) expression on monocytes to serve as a robust biomarker for activation of innate immunity and, particular, as a proxy for IFN-α production. Specifically, we investigated the effects of Toll-like receptor 9 agonism with MGN1703 (lefitolimod) across experimental conditions ex vivo, in humanized mice, and in clinical trial participants. Ex vivo we observed that the percentage of classical monocytes expressing CD169 increased dramatically from 10% pre-stimulation to 97% 24 hrs after MGN1703 stimulation (p<0.0001). In humanized NOG mice, we observed prominent upregulation of the proportions of monocytes expressing CD169 after two doses of MGN1703 where 73% of classical monocytes were CD169 positive in bone marrow following MGN1703 treatment vs 19% in vehicle treated mice (p=0.0159). Finally, in a clinical trial in HIV-infected individuals receiving immunotherapy treatment with MGN1703, we observed a uniform upregulation of CD169 on monocytes after dosing with 97% of classical monocytes positive for CD169 (p=0.002). Hence, in this comprehensive evaluation ex vivo, in an animal model, and in a clinical trial, we find increases in the percentage of CD169 positive monocytes to be a reliable and robust biomarker of immune activation following TLR9 agonist treatment.
The Gastrointestinal Load of Carbapenem-Resistant Enterobacteriacea Is Associated With the Transition From Colonization to Infection by Klebsiella pneumoniae Isolates Harboring the blaKPC Gene
Authors: Migliorini Letícia Busato , Leaden Laura , de Sales Romário Oliveira , Correa Nathalia Pellegrini , Marins Maryana Mara , Koga Paula Célia Mariko , Toniolo Alexandra do Rosario , de Menezes Fernando Gatti , Martino Marines Dalla Valle , Mingorance Jesús , Severino Patricia
Published: July 2022

Background

Healthcare-associated infections by carbapenem-resistant Klebsiella pneumoniae are difficult to control. Virulence and antibiotic resistance genes contribute to infection, but the mechanisms associated with the transition from colonization to infection remain unclear.

Objective

We investigated the transition from carriage to infection by K. pneumoniae isolates carrying the K. pneumoniae carbapenemase–encoding gene blaKPC (KpKPC).

Methods

KpKPC isolates detected within a 10-year period in a single tertiary-care hospital were characterized by pulsed-field gel electrophoresis (PFGE), multilocus sequencing typing, capsular lipopolysaccharide and polysaccharide typing, antimicrobial susceptibility profiles, and the presence of virulence genes. The gastrointestinal load of carbapenem-resistant Enterobacteriaceae and of blaKPC-carrying bacteria was estimated by relative quantification in rectal swabs. Results were evaluated as contributors to the progression from carriage to infection.

Results

No PGFE type; ST-, K-, or O-serotypes; antimicrobial susceptibility profiles; or the presence of virulence markers, such yersiniabactin and colibactin, were associated with carriage or infection, with ST437 and ST11 being the most prevalent clones. Admission to intensive and semi-intensive care units was a risk factor for the development of infections (OR 2.79, 95% CI 1.375 to 5.687, P=0.005), but higher intestinal loads of carbapenem-resistant Enterobacteriaceae or of blaKPC-carrying bacteria were the only factors associated with the transition from colonization to infection in this cohort (OR 8.601, 95% CI 2.44 to 30.352, P<0.001).

Conclusion

The presence of resistance and virulence mechanisms were not associated with progression from colonization to infection, while intestinal colonization by carbapenem-resistant Enterobacteriacea and, more specifically, the load of gastrointestinal carriage emerged as an important determinant of infection.
Resting Cardiac Power Predicts Adverse Outcome in Heart Failure Patients With Preserved Ejection Fraction: A Prospective Study
Authors: Wang Shiqi , Chen Aiqi , Duan Xiaokai
Published: July 2022

Background

We sought to explore the significance of resting cardiac power/mass in predicting adverse outcome in patients with heart failure with preserved ejection fraction (HFpEF).

Methods

This prospective cohort study included patients with HFpEF and without significant valve disease or right ventricular dysfunction. Cardiac power was normalized to left ventricular (LV) mass and expressed in W/100 g of LV myocardium. Multivariate Cox regression analysis was used to evaluate the association between resting cardiac power/mass and composite endpoint, which included all-cause mortality and heart failure (HF) hospitalization.

Results

A total of 2,089 patients were included in this study. After an average follow-up of 4.4 years, 612 (29.30%) patients had composite endpoint, in which 331 (15.84%) died and 391 (18.72%) experienced HF hospitalization. In multivariate Cox regression analysis, resting power/mass < 0.7 W/m2 was independently associated with composite endpoint, all-cause mortality, cardiovascular mortality and HF hospitalization, with hazard ratios (HR) of 1.309 [95% confidence interval (CI): 1.108–1.546, P = 0.002], 1.697 (95%CI: 1.344–2.143, P < 0.001), 2.513 (95%CI: 1.711–3.689, P < 0.001), and 1.294 (95%CI: 1.052–1.592, P = 0.015), respectively. For composite endpoint, cardiovascular mortality and HF hospitalization, the C statistic increased significantly when incorporating resting cardiac power/mass into a model with established risk factors. For composite endpoint, the continuous net reclassification index after adding resting cardiac power/mass in the original model with N-terminal pro-brain natriuretic peptide was 13.1% (95%CI: 2.9–21.6%, P = 0.007), and the integrated discrimination index was 1.9% (95%CI: 0.8–3.2%, P < 0.001).

Conclusion

Resting cardiac power determined by non-invasive echocardiography is independently associated with the risk of adverse outcomes in HFpEF patients and provides incremental prognostic information.
Emotional Agency at Work: The Development and Validation of a Measure
Authors: Hökkä Päivi Kristiina , Räikkönen Eija , Ikävalko Heini , Paloniemi Susanna , Vähäsantanen Katja
Published: July 2022

Despite intensive research on agency in education and work environments, the topic remains underexplored through the lens of emotions. This study conducted the development and validation of a quantitative measure to explore emotional agency in working life. Empirical data (N = 240) were collected via a web-based survey within the professional domains of healthcare and real estate services. The participants’ age, educational level, and gender corresponded to the domain-specific and general employee distribution in Finland. The questionnaire items were based on a theoretical construct of emotional agency at work. Exploratory factor analysis indicated that emotional agency includes two dimensions: Emotional Competence at Work and Influencing Emotions at Work. Exploratory structural equation modeling showed these dimensions to be equivalent across the studied professional domains. Furthermore, the convergent and discriminant validity of the measure was confirmed in relation to the emotional climate at work and work engagement. The study enriches the current theory of agency and emotions at work by exploring their connection. It also proposes a novel measure of emotional agency at work (the E-Ag measure), offered as a useful tool for researching and developing working life and organizational behavior.
Case Report: Reversible Hyperglycemia Following Rapamycin Treatment for Atypical Choroid Plexus Papilloma in an Infant
Authors: Liu Jiale , Luo Minjie , Lv Siyuan , Tao Shaohua , Wu Zhu , Yu Lihua , Lin Danna , Huang Lulu , Wu Li , Liao Xu , Zi Juan , Lai Xiaorong , Yuan Yuting , Zhang Wangming , Yang Lihua
Published: July 2022

In this study, atypical choroid plexus papilloma was treated with high-dose rapamycin for 17 days preoperatively in an infant. Rapamycin significantly reduced the blood supply to the tumor while reducing the tumor volume, and most of the tumor was resected successfully. However, the infant developed hyperglycemia related to the rapamycin dose, which was effectively controlled by adjusting the dose and applying insulin.
Saturation Effect of Body Mass Index on Bone Mineral Density in Adolescents of Different Ages: A Population-Based Study
Authors: Ouyang Yujuan , Quan Yingping , Guo Chengyi , Xie Songlin , Liu Changxiong , Huang Xiongjie , Huang Xinfeng , Chen Yanming , Xiao Xiangjun , Ma Nengqian , Xie Ruijie
Published: July 2022

Background

Adolescence is a critical period for bone development, and peak bone mass may be reached in late adolescence. Boosting bone accumulation at this time can help preserve adult bone health and avoid osteoporosis later in life. Body mass index (BMI) has been found to have a favorable impact on bone mineral density (BMD) in previous research. However, excessive obesity is harmful to health and may lead to various systemic diseases. Therefore, finding an appropriate BMI to maintain a balance between obesity and BMD is critical for adolescents.

Methods

The datasets from the National Health and Nutrition Examination Survey (NHANES) 2011–2020 were used in a cross-sectional investigation. Multivariate linear regression models were used to examine the linear connection between BMI and BMD. Fitted smoothing curves and threshold effect analysis were used to describe the nonlinear relationship. Subgroup analyses were then conducted based on gender and age.

Results

This population-based study included a total of 6,143 adolescents aged 8–19 years. In a multivariate linear regression analysis, a good association between BMI and total BMD was shown [0.014 (0.013, 0.014)]. This positive association was maintained in all subgroup analyses grouped by sex and age. Furthermore, the association between BMI and BMD was nonlinear with a saturation point present, as evidenced by smoothed curve fitting. According to the threshold effect study, with an age group of two years, adolescents of different ages had different BMI saturation values with respect to BMD.

Conclusions

Our study showed a significant positive and saturated association between BMI and BMD in adolescents aged 8–19 years. Maintaining BMI at saturation values may reduce other adverse effects while achieving optimal BMD.
Interval Prediction Method for Wind Speed Based on ARQEA Optimized by Beta Distribution and SWLSTM
Authors: Sun Zhenao , Shen Yongshan , Chen Zhe , Teng Yun , Qian Xiaoyi
Published: July 2022

The interval prediction of wind speed is crucial for the economic and safe operation of wind farms. To overcome the probability density function parameter optimization and long-term correlation of time series problems in an interval prediction method, a hybrid model based on the beta distribution of an allele real-coded quantum evolutionary algorithm (ARQEA) and a shared weight long short-term memory (SWLSTM) neural network is proposed for predicting the interval of short-term wind speed, which is beta–ARQEA–SWLSTM. Input variables are determined via autocorrelation functions, and the shape and position parameters in the beta distribution function are optimized by the ARQEA algorithm. An interval-divided multi-distribution function aggregation is proposed to deal with the fluctuation of wind speed series. Lastly, case studies are provided to demonstrate the effectiveness of the proposed method.
Case Report: Prenatal Whole-Exome Sequencing Identified a Novel Nonsense Mutation of the KCNH2 Gene in a Fetus With Familial 2q14.2 Duplication
Authors: Zhuang Jianlong , Chen Chunnuan , Wang Yuanbai , Zeng Shuhong , Chen Yu’e , Jiang Yuying , Xie Yingjun , Wang Gaoxiong
Published: July 2022

Background: Pathogenic mutations in the KCNH2 gene were associated with long QT syndrome 2 (LQT2), which typically manifest in a prolonged QT interval and may lead to recurrent syncopes, seizure, or sudden death. Limited reports indicated that the KCNH2 mutations would result in LQT2 combined with tetralogy of fallot. Our goal was to present an additional case of LQT2 combined with the tetralogy of fallot in a fetus with a novel KCNH2 mutation.

Case presentation: Enrolled in this study was a 23-year-old pregnant woman from Quanzhou Fujian province, China. In her pregnancy, fetal ultrasound anomalies were identified, including tetralogy of fallot, coronary sinus enlargement, and persistent left superior vena cava. No chromosomal abnormality was detected by fetal karyotype analysis. However, 238.1-kb duplication in the 2q14.2 region containing the GLI2 gene was observed in the fetus by chromosomal array analysis, which was inherited from the mother with normal clinical features and interpreted as a variant of uncertain significance (VOUS). Furthermore, whole-exome sequencing (WES) detection identified a novel nonsense c.1907C > G (p.S636*) mutation in the KCNH2 gene in the fetus, and it was classified as a likely pathogenic variant, according to the ACMG guidelines. Parental verification analysis indicated that c.1907C > G (p.S636*) mutation was inherited from the mother.

Conclusion: In this study, we believe that 2q14.2 duplication may not be the reason for fetal heart defects; moreover, we described an additional case with KCNH2 gene mutation, which may lead to LQTS and be associated with congenital heart defects. In addition, our study further confirms the application value of the WES technology in prenatal genetic etiology diagnosis of fetuses with structural anomalies and unexplained structural variants.
Integration of Bulk RNA Sequencing and Single-Cell RNA Sequencing to Reveal Uveal Melanoma Tumor Heterogeneity and Cells Related to Survival
Authors: Gao Guohong , Deng Aijun , Liang Shan , Liu Shengsheng , Fu Xinyi , Zhao Xiaoyan , Yu Zhilong
Published: July 2022

Molecular classification based on transcriptional characteristics is often used to study tumor heterogeneity. Human cancer has different cell populations with distinct transcription in tumors, and their heterogeneity is the focus of tumor therapy. Our purpose was to explore the tumor heterogeneity of uveal melanoma (UM) through RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq). Based on the consensus clustering assays of the prognosis-related immune gene set, the immune subtype (IS) of UM and its corresponding immune characteristics were comprehensively analyzed. The heterogeneous cell groups and corresponding marker genes of UM were identified from GSE138433 using scRNA-seq analysis. Pseudotime trajectory analysis and SCENIC analysis were conducted to explore the trajectory of cell differentiation and the regulatory network of single-cell transcription factors (TFs). Based on 37 immune gene sets, UM was divided into two different immune subtypes (IS1 and IS2). The two kinds of ISs have different characteristics in prognosis, immune-related molecules, immune score, and immune cell infiltration. According to 11,988 cells of scRNA-seq data from six UM samples, 11 cell clusters and 10 cell types were identified. The subsets of C1, C4, C5, C8, and C9 were related to the prognosis of UM, and different TF–target gene regulatory networks were involved. These five cell subsets differentiated into 3 different states. Our results provided valuable information about the heterogeneity of UM tumors and the expression patterns of TFs in different cell types.
High Number and Specific Comorbidities Could Impact the Immune Response in COVID-19 Patients
Authors: Liu Dafeng , Yuan Xiaoyan , Gao Fengjiao , Zhao Bennan , Ding Ling , Huan Mingchang , Liu Chao , Jiang Liangshuang
Published: July 2022

Background

Cellular immunodeficiency and comorbidities are common in COVID-19 patients.

Aim

The purpose of this study was to investigate comorbidities impacting on the cellular immunity in COVID-19 patients.

Methods

The research objects included 55 healthy controls and 718 COVID-19 patients who divided into the control group and the COVID-19 group, respectively. Those in the COVID-19 group were divided into subgroups on the basis of the number and types of comorbidities present. Lymphocyte itself and its subsets were compared between the control group and the COVID-19 group, the groups with comorbidities based on the different number and types of comorbidities, and the relationship between the lymphocyte counts and subsets with the number and types of comorbidities was investigated.

Results

Compared with the control group, the lymphocyte counts and T cell subsets were significantly increased in the groups with comorbidities, but both B and NK cell subsets were significantly decreased in the no comorbidity group and in most of the groups with comorbidities (all P<0.05). In the three comorbidities group, the lymphocyte counts and T cell subsets were all significantly decreased, but the CD56+ percentage was obviously increased (all P<0.05). The number of comorbidities was negatively correlated with the lymphocyte counts and the T and NK cell subsets. A negative correlation also existed between cancer and both the lymphocyte counts and the T cell subsets, between chronic hepatitis B and the lymphocyte counts, and between chronic kidney disease and the CD3+ counts. A positive correlation existed between nonalcoholic fatty liver disease (NAFLD) disease and both lymphocyte and CD3+ counts. The risk factors were number of comorbidities for the lymphocyte count, CD3+CD4+ and CD3+CD8+ percentages, NAFLD for the lymphocyte and CD3+ counts, cardiovascular diseases for CD3+CD4+ and CD3+CD8+ percentages, diabetes mellitus for the CD3+CD8+ percentage, and cancer for the CD3+ percentage, respectively.

Conclusions

High numbers of comorbidities and specific comorbidities could impact the immune response of COVID-19 patients. This study provides a reference for clinicians in the identification of suitable and timely immunotherapy for COVID-19 patients.

Clinical Trial Registry

https://www.chictr.org.cn/enindex.aspx, identifier ChiCTR2000034563.
GM-CSF: A Double-Edged Sword in Cancer Immunotherapy
Authors: Kumar Anil , Taghi Khani Adeleh , Sanchez Ortiz Ashly , Swaminathan Srividya
Published: July 2022

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that drives the generation of myeloid cell subsets including neutrophils, monocytes, macrophages, and dendritic cells in response to stress, infections, and cancers. By modulating the functions of innate immune cells that serve as a bridge to activate adaptive immune responses, GM-CSF globally impacts host immune surveillance under pathologic conditions. As with other soluble mediators of immunity, too much or too little GM-CSF has been found to promote cancer aggressiveness. While too little GM-CSF prevents the appropriate production of innate immune cells and subsequent activation of adaptive anti-cancer immune responses, too much of GM-CSF can exhaust immune cells and promote cancer growth. The consequences of GM-CSF signaling in cancer progression are a function of the levels of GM-CSF, the cancer type, and the tumor microenvironment. In this review, we first discuss the secretion of GM-CSF, signaling downstream of the GM-CSF receptor, and GM-CSF’s role in modulating myeloid cell homeostasis. We then outline GM-CSF’s anti-tumorigenic and pro-tumorigenic effects both on the malignant cells and on the non-malignant immune and other cells in the tumor microenvironment. We provide examples of current clinical and preclinical strategies that harness GM-CSF’s anti-cancer potential while minimizing its deleterious effects. We describe the challenges in achieving the Goldilocks effect during administration of GM-CSF-based therapies to patients with cancer. Finally, we provide insights into how technologies that map the immune microenvironment spatially and temporally may be leveraged to intelligently harness GM-CSF for treatment of malignancies.
Increased Interleukin-17 and Glucocorticoid Receptor-β Expression in Interstitial Lung Diseases and Corticosteroid Insensitivity
Authors: Lo Chun-Yu , Wang Chun-Hua , Wang Chih-Wei , Chen Chih-Jung , Huang Hung-Yu , Chung Fu-Tsai , Huang Yu-Chen , Lin Chang-Wei , Lee Chung-Shu , Lin Chun-Yu , Lin Chiung-Hung , Chang Po-Jui , Lin Ting-Yu , Heh Chih-Chen , He Jung-Ru , Chung Kian Fan
Published: July 2022

Background

Treatment responsiveness to corticosteroids is excellent for cryptogenic organizing pneumonia (COP) and sarcoidosis, but suboptimal for idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP). We hypothesise that the differential expression of IL-17 contributes to variable corticosteroid sensitivity in different interstitial lung diseases.

Objective

To determine the associations among expression of IL-17, glucocorticoid receptor-β and responsiveness to corticosteroid treatment in interstitial lung diseases.

Methods

Immunohistochemical (IHC) staining was performed on formalin-fixed paraffin-embedded (FFPE) lung tissues obtained by bronchoscopic, CT-guided or surgical biopsies, and quantified by both cell counting (% positive cells) by individuals and by software IHC Profiler plugin of ImageJ (opacity density score). We studied the effect of IL-17 on corticosteroid sensitivity in human fibroblast MRC5 cell line.

Results

Compared with specimens from patients with COP (n =13) and sarcoidosis (n =13), those from IPF patients (n = 21) had greater GR-β and IL-17 expression and neutrophil infiltration. Radiographic progression after oral corticosteroid treatment was positively correlated with the expression in IL-17 and GR-β/GR-α ratio in all patients (COP, sarcoidosis and IPF) and also within the IPF subgroup only. IL-17 expression level was positively associated with GR-β and GR-β/GR-α ratio. In MRC5 cells, exogenous IL-17 increased the production of collagen I and up-regulated GR-β expression and dexamethasone’s suppressive effect on collagen I production was impaired by IL-17, and silencing IL-17 receptor A gene attenuated the effect of IL-17.

Conclusion

Up-regulation of GR-β/GR-α ratio by IL-17 could be associated with the relative corticosteroid-insensitivity of IPF.
Grass Carp Mex3A Promotes Ubiquitination and Degradation of RIG-I to Inhibit Innate Immune Response
Authors: Jiang Zeyin , Sun Zhichao , Hu Jihuan , Li Dongming , Xu Xiaowen , Li Meifeng , Feng Zhiqing , Zeng Shanshan , Mao Huiling , Hu Chengyu
Published: July 2022

As one of the Mex3 family members, Mex3A is crucial in cell proliferation, migration, and apoptosis in mammals. In this study, a novel gene homologous to mammalian Mex3A (named CiMex3A, MW368974) was cloned and identified in grass carp, which is 1,521 bp in length encoding a putative polypeptide of 506 amino acids. In CIK cells, CiMex3A is upregulated after stimulation with LPS, Z-DNA, and especially with intracellular poly(I:C). CiMex3A overexpression reduces the expressions of IFN1, ISG15, and pro-inflammatory factors IL8 and TNFα; likewise, Mex3A inhibits IRF3 phosphorylation upon treatment with poly(I:C). A screening test to identify potential targets suggested that CiMex3A interacts with RIG-I exclusively. Co-localization analysis showed that Mex3A and RIG-I are simultaneously located in the endoplasmic reticulum, while they rarely appear in the endosome, mitochondria, or lysosome after exposure to poly(I:C). However, RIG-I is mainly located in the early endosome and then transferred to the late endosome following stimulation with poly(I:C). Moreover, we investigated the molecular mechanism underlying CiMex3A-mediated suppression of RIG-I ubiquitination. The results demonstrated that Mex3A truncation mutant (deletion in the RING domain) can still interact physically with RIG-I, but fail to degrade it, suggesting that Mex3A also acts as a RING-type E3 ubiquitin ligase. Taken together, this study showed that grass carp Mex3A can interact with RIG-I in the endoplasmic reticulum following poly(I:C) stimulation, and then Mex3A facilitates the ubiquitination and degradation of RIG-I to inhibit IRF3-mediated innate antiviral immune response.
Innate/Inflammatory Bioregulation of Surfactant Protein D Alleviates Rat Osteoarthritis by Inhibiting Toll-Like Receptor 4 Signaling
Authors: Jiang Huanyu , Zhang Yubiao , Hu Geliang , Shang Xiaobin , Ming Jianghua , Deng Ming , Li Yaming , Ma Yonggang , Liu Shiqing , Zhou Yan
Published: July 2022

Osteoarthritis (OA) is a deteriorating disease of cartilage tissues mainly characterized as low-grade inflammation of the joint. Innate immune molecule surfactant protein D (SP-D) is a member of collectin family of collagenous Ca2+-dependent defense lectins and plays a vital role in the inflammatory and innate immune responses. The present study investigated the SP-D-mediated innate/inflammatory bioregulation in OA and explored the underlying molecular mechanism. Transcriptome analysis revealed that SP-D regulated genes were strongly enriched in the inflammatory response, immune response, cellular response to lipopolysaccharide (LPS), PI3K-Akt signaling, Toll-like receptor (TLR) signaling, and extracellular matrix (ECM)-receptor interaction pathways. Knockdown of the SP-D gene by the recombinant adeno-associated virus promoted the macrophage specific markers of CD68, F4/80 and TLR4 in the articular cartilage in vivo. SP-D alleviated the infiltration of synovial macrophages and neutrophils, and inhibited TLR4, TNF-α and the phosphorylation of PI3K, Akt and NF-κB p65 in cartilage. SP-D suppressed cartilage degeneration, inflammatory and immune responses in the rat OA model, whilst TAK-242 strengthened this improvement. In in vitro conditions, SP-D pre-treatment inhibited LPS-induced overproduction of inflammation-correlated cytokines such as IL-1β and TNF-α, and suppressed the overexpression of TLR4, MD-2 and NLRP3. SP-D prevented the LPS-induced degradation of ECM by down-regulating MMP-13 and up-regulating collagen II. Blocking of TLR4 by TAK-242 further enhanced these manifestations. We also demonstrated that SP-D binds to the TLR4/MD-2 complex to suppress TLR4-mediated PI3K/Akt and NF-κB signaling activation in chondrocytes. Taken together, these findings indicate that SP-D has chondroprotective properties dependent on TLR4-mediated PI3K/Akt and NF-κB signaling and that SP-D has an optimal bioregulatory effect on the inflammatory and innate responses in OA.
Human Hepatic CD56bright NK Cells Display a Tissue-Resident Transcriptional Profile and Enhanced Ability to Kill Allogenic CD8+ T Cells
Authors: Jameson Gráinne , Harmon Cathal , Santiago Rhyla Mae , Houlihan Diarmaid D. , Gallagher Tom K. , Lynch Lydia , Robinson Mark W. , O’Farrelly Cliona
Published: July 2022

Liver-resident CD56brightCD16-natural killer (NK) cells are enriched in the human liver and are phenotypically distinct from their blood counterparts. Although these cells are capable of rapid cytotoxic effector activity, their functional role remains unclear. We hypothesise that they may contribute to immune tolerance in the liver during transplantation. RNA sequencing was carried out on FACS sorted NK cell subpopulations from liver perfusates (n=5) and healthy blood controls (n=5). Liver-resident CD56brightCD16+/-NK cells upregulate genes associated with tissue residency. They also upregulate expression ofCD160andLY9, both of which encode immune receptors capable of activating NK cells. Co-expression of CD160 and Ly9 on liver-resident NK cells was validated using flow cytometry. Hepatic NK cell cytotoxicity against allogenic T cells was tested using anin vitroco-culture system of liver perfusate-derived NK cells and blood T cells (n=10-13). In co-culture experiments, hepatic NK cells but not blood NK cells induced significant allogenic T cell death (p=0.0306). Allogenic CD8+T cells were more susceptible to hepatic NK cytotoxicity than CD4+T cells (p<0.0001). Stimulation of hepatic CD56brightNK cells with an anti-CD160 agonist mAb enhanced this cytotoxic response (p=0.0382). Our results highlight a role for donor liver NK cells in regulating allogenic CD8+T cell activation, which may be important in controlling recipient CD8+T cell-mediated rejection post liver-transplant.
A Novel MicroRNA and the Target Gene TAB2 Can Regulate the Process of Sucking Blood in and the Spawn Rate of Hyalomma asiaticum (Acari: Ixodidae) Ticks
Authors: Luo Jin , Wu Feng , Liu Wenge , Ren Qiaoyun , Diao Peiwen , Guan Guiquan , Luo Jianxun , Yin Hong , Liu Guangyuan
Published: July 2022

Ticks are blood-sucking parasites that are harmful to humans and animals. MicroRNAs are a class of conserved small noncoding RNAs that play regulatory roles in the expression of many genes at the posttranscriptional level. Here, a novel miRNA (nov-miR-17) was identified from a small RNA data library of Hyalomma asiaticum by next-generation sequencing. PCR was used to obtain precursor nov-miR-17 by RACE using mature loop primers. The secondary structure was predicted with UNAFold. The interaction of nov-miR-17 with its target gene TAB2 was predicted using RNAhybrid software and identified in vitro by luciferase assays. Moreover, the interaction was confirmed in vivo by phenotype rescue experiments in which dsTAB2 was used for RNA interference (RNAi) and an antagomir of nov-miR-17 was used for miRNA silencing. The expression levels of nov-miR-17 and TAB2 in ticks at different developmental stages and the expression of nov-miR-17 in different tissues were analyzed by real-time qPCR. All data were analyzed using GraphPad Prism version 5. Results: The results showed that TAB2 was a target gene of nov-miR-17. When the blood-sucking process of larval, nymph and adult ticks was prolonged, the expression of nov-miR-17 was decreased, and TAB2 expression was increased. However, the level of nov-miR-17 in the midgut of engorged ticks was highest at all stages. Therefore, nov-miR-17 plays an important role in the blood-sucking process. The overexpression of nov-miR-17 indicated that this miRNA affected the engorged weight (P < 0.001) and spawn rate (P < 0.001) of female ticks. RNAi of TAB2 also had the same effect. dsRNA not only impacted the weight (P < 0.01) but also reduced the spawn rate (P < 0.001) of the ticks. Furthermore, significant recovery was observed in nov-miR-17-silenced ticks after TAB2 silencing by RNAi. nov-miR-17 silencing by antagomir not only impacted the engorged weight of the female ticks (P < 0.001) but also the number of days that the females needed to progress from engorgement to spawning (P < 0.001). The study showed that nov-miR-17, as a new miRNA, plays an important role along with its target gene TAB2 in the blood-sucking and spawning processes in female ticks.
The Multi-Annual Residency of Juvenile Smooth Hammerhead Shark in an Oceanic Island Nursery
Authors: Afonso Pedro , Gandra Miguel , Graça Gonçalo , Macena Bruno , Vandeperre Frederic , Fontes Jorge
Published: July 2022

The increased risk of local extinction becomes critical for sharks depending on the narrow and isolated coastal habitats of oceanic islands. This includes large pelagic oceanic sharks that use such habitats as nurseries, as previously hypothesized for the smooth hammerhead Sphyrna zygaena, the least known of cosmopolitan large hammerhead sharks. We used a combination of acoustic and satellite telemetry in a juvenile population of Faial and Pico islands, Azores, mid-north Atlantic, to confirm if this isolated archipelago holds nurseries, and to answer questions related to their function and spatial–temporal stability. Our long-term acoustic tracking data showed a cluster of individual core home ranges in specific areas of north shore Faial, and surface positions from five Argos-linked tagged individuals also showed a clustering overlap in those areas for up to 1 year. These patterns seem to reveal a true habitat preference within the Faial-Pico island (sub) population of juvenile smooth hammerhead shark, and thus constitute strong evidence for this area to be considered a nursery. Some individuals remained in this nursery for up to 4 years, especially during summers. Sharks also showed a strong diel behavior, typically using the inshore nurseries during the day and moving further offshore during the night, during which they increased activity and dove deeper, most possibly to feed. We speculate that a combination of increased feeding opportunities, expanded trophic niche, and reduced predatory pressure may be a key evolutionary driver for the existence, prolonged use, and even preference of coastal nurseries at oceanic islands by juvenile smooth hammerhead shark. Given that these nurseries may constitute essential fish habitat for this species, they should be explicitly included in spatial management measures at the local and regional scales, as they may also play a role of greater importance to the north Atlantic population of this oceanic species.
Depicting Developing Trend and Core Knowledge of Primary Open-Angle Glaucoma: A Bibliometric and Visualized Analysis
Authors: Zhao Liting , Li Jinfei , Feng Lemeng , Zhang Cheng , Zhang Wulong , Wang Chao , He Ye , Wen Dan , Song Weitao
Published: July 2022

Objective

The prevalence of glaucoma is rising due to an increasing aging population. Because of its insidious and irreversible nature, glaucoma has gradually become the focus of attention. We assessed primary open angle glaucoma, the most common type of glaucoma, to study its present status, global trend, and state of clinical research.

Methods

Publications from 2000 to 2021 in Web of Science database were retrieved and analyzed by bibliometrics. VOSviewer and Citespace were used for analysis.

Results

A total of 6,401 publications were included in this review, and we found that the number of publications increased from 139 in 2000 to 563 in 2021. American researchers have published the most papers and had the highest h-index and the most citations, while the Journal of Glaucoma has published the most papers on this topic. Some key researchers, contributing institutions, their partnerships, and scientific masterpieces were identified. The publications we reviewed fall into seven categories: publications on intraocular pressure, normal tension glaucoma, risk factors, the trabecular meshwork, optical coherence tomography, surgery, and mutation. Clear study hotspots were described, which began with epidemiology and transitioned to pathogenesis and diagnosis and then to treatment.

Conclusion

Studies on primary open angle glaucoma extend well beyond ophthalmology to biochemistry molecular biology, general internal medicine, pharmacology, pharmacy, science technology, and other areas. Interest, research and publications on primary open angle glaucoma are on the rise.