bluuebunny/crossref_metadata_2025 huggingface dataset:
Antithrombotic Therapy With Ticagrelor in Atrial Fibrillation Subjects After Percutaneous Coronary Intervention
Authors: Lu Wenbin , Wang Yu , Chen Lijuan , Li Yongjun , Zhang Rui , Chen Zhongpu , Yan Jinchuan , Yang Mingming , Han Bing , Wang Zhirong , He Shenghu , Chen Lianglong , Wu Xiang , Zeng Hesong , Ma Likun , Shi Guoping , Yin Jianrong , Chen Jiyan , Ma GenShan
Published: October 2021

Background: Warfarin, along with aspirin and clopidogrel, has long been recommended for patients with atrial fibrillation (AF) who are undergoing percutaneous coronary intervention with a drug-eluting stent (PCI-DES). However, this triple therapy has been known to increase the risk of bleeding complications. Meanwhile, there is no evidence from prospective trials on the use of ticagrelor in a dual therapy. We here aimed to compare the antiplatelet drug ticagrelor as a dual antithrombotic agent to aspirin and clopidogrel in bleeding events.

Methods: In this multicenter, active-controlled, open-label, randomized trial, patients with AF taking warfarin who had undergone PCI-DES were randomly assigned to the ticagrelor therapy group (Dual group) or the clopidogrel plus aspirin therapy group (Triple group). The primary and secondary endpoints were overall bleeding events and major bleeding events, respectively, according to the Thrombolysis in Myocardial Infarction (TIMI) criteria at 6 months. Cardiovascular events [re-PCI, surgical bypass, myocardial infarction (MI), heart failure, rehospitalization due to angina pectoris, stent thrombosis and death due to cardiovascular causes] at 6 months were also recorded.

Results: A total of 296 patients from 12 medical centers in China were randomized after PCI-DES to either the Dual therapy group (n = 148) or the Triple group (n = 146) for 6 months. The overall incidence of bleeding events at 6 months was 36.49% in the Dual therapy group and 35.62% in the Triple group [hazard ratio, 0.930; 95% confidence interval (CI), 0.635 to 1.361; P = 0.7088]. The incidence of the secondary endpoint over 6 months was 4.73% in the Dual therapy group and 1.37% in the Triple group (hazard ratio, 0.273; 95% CI, 0.057 to 1.315; P = 0.1056). Cardiovascular event occurrence was also comparable in both groups at 6 months (18.24 vs. 16.44%; hazard ratio, 0.845; 95% CI, 0.488 to 1.465; P = 0.5484).

Conclusions: The incidence of total bleeding events in AF patients treated with ticagrelor was comparable to that in patients treated with clopidogrel plus aspirin at 6 month; Meanwhile, the incidence of cardiovascular events were also comparable between the groups.

Clinical Trial Registration: MANJUSRI, ClinicalTrials.gov# NCT02206815, 2014, August 1st
Defects and Safety of NiTi Root Canal Instruments: A Systematic Review and Meta-Analysis
Authors: Yon Madeline Jun-yu , Tang Mark Ho-yeung , Cheung Gary Shun-pan
Published: October 2021

Aim: To review the reported defect and fracture rates of various NiTi instrumentation systems and identify factors that may influence the chance of NiTi file separation clinically.

Data Sources: PubMed, EMBASE, and SCOPUS with controlled vocabulary and keywords in various combinations to identify articles that reported on the defects and/or fracture of NiTi instrument used clinically (Jan 1980 till Aug 2021), with additional search manually by going through the list of references of the initially screened articles. Those satisfying the inclusion and exclusion criteria were entered into the analysis.

Study Eligibility Criteria, Participants, and Interventions: All studies from the said databases reporting on NiTi root canal instruments that were deformed or separated during normal clinical use.

Study Appraisal and Synthesis Methods: Studies with data available and suitable for meta-analysis were grouped according to the general design of the NiTi instruments for comparison. Safety quotient value was calculated based on the rate of instrument distortion and fracture.

Results: Various instrument designs exhibited different incidences of distortion and fracture, hence a different “safety quotient” (ratio of the amount of deformed instruments to that of fractures in use). Heat-treated files showed the highest safety quotient value. All brands of NiTi file demonstrated a statistically significantly lower incidence of fracture, if treated as disposable instruments after clinical use in a patient.

Limitations: Inclusion of articles written in English only, and grouping of file systems into general design types in the analysis.

Conclusions and Implications of Key Findings: NiTi endodontic files should be scrutinized for defects before being used in the root canal. Disposing the NiTi instruments after clinical use in a patient (so-called “single use”) is recommended for minimizing fracture clinically. Certain instrument designs tend to show discernible deformation before they should fracture in the next use.
Artificial Ground Freezing Impact on Shear Strength and Microstructure of Granite Residual Soil Under an Extremely Low Temperature
Authors: An Ran , Zhang Xianwei , Kong Lingwei , Gong Jianwu , Lei Xuewen
Published: October 2021

The Artificial Ground Freezing (AGF) method, which is widely used in tunnel excavations, significantly affects the properties of geotechnical materials in frozen walls under extremely low temperatures. In order to simulate the AGF process, the freezing treatment with a temperature of −30°C and thawing treatment temperature of 25°C were performed on natural specimens of granite residual soil (GRS). Subsequently, triaxial (TRX) tests were conducted to evaluate mechanical properties and Nuclear Magnetic Resonance Image (NMRI) tests were applied to detect pore distributions of GRS. To clarify variations of microstructure after freezing-thawing, the relaxation time (T2) distribution curves and T2-weighted images from NMRI results were thoroughly analyzed from the perspective of quantization and visualization. Results show that the shear strength as well as the cohesion of GRS are reduced sharply by the AGF process, while the internal friction angle decreases gently. The pore size distribution (PSD) converted from the T2 curve is constituted of two different peaks, corresponding to micro-pores with diameters from 0.1 to 10 µm and macro-pores with diameters from 10 to 1,000 µm. Under the AGF impact, the expansion in macro-pores and shrinkage in micro-pores simultaneously exist in the specimen, which was verified from a visualized perspective by T2-weighted images. The frost heaving damage on shear strength is attributed to the microstructural disturbance caused by the presence of large-scale pores and uneven deformations in GRS, which is subjected to the AGF impact under an extremely low temperature.
Influence of Response-Option Combinations when Measuring Sense of Efficacy for Teaching: Trivial, or Substantial and Substantive?
Authors: Trevethan Robert , Ma Kang
Published: October 2021

Certain combinations of number and labeling of response options on Likert scales might, because of their interaction, influence psychometric outcomes. In order to explore this possibility with an experimental design, two versions of a scale for assessing sense of efficacy for teaching (SET) were administered to preservice teachers. One version had seven response options with labels at odd-numbered points; the other had nine response options with labels only at the extremes. Before outliers in the data were adjusted, the first version produced a range of more desirable psychometric outcomes but poorer test–retest reliability. After outliers were addressed, the second version had more undesirable attributes than before, and its previously high test–retest reliability dropped to poor. These results are discussed in relation to the design of scales for assessing SET and other constructs as well as in relation to the need for researchers to examine their data carefully, consider the need to address outlying data, and conduct analyses appropriately and transparently.
Social, Personal, and Innovative Competencies Effect of Service-Learning in Physical Education Teacher Education: A Mixed-Methods Analysis
Authors: Capella-Peris Carlos , Martí-Puig Manuel , Salvador-García Celina , Maravé-Vivas María
Published: October 2021

The purpose of this study was to compare the development of social entrepreneurship competency in physical education teacher education students (n = 89), through two modalities of intervention from the same service-learning program. The student teachers provided a direct service to children with motor functional diversity, promoting their motor skills and counteracting their lack of social attention. The study was conducted using mixed methods with methodological triangulation. Quantitative evidence was gathered through a quasi-experimental design of two non-equivalent experimental groups implementing the Social Entrepreneurship Competency Scale. Qualitative analysis was undertaken by elaborating 12 life histories of multiple crossed stories. Quantitative results provide significant evidence about the social entrepreneurship competency effect of service-learning on physical education teacher education students while qualitative interpretation complements this view, reflecting how this competency was developed. We provide original findings on promotion of personal, social, and innovative social entrepreneurship competency features as well as the promotion of moral and civic values.
Effects of Prior Knowledge on Comprehending Text About Learning Strategies
Authors: Kikas Eve , Silinskas Gintautas , Mädamürk Kaja , Soodla Piret
Published: October 2021

Good knowledge and skills in using different learning strategies is important for learning with understanding and even more critical during distance learning. Findings indicate that students tend to use and value ineffective learning strategies, thus there is need to educate students. This study aimed to analyze the possibility of using refutation text on learning strategies that students can study independently. The study examined how reported use of learning strategies and preexisting beliefs about the effectiveness of rehearsal and comprehension-oriented strategies relate to the comprehension of text about learning strategies, and how text comprehension is related to later use of strategies and the completion of learning tasks. Participants included 2,706 students from primary school (Grades 3 and 4) and 3,782 students from the end of middle school (Grade 9) across Estonia. Students’ learning strategies and learning outcomes were assessed via a web-based word list memorization task with follow-up questions. Students were asked to read a written text that was specifically developed to explain the advantages of abstract grouping. Text comprehension was assessed using multiple-choice questions. SEM models were used to answer the research questions. At both school levels, valuing comprehension-oriented learning strategies enhanced text comprehension, suggesting that prior beliefs are important to fully understand written text. In addition, student beliefs and text comprehension also increased use of more advanced strategies. However, students who used comprehension-oriented strategies showed ambiguous improvements in word memorization performance. These findings emphasize that reading about complex topics may be a starting point for learning, but should be followed up with additional discussions, examples, demonstrations, and practice.
Developmental and Reproductive Outcomes in Male Rats Exposed to Triclosan: Two-Generation Study
Authors: Montagnini Bruno Garcia , Forcato Simone , Pernoncine Karine Vandressa , Monteiro Mariana Cunha , Pereira Marina Rangel Ferro , Costa Nathalia Orlandini , Moreira Estefânia Gastadello , Anselmo-Franci Janete Aparecida , Gerardin Daniela Cristina Ceccatto
Published: October 2021

Triclosan (TCS) is a phenolic compound with broad-spectrum antimicrobial action that has been incorporated into a variety of personal care products and other industry segments such as toys, textiles, and plastics. Due to its widespread use, TCS and its derivatives have been detected in several environmental compartments, with potential bioaccumulation and persistence. Indeed, some studies have demonstrated that TCS may act as a potential endocrine disruptor for the reproductive system. In the current study, we are reporting on the results obtained for male rats after a two-generation reproduction toxicity study conducted with TCS. Female and male Wistar rats were treated daily by gavage with TCS at doses of 0.8, 2.4, and 8.0 mg/kg/day or corn oil (control group) over 10 weeks (F0) and over 14 weeks (F1) before mating and then throughout mating, until weaning F2 generations, respectively. TCS exposure decreased sperm viability and motility of F1 rats at the dose of 2.4 mg/kg. The effects of TCS on sperm quality may be related to the exposure window, which includes the programming of reproductive cells that occurs during fetal/neonatal development.
The Association Between Triglyceride-Glucose Index as a Marker of Insulin Resistance and the Risk of Breast Cancer
Authors: Panigoro Sonar Soni , Sutandyo Noorwati , Witjaksono Fiastuti , Siregar Nurjati Chairani , Ramli Ramadhan , Hariani Ririn , Pangarsa Eko Adhi , Prajoko Yan Wisnu , Puruhita Niken , Hamdani William , Bayu Dimas , Madjid Mardiana , Yulidar Dedy , Fransiska Jane Estherina , Widyawati Retno , Tripriadi Effif Syofra , F. W. Wiwit Ade , Yunda Dewi Krisna , Pranata Raymond
Published: October 2021

Background

This study aims to evaluate the association and dose-response between triglyceride-glucose (TyG) index and breast cancer.

Method

This is a multicenter case-control study conducted in six public referral hospitals in Indonesia. Cases are individuals aged 19 years or above who were diagnosed with breast cancer within 1 year of diagnosis, based on histopathology and immunohistochemistry. Controls were recruited from corresponding hospitals. TyG index was determined by the formula: ln (fasting TG [mg/dl] × fasting glucose [mg/dl]).

Results

There were 212 participants in the breast cancer group and 212 participants in the control group. TyG index was higher in patients with breast cancer (median 8.65 [7.38, 10.9] vs. 8.30 [7.09, 10.84], p < 0.001). When compared with TyG quartile of Q1, Q4 was associated with an OR of 2.42 (1.77, 3.31), p < 0.001, Q3 was associated with an OR of 1.53 (1.21, 1.93), p < 0.001, Q2 was associated with an OR of 1.39 (1.12, 1.73), p = 0.002 for the risk of breast cancer. The dose-response relationship was nonlinear (p < 0.001). On univariate analysis, smoking (OR 2.15 [1.44, 3.22], p < 0.001), use of contraception (1.73 [1.15, 2.60], p = 0.008), alcohol consumption (OR 2.04 [0.96, 4.35], p = 0.064), and TyG Index >8.87 (OR 3.08 [1.93, 4.93], p < 0.001) were associated with risk of breast cancer. Independently associated with increased risk of breast cancer included smoking (OR 1.93 [1.23, 3.01], p = 0.004), use of contraception (OR 1.59 [1.02, 2.48], p = 0.039), and TyG Index >8.87 (OR 2.93 [1.72, 4.98], p < 0.001)

Conclusion

TyG index was associated with breast cancer in a nonlinear dose-response fashion.
Case Report: Lipoma of the Tuber Cinereum Mimicking a Pituitary Gland Abnormality in a Girl With Central Precocious Puberty
Authors: Giacomozzi Claudio , Nicolì Lisa , Sozzi Carlo , Piovan Enrico , Maghnie Mohamad
Published: October 2021

Introduction

Magnetic Resonance Imaging (MRI) is the best approach to investigate the hypothalamic-pituitary region in children with central precocious puberty (CPP). Routine scanning is controversial in girls aged 6-8 year, due to the overwhelming prevalence of idiopathic forms and unrelated incidentalomas. Cerebral lipomas are rare and accidental findings, not usually expected in CPP. We report a girl with CPP and an unusually shaped posterior pituitary gland on SE-T1w sequences.

Case Description

A 7.3-year-old female was referred for breast development started at age 7. Her past medical history and physical examination were unremarkable, apart from the Tanner stage 2 breast. X-ray of the left-hand revealed a bone age 2-years ahead of her chronological age, projecting her adult height prognosis below the mid parental height. LHRH test and pelvic ultrasound were suggestive for CPP. Routine brain MRI sequences, SE T1w and TSE T2w, showed the posterior pituitary bright spot increased in size and stretched upward. The finding was considered as an anatomical variant, in an otherwise normal brain imaging. Patient was started on treatment with GnRH analogue. At a thorough revaluation, imaging overlap with adipose tissue was suspected and a new MRI scan with 3D-fat-suppression T1w-VIBE sequences demonstrated a lipoma of the tuber cinereum, bordering a perfectly normal neurohypophysis. 3D-T2w-SPACE sequences, acquired at first MRI scan, would have provided a more correct interpretation if rightly considered.

Conclusion

This is the first evidence, to our knowledge, of a cerebral lipoma mimicking pituitary gland abnormalities. Our experience highlights the importance of considering suprasellar lipomas in the MRI investigation of children with CPP, despite their rarity, should the T1w sequences show an unexpected pituitary shape. 3D-T2w SPACE sequences could be integrated into standard ones, especially when performing MRI routinely, to avoid potential misinterpretations.
Investigation of Optimal PV Allocation to Minimize System Losses and Improve Voltage Stability for Distribution and Transmission Networks Using MATLAB and DigSilent
Authors: Rasheed Mohamed Abdul , Verayiah Renuga
Published: October 2021

Electricity generation from renewable energy sources such as solar energy is an emerging sustainable solution. In the last decade, this sustainable source was not only being used as a source of power generation but also as distributed generation (DG). Many literatures have been published in this field with the objective to minimize losses by optimizing the DG size and location. System losses and voltage profile go hand-in-hand; as a result, when system losses are minimized, eventually the voltage profile improves. With improvement in inverter technologies, PV-DG units do not have to operate at a unity power factor. The majority of proposed algorithms and methods do not consider power factor optimization as a necessary optimization. This article aims to optimize the size, location, and power factor of PV-DG units. The simulations are performed on the IEEE 33 bus radial distribution network and IEEE 14 bus transmission network. The methodologies developed in this article are divided into two sections. The first section aims to optimize the PV-DG size and location. A multi-objective function is developed by using system losses and a voltage deviation index. Genetic algorithm (GA) is used to optimize the multi-objective function. Next, analytical processes are developed for verification. The second section aims to further enhance PV-DG by optimizing the power factor of PV-DG. The simulation is performed for static load in both systems, which are the IEEE 33 bus radial distribution network and IEEE 14 bus transmission network. A mathematical analytical method was developed, and it was found to be sufficient to optimize the power factor of the PV-DG unit. The results obtained show that voltage stability indices help minimize the computation time by determining the optimal locations for DG placement in both networks. In addition, the GA method attained faster convergence than the analytical method and hence is the best optimal sizing for both test systems with minimum computation time. Additionally, the optimization of the power factor for both test systems has demonstrated further improvement in the voltage profile and loss minimization. In conclusion, the proposed methodology has shown promising results for both transmission and distribution networks.
Co-Combustion Characteristics of Typical Biomass and Coal Blends by Thermogravimetric Analysis
Authors: Yuan Ye , He Yong , Tan Jiaxin , Wang Yongmeng , Kumar Sunel , Wang Zhihua
Published: October 2021

In this study, the co-combustion characteristics of coal and biomass blends (20, 40, 60, 80, and 100 wt%) were investigated by thermogravimetric analysis. All the samples were operated under an oxidative atmosphere, with a heating rate of 20 C/min. The reaction stages, ignition and burnout temperature, maximum weight loss rate, and different combustion indices were determined. When the percentage of biomass in the blends was increased, the maximum mass loss rate was enhanced in the second region, and the ignition and burnout temperature was lowered, indicating the higher reactivity and better combustion performance of the samples. The comprehensive performance index presented an N shape with the increasing biomass blending ratio. Based on various combustion indices, 20% was an optimum percentage for the co-utilization of coal-biomass blends. A significant promoting interaction was observed between corn straw and rice straw blends, while inhibiting effects occurred between rice husk and coal. The kinetic parameters of the blends were evaluated by the Coats and Redfern method using the nth-order reaction model. The value of activation energy and the pre-exponential factor increased with the decreasing biomass percentage in the blends.
Genome-Wide Detection of Genetic Loci and Candidate Genes for Body Conformation Traits in Duroc × Landrace × Yorkshire Crossbred Pigs
Authors: Zhang Hui , Zhuang Zhanwei , Yang Ming , Ding Rongrong , Quan Jianping , Zhou Shenping , Gu Ting , Xu Zheng , Zheng Enqin , Cai Gengyuan , Yang Jie , Wu Zhenfang
Published: October 2021

The Duroc × (Landrace × Yorkshire) hybrid pigs (DLY) are the most popular commercial pigs, providing consumers with the largest source of pork. In order to gain more insights into the genetic architecture of economically important traits in pigs, we performed a genome-wide association study (GWAS) using the GeneSeek Porcine 50 K SNP Chip to map the genetic markers and genes associated with body conformation traits (BCT) in 311 DLY pigs. The quantitative traits analyzed included body weight (BW), carcass length (CL), body length (BL), body height (BH), and body mass index (BMI). BMI was defined as BMICL, BMIBL, and BMIBH, respectively, based on CL, BL, and BH phenotypic data. We identified 82 SNPs for the seven traits by GEMMA-based and FarmCPU-based GWASs. Both methods detected two quantitative trait loci (QTL) on SSC8 and SSC17 for body conformation traits. Several candidate genes (such as TNFAIP3, KDM4C, HSPG2, BMP2, PLCB4, and GRM5) were found to be associated with body weight and body conformation traits in pigs. Notably, the BMP2 gene had pleiotropic effects on CL, BL, BH, BMICL, and BMIBL and is proposed as a strong candidate gene for body size due to its involvement in growth and bone development. Furthermore, gene set enrichment analysis indicated that most of the pathway terms are associated with regulation of cell growth, negative regulation of cell population proliferation, and chondrocyte differentiation. We anticipate that these results further advance our understanding of the genetic architecture of body conformation traits in the popular commercial DLY pigs and provide new insights into the genetic architecture of BMI in pigs.
Single-Trait and Multiple-Trait Genomic Prediction From Multi-Class Bayesian Alphabet Models Using Biological Information
Authors: Wang Zigui , Cheng Hao
Published: October 2021

Genomic prediction has been widely used in multiple areas and various genomic prediction methods have been developed. The majority of these methods, however, focus on statistical properties and ignore the abundant useful biological information like genome annotation or previously discovered causal variants. Therefore, to improve prediction performance, several methods have been developed to incorporate biological information into genomic prediction, mostly in single-trait analysis. A commonly used method to incorporate biological information is allocating molecular markers into different classes based on the biological information and assigning separate priors to molecular markers in different classes. It has been shown that such methods can achieve higher prediction accuracy than conventional methods in some circumstances. However, these methods mainly focus on single-trait analysis, and available priors of these methods are limited. Thus, in both single-trait and multiple-trait analysis, we propose the multi-class Bayesian Alphabet methods, in which multiple Bayesian Alphabet priors, including RR-BLUP, BayesA, BayesB, BayesCΠ, and Bayesian LASSO, can be used for markers allocated to different classes. The superior performance of the multi-class Bayesian Alphabet in genomic prediction is demonstrated using both real and simulated data. The software tool JWAS offers open-source routines to perform these analyses.
SS-RNN: A Strengthened Skip Algorithm for Data Classification Based on Recurrent Neural Networks
Authors: Cao Wenjie , Shi Ya-Zhou , Qiu Huahai , Zhang Bengong
Published: October 2021

Recurrent neural networks are widely used in time series prediction and classification. However, they have problems such as insufficient memory ability and difficulty in gradient back propagation. To solve these problems, this paper proposes a new algorithm called SS-RNN, which directly uses multiple historical information to predict the current time information. It can enhance the long-term memory ability. At the same time, for the time direction, it can improve the correlation of states at different moments. To include the historical information, we design two different processing methods for the SS-RNN in continuous and discontinuous ways, respectively. For each method, there are two ways for historical information addition: 1) direct addition and 2) adding weight weighting and function mapping to activation function. It provides six pathways so as to fully and deeply explore the effect and influence of historical information on the RNNs. By comparing the average accuracy of real datasets with long short-term memory, Bi-LSTM, gated recurrent units, and MCNN and calculating the main indexes (Accuracy, Precision, Recall, and F1-score), it can be observed that our method can improve the average accuracy and optimize the structure of the recurrent neural network and effectively solve the problems of exploding and vanishing gradients.
Deciphering the Pyroptosis-Related Prognostic Signature and Immune Cell Infiltration Characteristics of Colon Cancer
Authors: Wei Ran , Li Shuofeng , Yu Guanhua , Guan Xu , Liu Hengchang , Quan Jichuan , Jiang Zheng , Wang Xishan
Published: October 2021

Background: Colon cancer (CC) remains one of the most common malignancies with a poor prognosis. Pyroptosis, referred to as cellular inflammatory necrosis, is thought to influence tumor development. However, the potential effects of pyroptosis-related regulators (PRRs) on the CC immune microenvironment remain unknown.

Methods: In this study, 27 PRRs reported in the previous study were used to cluster the 1,334 CC samples into three pyroptosis-related molecular patterns. Through subtype pattern differential analysis and structure network mining using Weighted Gene Co-expression Network Analysis (WGCNA), 854 signature genes associated with the PRRs were discovered. Further LASSO-penalized Cox regression of these genes established an eight-gene assessment model for predicting prognosis.

Results: The CC patients were subtyped based on three distinct pyroptosis-related molecular patterns. These pyroptosis-related patterns were correlated with different clinical outcomes and immune cell infiltration characteristics in the tumor microenvironment. The pyroptosis-related eight-signature model was established and used to assess the prognosis of CC patients with medium-to-high accuracy by employing the risk scores, which was named “PRM-scores.” Greater inflammatory cell infiltration was observed in tumors with low PRM-scores, indicating a potential benefit of immunotherapy in these patients.

Conclusions: This study suggests that PRRs have a significant effect on the tumor immune microenvironment and tumor development. Evaluating the pyroptosis-related patterns and related models will promote our understanding of immune cell infiltration characteristics in the tumor microenvironment and provide a theoretical basis for future research targeting pyroptosis in cancer.
Super Enhancer Profiles Identify Key Cell Identity Genes During Differentiation From Embryonic Stem Cells to Trophoblast Stem Cells Super Enhencers in Trophoblast Differentiation
Authors: Jia Rongpu , Gao Yu , Guo Song , Li Si , Zhou Liangji , Gou Chenyu , Huang Yijuan , Fan Meiqiong , Chen Yuanqiu
Published: October 2021

Trophoblast stem cells (TSCs) are derived from blastocysts and the extra-embryonic ectoderm (ExE) of post-implantation embryos and play a significant role in fetal development, but the roles that TSCs play in the earlier status of fetal diseases need further exploration. Super enhancers (SEs) are dense clusters of stitched enhancers that control cell identity determination and disease development and may participate in TSC differentiation. We identified key cell identity genes regulated by TSC-SEs via integrated analysis of H3K27ac and H3K4me1 chromatin immunoprecipitation sequencing (ChIP-seq), RNA-sequencing (RNA-seq) and ATAC-sequencing (ATAC-seq) data. The identified key TSC identity genes regulated by SEs, such as epidermal growth factor receptor (EGFR), integrin β5 (ITGB5) and Paxillin (Pxn), were significantly upregulated during TSC differentiation, and the transcription network mediated by TSC-SEs enriched in terms like focal adhesion and actin cytoskeleton regulation related to differentiation of TSCs. Additionally, the increased chromatin accessibility of the key cell identity genes verified by ATAC-seq further demonstrated the regulatory effect of TSC-SEs on TSC lineage commitment. Our results illustrated the significant roles of the TSC-SE-regulated network in TSC differentiation, and identified key TSC identity genes EGFR, ITGB5 and Pxn, providing novel insight into TSC differentiation and lays the foundation for future studies on embryo implantation and related diseases.
Targeting DNA Repair Response Promotes Immunotherapy in Ovarian Cancer: Rationale and Clinical Application
Authors: Xie Hongyu , Wang Wenjie , Qi Wencai , Jin Weilin , Xia Bairong
Published: October 2021

Immune checkpoint inhibitors (ICI) have emerged as a powerful oncologic treatment modality for patients with different solid tumors. Unfortunately, the efficacy of ICI monotherapy in ovarian cancer is limited, and combination therapy provides a new opportunity for immunotherapy in ovarian cancer. DNA damage repair (DDR) pathways play central roles in the maintenance of genomic integrity and promote the progression of cancer. A deficiency in DDR genes can cause different degrees of DNA damage that enhance local antigen release, resulting in systemic antitumor immune responses. Thus, the combination of DDR inhibitors with ICI represents an attractive therapeutic strategy with the potential to improve the clinical outcomes of patients with ovarian cancer. In this review, we provide an overview of the interconnectivity between DDR pathway deficiency and immune response, summarize available clinical trials on the combination therapy in ovarian cancer, and discuss the potential predictive biomarkers that can be utilized to guide the use of combination therapy.
Fecal Microbiota Transplantation Modulates Renal Phenotype in the Humanized Mouse Model of IgA Nephropathy
Authors: Lauriero Gabriella , Abbad Lilia , Vacca Mirco , Celano Giuseppe , Chemouny Jonathan M. , Calasso Maria , Berthelot Laureline , Gesualdo Loreto , De Angelis Maria , Monteiro Renato C.
Published: October 2021

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis. Several observations suggest that gut microbiota could be implicated in IgAN pathophysiology. Aiming at exploring whether microbiota modulation is able to influence disease outcome, we performed fecal microbiota transplantation (FMT) from healthy controls (HC-sbjs), non-progressor (NP-pts) and progressor (P-pts) IgAN patients to antibiotic-treated humanized IgAN mice (α1KI-CD89Tg), by oral gavage. FMT was able to modulate renal phenotype and inflammation. On one hand, the microbiota from P-pts was able to induce an increase of serum BAFF and galactose deficient-IgA1 levels and a decrease of CD89 cell surface expression on blood CD11b+ cells which was associated with soluble CD89 and IgA1 mesangial deposits. On the other hand, the microbiota from HC-sbjs was able to induce a reduction of albuminuria immediately after gavage, an increased cell surface expression of CD89 on blood CD11b+ cells and a decreased expression of KC chemokine in kidney. Higher serum BAFF levels were found in mice subjected to FMT from IgAN patients. The main bacterial phyla composition and volatile organic compounds profile significantly differed in mouse gut microbiota. Microbiota modulation by FMT influences IgAN phenotype opening new avenues for therapeutic approaches in IgAN.
Alternative Complement Pathway Inhibition Abrogates Pneumococcal Opsonophagocytosis in Vaccine-Naïve, but Not in Vaccinated Individuals
Authors: Muri Lukas , Ispasanie Emma , Schubart Anna , Thorburn Christine , Zamurovic Natasa , Holbro Thomas , Kammüller Michael , Pluschke Gerd
Published: October 2021

To assess the relative contribution of opsonisation by antibodies, classical and alternative complement pathways to pneumococcal phagocytosis, we analyzed killing of pneumococci by human blood leukocytes collected from vaccine-naïve and PCV13-vaccinated subjects. With serotype 4 pneumococci as model, two different physiologic opsonophagocytosis assays based on either hirudin-anticoagulated whole blood or on washed cells from EDTA-anticoagulated blood reconstituted with active serum, were compared. Pneumococcal killing was measured in the presence of inhibitors targeting the complement components C3, C5, MASP-2, factor B or factor D. The two assay formats yielded highly consistent and comparable results. They highlighted the importance of alternative complement pathway activation for efficient opsonophagocytic killing in blood of vaccine-naïve subjects. In contrast, alternative complement pathway inhibition did not affect pneumococcal killing in PCV13-vaccinated individuals. Independent of amplification by the alternative pathway, even low capsule-specific antibody concentrations were sufficient to efficiently trigger classical pathway mediated opsonophagocytosis. In heat-inactivated or C3-inhibited serum, high concentrations of capsule-specific antibodies were required to trigger complement-independent opsonophagocytosis. Our findings suggest that treatment with alternative complement pathway inhibitors will increase susceptibility for invasive pneumococcal infection in non-immune subjects, but it will not impede pneumococcal clearance in vaccinated individuals.
Intranasal Vaccination With Recombinant Antigen-FLIPr Fusion Protein Alone Induces Long-Lasting Systemic Antibody Responses and Broad T Cell Responses
Authors: Hsieh Ming-Shu , Hsu Chia-Wei , Tu Ling-Ling , Chai Kit Man , Yu Li-Lu , Wu Chiao-Chieh , Chen Mei-Yu , Chiang Chen-Yi , Liu Shih-Jen , Liao Ching-Len , Chen Hsin-Wei
Published: October 2021

A simple formulation is urgently needed for mucosal vaccine development. We employed formyl peptide receptor-like 1 inhibitory protein (FLIPr), an FcγR antagonist secreted by Staphylococcus aureus, as a vector to target ovalbumin (OVA) to dendritic cells (DCs) via intranasal administration. Our results demonstrate that intranasal administration of recombinant OVA-FLIPr fusion protein (rOVA-FLIPr) alone efficiently delivers OVA to DCs in nasal lymphoid tissue. Subsequently, OVA-specific IgG and IgA antibodies in the circulatory system and IgA antibodies in mucosal tissue were detected. Importantly, activation of OVA-specific CD4+ and CD8+ T cells and induction of a broad-spectrum cytokine secretion profile were detected after intranasal administration of rOVA-FLIPr alone in immunocompetent C57BL/6 mice. Furthermore, we employed immunodeficient AG129 mice as a Zika virus infection model and demonstrated that intranasal administration of recombinant Zika virus envelope protein domain III-FLIPr fusion protein induced protective immune responses against the Zika virus. These results suggest that antigen-FLIPr fusion protein alone via intranasal administration can be applied to mucosal vaccine development.
Calcium/Calmodulin Dependent Protein Kinase Kinase 2 Regulates the Expansion of Tumor-Induced Myeloid-Derived Suppressor Cells
Authors: Huang Wei , Liu Yaping , Luz Anthony , Berrong Mark , Meyer Joel N. , Zou Yujing , Swann Excel , Sundaramoorthy Pasupathi , Kang Yubin , Jauhari Shekeab , Lento William , Chao Nelson , Racioppi Luigi
Published: October 2021

Myeloid-derived suppressor cells (MDSCs) are a hetero geneous group of cells, which can suppress the immune response, promote tumor progression and impair the efficacy of immunotherapies. Consequently, the pharmacological targeting of MDSC is emerging as a new immunotherapeutic strategy to stimulate the natural anti-tumor immune response and potentiate the efficacy of immunotherapies. Herein, we leveraged genetically modified models and a small molecule inhibitor to validate Calcium-Calmodulin Kinase Kinase 2 (CaMKK2) as a druggable target to control MDSC accumulation in tumor-bearing mice. The results indicated that deletion of CaMKK2 in the host attenuated the growth of engrafted tumor cells, and this phenomenon was associated with increased antitumor T cell response and decreased accumulation of MDSC. The adoptive transfer of MDSC was sufficient to restore the ability of the tumor to grow in Camkk2-/- mice, confirming the key role of MDSC in the mechanism of tumor rejection. In vitro studies indicated that blocking of CaMKK2 is sufficient to impair the yield of MDSC. Surprisingly, MDSC generated from Camkk2-/- bone marrow cells also showed a higher ability to terminally differentiate toward more immunogenic cell types (e.g inflammatory macrophages and dendritic cells) compared to wild type (WT). Higher intracellular levels of reactive oxygen species (ROS) accumulated in Camkk2-/- MDSC, increasing their susceptibility to apoptosis and promoting their terminal differentiation toward more mature myeloid cells. Mechanistic studies indicated that AMP-activated protein kinase (AMPK), which is a known CaMKK2 proximal target controlling the oxidative stress response, fine-tunes ROS accumulation in MDSC. Accordingly, failure to activate the CaMKK2-AMPK axis can account for the elevated ROS levels in Camkk2-/- MDSC. These results highlight CaMKK2 as an important regulator of the MDSC lifecycle, identifying this kinase as a new druggable target to restrain MDSC expansion and enhance the efficacy of anti-tumor immunotherapy.
Importance of Protection Service Against Erosion and Storm Events Provided by Coastal Ecosystems Under Climate Change Scenarios
Authors: Cunha Jacinto , Cardona Fábio Santos , Bio Ana , Ramos Sandra
Published: October 2021

Increasing sea level rise (SLR), and frequency and intensity of storms, paired with degrading ecosystems, are exposing coastal areas to higher risks of damage by storm events. Coastal natural habitats, such as dunes or saltmarshes, can reduce exposure of coastlines to these events and help to reduce the impacts and the potential damage to coastal property. The goal of our study was to evaluate the current vulnerability of the Portuguese northern coast to erosion and flooding caused by extreme events and to assess the contribution of natural habitats in reducing both vulnerability and property damages considering SLR scenarios. The Integrated Valuation of Environmental Services and Trade-offs (InVEST) Coastal Vulnerability model was used to produce an Exposure Index (EI) for the northern Portuguese coastline, for the current situation, and for future International Panel for Climate Change (IPCC) scenarios Representative Concentration Pathway (RCP) 2.6, RCP4.5, and RCP8.5, considering the presence and absence of coastal habitats. Results showed an increase in exposure with rising sea levels and expansion of high vulnerability areas. Coastal habitats contributed to a 28% reduction of high exposed segments for the Current scenario, corresponding to a potential reduction of coastal property damage of 105 M€ during extreme events. For the SLR scenarios, coastal habitats could potentially reduce the amount of property damage by 190 M€ in 2050 and 285 M€ in 2100, considering RCP8.5 projections. This study highlighted the importance of natural habitats in protecting vulnerable coastlines and reducing the potential damages to properties from flooding. Such results can be incorporated in management plans and support decision-making toward implementing an ecosystem-based approach to increase the resilience of coastal communities to cope with future environmental changes.
Separating Paternal and Maternal Contributions to Thermal Transgenerational Plasticity
Authors: Chang Sarah L. , Lee Who-Seung , Munch Stephan B.
Published: October 2021

Climate change is rapidly altering the thermal environment in terrestrial and aquatic systems. Transgenerational thermal plasticity (TGP) – which occurs when the temperatures experienced by the parental generation prior to the fertilization of gametes results in a change in offspring reaction norms – may mitigate the effects of climate change. Although “maternal effects” have been widely studied, relatively little is known about TGP effects in vertebrates, particularly paternal contributions. We used artificial fertilization to cross sheepshead minnow (Cyprinodon variegatus) parents exposed to either low (26°C) or high (32°C) temperatures and measured growth rates of the offspring over the first 8 weeks of life at both low and high temperatures. A linear mixed effects model was employed to quantify the effects of maternal, paternal, and offspring temperatures on offspring growth and fecundity. We found that the offspring growth rate up to 63 days post-hatch was affected by both the temperature they experienced directly and parental temperatures prior to fertilization. Growth was lowest when neither parents’ temperature matched the offspring temperature, indicating a strong transgenerational effect. Notably, offspring growth was highest when all three (offspring, sire, and dam) temperatures matched [although the three-way interaction was found to be marginally non-significant (P = 0.155)], suggesting that TGP effects were additive across significant sire-offspring (P < 0.001) and dam-offspring interactions (P < 0.001). Transgenerational effects on fecundity (GSI) were suggestive for both maternal and paternal effects, but not significant. The finding that thermal TGP is contributed by both parents strongly suggests that it has an epigenetic basis.
Comparative Genomics and Transcriptomics Depict Marine Algicolous Arthrinium Species as Endosymbionts That Help Regulate Oxidative Stress in Brown Algae
Authors: Heo Young Mok , Oh Seung-Yoon , Kim Kyeongwon , Han Sang-Il , Kwon Sun Lul , Yoo Yeonjae , Kim Dongjun , Khim Jong Seong , Kang Seunghyun , Lee Hanbyul , Kim Jae-Jin
Published: October 2021

The whole genome and transcriptome analyses were performed for prediction of the ecological characteristics of Arthrinium and the genes involved in gentisyl alcohol biosynthesis. Whole genome sequences of A. koreanum KUC21332 and A. saccharicola KUC21221 were analyzed, and the genes involved in interspecies interaction, carbohydrate-active enzymes, and secondary metabolites were investigated. Three of the seven genes associated with interspecies interactions shared by four Arthrinium spp. were involved in pathogenesis. A. koreanum and A. saccharicola exhibit the enzyme profiles similar to those observed in plant pathogens and endophytes rather than saprobes. Furthermore, six of the seven metabolites of known clusters identified in the genomes of the four Arthrinium spp. are associated with plant virulence. These results indicate that Arthrinium spp. are potentially pathogenic to plants. Subsequently, different conditions for gentisyl alcohol production in A. koreanum were established, and mRNA extracted from cultures of each condition was subjected to RNA-Seq to analyze the differentially-expressed genes. The gentisyl alcohol biosynthetic pathway and related biosynthetic gene clusters were identified, and gentisyl alcohol biosynthesis was significantly downregulated in the mannitol-supplemented group where remarkably low antioxidant activity was observed. These results indicate that gentisyl alcohol production in algicolous Arthrinium spp. is influenced by mannitol. It was suggested that the algicolous Arthrinium spp. form a symbiotic relationship that provides antioxidants when the photosynthetic activity of brown algae decreases in exchange for receiving mannitol. This is the first study to analyze the lifestyle of marine algicolous Arthrinium spp. at the molecular level and suggests a symbiotic mechanism with brown algae. It also improves the understanding of fungal secondary metabolite production via identification of the gentisyl alcohol biosynthetic gene clusters in Arthrinium spp.
Toward a Global Public Repository of Community Protocols to Encourage Best Practices in Biomolecular Ocean Observing and Research
Authors: Samuel Robyn M. , Meyer Raissa , Buttigieg Pier Luigi , Davies Neil , Jeffery Nicholas W. , Meyer Christopher , Pavloudi Christina , Pitz Kathleen Johnson , Sweetlove Maxime , Theroux Susanna , van de Kamp Jodie , Watts Alison
Published: October 2021

Biomolecular ocean observing and research is a rapidly evolving field that uses omics approaches to describe biodiversity at its foundational level, giving insight into the structure and function of marine ecosystems over time and space. It is an especially effective approach for investigating the marine microbiome. To mature marine microbiome research and operations within a global ocean biomolecular observing network (OBON) for the UN Decade of Ocean Science for Sustainable Development and beyond, research groups will need a system to effectively share, discover, and compare “omic” practices and protocols. While numerous informatic tools and standards exist, there is currently no global, publicly-supported platform specifically designed for sharing marine omics [or any omics] protocols across the entire value-chain from initiating a study to the publication and use of its results. Toward that goal, we propose the development of the Minimum Information for an Omic Protocol (MIOP), a community-developed guide of curated, standardized metadata tags and categories that will orient protocols in the value-chain for the facilitated, structured, and user-driven discovery of suitable protocol suites on the Ocean Best Practices System. Users can annotate their protocols with these tags, or use them as search criteria to find appropriate protocols. Implementing such a curated repository is an essential step toward establishing best practices. Sharing protocols and encouraging comparisons through this repository will be the first steps toward designing a decision tree to guide users to community endorsed best practices.