bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Subgoal Labeling on Online Worked Example Learning in Mathematics for Primary School Students
Authors: Guan Xiao , Du Xuejiao , Lin Hongxin
Published: April 2022

The no-subgoal-worked examples and the subgoal-worked examples are “one problem and two solutions.” Previous studies have found that the effect of subgoal-worked examples learning is better than that of no-subgoal-worked examples. However, there is still ambiguity around the subgoal-worked examples learning effect and mechanism of the subgoal labeling form. To address this issue, the current study recruited a total of 130 Chinese children (Mage = 8.78 years) to mathematical online learning under different worked example forms. The results revealed that, as compared with the no-subgoal-worked example, the subgoal-worked example increased primary school students’ working memory resource depletion. However, it did not improve their scores. Moreover, as compared with the subgoal-worked example, the focused subgoal-labeled worked example did not promote primary school students’ learning effectiveness in mathematics. However, the individual choice subgoal-labeled worked example improved primary school students’ near-transfer scores. It also reduced their mental effort and working memory resource depletion. It, therefore, appears to be a more effective subgoal-labeled worked example learning approach.
Sparse System Identification of Leptin Dynamics in Women With Obesity
Authors: Amin Md. Rafiul , Pednekar Divesh Deepak , Azgomi Hamid Fekri , van Wietmarschen Herman , Aschbacher Kirstin , Faghih Rose T.
Published: April 2022

The prevalence of obesity is increasing around the world at an alarming rate. The interplay of the hormone leptin with the hypothalamus-pituitary-adrenal axis plays an important role in regulating energy balance, thereby contributing to obesity. This study presents a mathematical model, which describes hormonal behavior leading to an energy abnormal equilibrium that contributes to obesity. To this end, we analyze the behavior of two neuroendocrine hormones, leptin and cortisol, in a cohort of women with obesity, with simplified minimal state-space modeling. Using a system theoretic approach, coordinate descent method, and sparse recovery, we deconvolved the serum leptin-cortisol levels. Accordingly, we estimate the secretion patterns, timings, amplitudes, number of underlying pulses, infusion, and clearance rates of hormones in eighteen premenopausal women with obesity. Our results show that minimal state-space model was able to successfully capture the leptin and cortisol sparse dynamics with the multiple correlation coefficients greater than 0.83 and 0.87, respectively. Furthermore, the Granger causality test demonstrated a negative prospective predictive relationship between leptin and cortisol, 14 of 18 women. These results indicate that increases in cortisol are prospectively associated with reductions in leptin and vice versa, suggesting a bidirectional negative inhibitory relationship. As dysregulation of leptin may result in an abnormality in satiety and thereby associated to obesity, the investigation of leptin-cortisol sparse dynamics may offer a better diagnostic methodology to improve better treatments plans for individuals with obesity.
Relationship Between Fuel Reliability and I-131/I-133 in the Primary Coolant of CPR1000 PWRs
Authors: Fu Pengtao , Liang Shan , Lu Shengbo , Zhou Wenzhong , Yang Xiaohuan , Xu Jiehao , Han Song
Published: April 2022

The production and release of fission products in fuel rods and the primary coolant have been simulated by the kinetic model during the normal operation of a pressurized water reactor. The typical ratio of I-131/I-133 in the primary coolant has been theoretically estimated at the equilibrium conditions for intact fuels and fuel failure with small or large defects, respectively. The radiochemical data in the primary loops have been gathered and compiled from thirty-six cycles in the operating CPR1000 PWR units. The statistical results show that the predictions made by the model and the statistical results in the operating CPR1000 PWR units are qualitatively in agreement for both intact fuel and fuel failure. It also indicates that the conventional threshold I-131/I-133 ≥ 0.1 for fuel failure may cause misjudgment due to the overlap of distributions, and I-131/I-133 ≥ 0.15 can distinguish 98% operation date for intact fuel rods and 94% operation data for fuel failure.
The Recent Relationships Between Andean Ice-Core Dust Record and Madeira River Suspended Sediments on the Wet Season
Authors: Reis Rafael S. dos , da Rocha Ribeiro Rafael , Delmonte Barbara , Ramirez Edson , Dani Norberto , Mayewski Paul A. , Simões Jefferson C.
Published: April 2022

Dust particle studies in ice cores from the tropical Andes provide important information about climate dynamics. We investigated dust concentrations from a 22.7 m ice-core recovered from the Quelccaya Ice Cap (QIC) in 2018, representing 14 years of snow accumulation. The dust seasonality signal was still preserved with homogenization of the record due to surface melting and percolation. Using a microparticle counter, we measured the dust concentration from 2 to 60 µm and divided the annual dust concentration into three distinct groups: fine particle percentage (FPP, 2–10 µm), coarse particle percentage (CPP, 10–20 μm), and giant particle percentage (GPP, 20–60 μm). Increased dust was associated with the warm stage of the Pacific Decadal Oscillation index (PDO) after 2013 with significant increases in FPP and a relative decrease in CPP and GPP. There was a positive correlation between PDO and FPP (r = 0.70, p-value < 0.005). CPP and GPP were dominant during the mainly PDO cold phase (2003–2012). The FPP increase record occurs during the positive phase of PDO and snow accumulation decrease. We also revealed a potential link between QIC record and Madeira River during the wet season through two relationships: between QIC snow accumulation and runoff during transitional season, QIC dust, and suspended sediments during high-water discharge. The snow accumulation (during September-November) and runoff (during November-January) relationship present similar variability using a time-lag (60 days) while total dust and FPP group are associated with average suspended sediments concentration during February-April. Assessing dust record variability by distinct size groups can help to improve our knowledge of how the Pacific ocean influence dust record in the QIC. In addition, the association of snow accumulation and dust variability with dynamic changes in suspended sediments load and runoff in the Madeira River system demonstrates the potential for future investigation of linkages between QIC record and Amazon basin rivers.
The Impact of Emissions Trading Program on the Labor Demand of Enterprises: Evidence From China
Authors: Wang Chang’an , Liu Xiaoqian , Xi Qian , Zhang Ying
Published: April 2022

The emissions trading program (ETP) is an effective means to fight environmental pollution. However, it may also spur the increase of enterprise costs, which affects employment and economic development. Adopting a difference-in-differences method and exploiting China’s emissions trading policy in 2007 as a quasi-natural experiment, we investigate the impact of the ETP on firms’ labor demand and the mechanism facilitating this effect. The results show that the ETP significantly reduces firms’ labor demand. The conclusion remains robust after using an instrumental variable to alleviate the possible endogeneity problem. Mechanism analysis indicates that the ETP reduces firms’ labor demand via increasing firms’ environmental expenditure and reducing profits. The heterogeneity analysis shows that the ETP significantly reduces the labor demand of SO2 emitting firms and heavy polluting firms, while having no significant impact on the labor demand of non-SO2 emitting firms and non-heavy polluting firms. This negative impact is more prominent for resource-based cities and old industrial base cities. This paper provides empirical evidence and policy implications for implementing the ETP in developing countries.
Forest Structure and Composition Diverge Following Harvesting Compared to a Spruce Budworm Choristoneura fumiferana (Clem.) Outbreak
Authors: Kneeshaw Daniel D. , De Grandpré Louis , D’Orangeville Loïc , Marchand Maryse , Moisan-Perrier Jeanne , Robert Louis-Etienne , Bouchard Mathieu
Published: April 2022

Balsam fir (Abies balsamea) is the most vulnerable species to the spruce budworm (Choristoneura fumiferana), one of the most devastating defoliators in the world. For decades, pest managers have advocated for reducing its abundance in the landscape to minimize losses to the spruce budworm (SBW). Although reduction of fir occurred during the endemic phase of the SBW cycle, there is little information about the extent to which this general principle (reduction of fir) was applied during an outbreak and whether it occurs at both stand and landscape levels. The objective of this paper is to compare the effect of insect and harvest disturbances on forest structure during the 1970–80s outbreak in Québec. We evaluate whether, (i) forest management activities targeted fir forests and whether patch size of host species influences management or SBW disturbance, (ii) SBW outbreaks and logging have similar or divergent effects on forest composition. Although data are from an earlier outbreak, they are at a scale rarely studied and will be useful in guiding decisions made at larger scales in the current and future outbreaks. Our results show that spruce was targeted preferentially by harvesting (up to 69% of plots) during the outbreak period, while it represented less than one third of plots defoliated by the SBW. On the other hand, fir stands represented up to 75% of plots that were defoliated by the SBW but less than 35% of plots that underwent harvesting. Harvesting targeted large blocks of spruce forest more than large blocks of fir-dominated forest while the opposite was observed for the SBW. In terms of regeneration, SBW tends to reduce fir and favor spruce recruitment, along with non-host species, whereas the opposite tendency was observed following harvesting. In terms of spatial organization of stands, our results support the suggestion that small stands of fir and large stands of spruce undergo the least SBW damage. Thus, in order to attenuate SBW impacts in the future, efforts should be made to ensure that spruce recruitment is favored and that its abundance increases at both the stand and landscape scale.
A Simulation Study of the Ecological Speciation Conditions in the Galician Marine Snail Littorina saxatilis
Authors: Fernández-Meirama M. , Rolán-Alvarez E. , Carvajal-Rodríguez A.
Published: April 2022

In the last years, the interest in evolutionary divergence at small spatial scales has increased and so did the study of speciation caused by ecologically based divergent natural selection. The evolutionary interplay between gene flow and local adaptation can lead to low-dispersal locally adapted specialists. When this occurs, the evolutionary interplay between gene flow and local adaptation could eventually lead to speciation. TheL. saxatilissystem consists of two ecotypes displaying a microhabitat-associated intraspecific dimorphism along the wave-exposed rocky shores of Galicia. Despite being a well-known system, the dynamics of the ecotype formation remain unclear and cannot be studied from empirical evidence alone. In this study, individual-based simulations were used to incorporate relevant ecological, spatial, and genetic information, to check different evolutionary scenarios that could evolve non-random mating preferences and finally may facilitate speciation. As main results, we observed the evolution of intermediate values of choice which matches the estimates from empirical data ofL.saxatilisin Galician shores and coincides with previous theoretical outcomes. Also, the use of the mating correlation as a proxy for assortative mating led to spuriously inferring greater reproductive isolation in the middle habitat than in the others, which does not happen when directly considering the choice values from the simulations. We also corroborate the well-known fact that the occurrence of speciation is influenced by the strength of selection. Taken together, this means, also according to otherL.saxatilissystems, that speciation is not an immediate consequence of local divergent selection and mating preferences, but a fine tuning among several factors including the ecological conditions in the shore levels, the selection strength, the mate choice stringency, and cost to choosiness. TheL.saxatilissystem could correspond to a case of incomplete reproductive isolation, where the choice intensity is intermediate and local adaptation within the habitat is strong. These results support previous interpretations of theL.saxatilismodel system and indicate that further empirical studies would be interesting to test whether the mate choice mechanism functions as a similarity-like mechanism as has been shown in other littorinids.
Sex-Specific Differences in MicroRNA Expression During Human Fetal Lung Development
Authors: Lin Nancy W. , Liu Cuining , Yang Ivana V. , Maier Lisa A. , DeMeo Dawn L. , Wood Cheyret , Ye Shuyu , Cruse Margaret H. , Smith Vong L. , Vyhlidal Carrie A. , Kechris Katerina , Sharma Sunita
Published: April 2022

Background: Sex-specific differences in fetal lung maturation have been well described; however, little is known about the sex-specific differences in microRNA (miRNA) expression during human fetal lung development. Interestingly, many adult chronic lung diseases also demonstrate sex-specific differences in prevalence. The developmental origins of health and disease hypothesis suggests that these sex-specific differences in fetal lung development may influence disease susceptibility later in life. In this study, we performed miRNA sequencing on human fetal lung tissue samples to investigate differential expression of miRNAs between males and females in the pseudoglandular stage of lung development. We hypothesized that differences in miRNA expression are present between sexes in early human lung development and may contribute to the sex-specific differences seen in pulmonary diseases later in life.

Methods: RNA was isolated from human fetal lung tissue samples for miRNA sequencing. The count of each miRNA was modeled by sex using negative binomial regression models in DESeq2, adjusting for post-conception age, age2, smoke exposure, batch, and RUV factors. We tested for differential expression of miRNAs by sex, and for the presence of sex-by-age interactions to determine if miRNA expression levels by age were distinct between males and females.

Results: miRNA expression profiles were generated on 298 samples (166 males and 132 females). Of the 809 miRNAs expressed in human fetal lung tissue during the pseudoglandular stage of lung development, we identified 93 autosomal miRNAs that were significantly differentially expressed by sex and 129 miRNAs with a sex-specific pattern of miRNA expression across the course of the pseudoglandular period.

Conclusion: Our study demonstrates differential expression of numerous autosomal miRNAs between the male and female developing human lung. Additionally, the expression of some miRNAs are modified by age across the pseudoglandular stage in a sex-specific way. Some of these differences in miRNA expression may impact susceptibility to pulmonary disease later in life. Our results suggest that sex-specific miRNA expression during human lung development may be a potential mechanism to explain sex-specific differences in lung development and may impact subsequent disease susceptibility.
A Novel Inflammatory Response–Related Gene Signature Improves High-Risk Survival Prediction in Patients With Head and Neck Squamous Cell Carcinoma
Authors: Han Yanxun , Ding Zhao , Chen Bangjie , Liu Yuchen , Liu Yehai
Published: April 2022

Background: Head and neck squamous cell carcinoma (HNSCC) is a highly prevalent and malignant tumor that is difficult to effectively prognosticate outcomes. Recent reports have suggested that inflammation is strongly related to tumor progression, and several biomarkers linked to inflammation have been demonstrated to be useful for making a prognosis. The goal of this research was to explore the relevance between the inflammatory-related genes and HNSCC prognosis.

Methods: The clinical information and gene expression data of patients with HNSCC were acquired from publicly available data sources. A multigene prognostic signature model was constructed in The Cancer Genome Atlas and verified in the Gene Expression Omnibus database. According to the risk score calculated for each patient, they were divided into low- and high-risk groups based on the median. The Kaplan–Meier survival curve and receiver operating characteristic curve were applied to determine the prognostic value of the risk model. Further analysis identified the independent prognostic factors, and a prognostic nomogram was built. The relationship between tumor immune infiltration status and risk scores was investigated using Spearman correlation analysis. Finally, to confirm the expression of genes in HNSCC, quantitative real-time polymerase chain reaction (qRT-PCR) was performed.

Results: A prognostic model consisting of 14 inflammatory-related genes was constructed. The samples with a high risk had an apparently shorter overall survival than those with a low risk. Independent prognostic analysis found that risk scores were a separate prognostic factor in HNSCC patients. Immune infiltration analysis suggested that the abundance of B cells, CD8 T cells, M2 macrophages, myeloid dendritic cells, and monocytes in the low-risk group was higher, while that of M0, M1 macrophages, and resting NK cells was obviously higher in the high-risk group. The risk scores were related to chemotherapeutic sensitivity and the expression of several immune checkpoint genes. Moreover, CCL22 and IL10 were significantly higher in HNSCC tissues, as determined by qRT-PCR.

Conclusion: Taken together, we constructed a novel inflammatory response–related gene signature, which may be used to estimate outcomes for patients with HNSCC and may be developed into a powerful tool for forecasting the efficacy of immunotherapeutic and chemotherapeutic drugs for HNSCC.
Transcriptome Analysis and Identification of the Cholesterol Side Chain Cleavage Enzyme BbgCYP11A1 From Bufo bufo gargarizans
Authors: Li Guangli , An Tianyue , Li Yu , Yue Jinyang , Huang Ruoshi , Huang Jia , Liang Jincai , Yao Wei , Huang Liufang , Chen Yidu , Zhang Rongrong , Ji Aijia , Duan Lixin
Published: April 2022

Bufo bufo gargarizans Cantor are precious medicinal animals in traditional Chinese medicine (TCM). Bufadienolides as the major pharmacological components are generated from the venomous glands of B. bufo gargarizans. Bufadienolides are one type of cardiac aglycone with a six-member lactone ring and have properties of antitumor, cardiotonic, tonsillitis, and anti-inflammatory. The biosynthesis of bufadienolides is complex and unclear. This study explored the transcriptome of three different tissues (skin glands, venom glands, and muscles) of B. bufo gargarizans by high-throughput sequencing. According to the gene tissue–specific expression profile, 389 candidate genes were predicted possibly participating in the bufadienolides biosynthesis pathway. Then, BbgCYP11A1 was identified as a cholesterol side chain cleaving the enzyme in engineering yeast producing cholesterol. Furthermore, the catalytic activity of BbgCYP11A1 was studied with various redox partners. Interestingly, a plant NADPH-cytochrome P450 reductase (CPR) from Anemarrhena asphodeloides showed notably higher production than BbgAdx-2A-BbgAdR from B. bufo gargarizans. These results will provide certainly molecular research to reveal the bufadienolides biosynthesis pathway in B. bufo gargarizans.
Identification of Hub Genes in Idiopathic Pulmonary Fibrosis and NSCLC Progression:Evidence From Bioinformatics Analysis
Authors: Yao Yuanshan , Li Zheng , Gao Wen
Published: April 2022

Background: Lung cancer is the most common comorbidity of idiopathic pulmonary fibrosis. Thus there is an urgent need for the research of IPF and carcinogenesis

Objective: The objective of this study was to explore hub genes which are common in pulmonary fibrosis and lung cancer progression through bioinformatic analysis.

Methods: All the analysis was performed in R software. Differentially expressed genes (DEGs) were explored by comparing gene expression profiles between IPF tissues and healthy lung tissues from GSE24206, GSE53845, GSE101286 and GSE110147 datasets. Venn Diagram analysis was used to identify the overlapping genes, while GO and KEGG pathway enrichment analysis were used to explore the biological functions of the DEGs using clusterprofiler package. Hub genes were identified by analyzing protein-protein interaction networks using Cytoscape software. Nomogram was constructed using the rms package. Tumor immune dysfunction and exclusion (TIDE) and Genomics of Drug Sensitivity in Cancer (GDSC) analysis was used to quantify the immunotherapy and chemotherapy sensitivity of non-small cell lung cancer (NSCLC) patients.

Results:COL1A1, COL3A1, MMP1, POSTN1 and TIMP3 were identified as the top five hub genes. The five hub genes were used to construct a diagnostic nomogram that was validated in another IPF dataset. Since the hub genes were also associated with lung cancer progression, we found that the nomogram also had diagnostic value in NSCLC patients. These five genes achieved a statistically difference of overall survival in NSCLC patients (p < 0.05). The expression of the five hub genes was mostly enriched in fibroblasts. Fibroblasts and the hub genes also showed significant ability to predict the susceptibility of NSCLC patients to chemotherapy and immunotherapy.

Conclusion: We identified five hub genes as potential biomarkers of IPF and NSCLC progression. This finding may give insight into the underlying molecular mechanisms of IPF and lung cancer progression and provides potential targets for developing new therapeutic agents for IPF patients.
Transcriptomic and Drug Discovery Analyses Reveal Natural Compounds Targeting the KDM4 Subfamily as Promising Adjuvant Treatments in Cancer
Authors: del Moral-Morales Aylin , Salgado-Albarrán Marisol , Ortiz-Gutiérrez Elizabeth , Pérez-Hernández Gerardo , Soto-Reyes Ernesto
Published: April 2022

KDM4 proteins are a subfamily of histone demethylases that target the trimethylation of lysines 9 and 36 of histone H3, which are associated with transcriptional repression and elongation respectively. Their deregulation in cancer may lead to chromatin structure alteration and transcriptional defects that could promote malignancy. Despite that KDM4 proteins are promising drug targets in cancer therapy, only a few drugs have been described as inhibitors of these enzymes, while studies on natural compounds as possible inhibitors are still needed. Natural compounds are a major source of biologically active substances and many are known to target epigenetic processes such as DNA methylation and histone deacetylation, making them a rich source for the discovery of new histone demethylase inhibitors. Here, using transcriptomic analyses we determined that the KDM4 family is deregulated and associated with a poor prognosis in multiple neoplastic tissues. Also, by molecular docking and molecular dynamics approaches, we screened the COCONUT database to search for inhibitors of natural origin compared to FDA-approved drugs and DrugBank databases. We found that molecules from natural products presented the best scores in the FRED docking analysis. Molecules with sugars, aromatic rings, and the presence of OH or O- groups favor the interaction with the active site of KDM4 subfamily proteins. Finally, we integrated a protein-protein interaction network to correlate data from transcriptomic analysis and docking screenings to propose FDA-approved drugs that could be used as multitarget therapies or in combination with the potential natural inhibitors of KDM4 enzymes. This study highlights the relevance of the KDM4 family in cancer and proposes natural compounds that could be used as potential therapies.
Microsatellite Loci Reveal High Genetic Diversity, Mutation, and Migration Rates as Invasion Drivers of Callery Pear (Pyrus calleryana) in the Southeastern United States
Authors: Sapkota Shiwani , Boggess Sarah L. , Trigiano Robert N. , Klingeman William E. , Hadziabdic Denita , Coyle David R. , Nowicki Marcin
Published: April 2022

Pyrus calleryanaDecne. (Callery pear) is a deciduous tree native to China, Japan, Korea, and Taiwan. It is a popular ornamental tree in the United States (US) with early spring blooms and vibrant fall color. There are at least 26 cultivars ofP. calleryanaavailable in the US of which “Bradford” is the most well-known. Open-pollinatedP. calleryanaescapees are becoming one of the most common invasive tree species in the eastern United States. Developing better management practices for invasiveP. calleryanarequires detailed knowledge about reproductive biology and genetic diversity of the species, however, little is currently known about genetic variability within those open-pollinated populations. We investigated genetic diversity and population structure of non-cultivated, escapedP. calleryanapopulations within a ∼177 km radius in the southeastern United States. BecauseP. calleryanaexhibits a range of morphological variation with great evolutionary potential, we hypothesized that a high genetic diversity would be manifested among escapedP. calleryana. Using 15 previously developed microsatellite loci, we genotyped 180 open-pollinatedP. calleryanaindividuals that were collected across six naturally occurring sites in Tennessee, Georgia, and South Carolina, United States. Our results demonstrated the presence of a population structure with high genetic diversity, high gene flow, and high genetic differentiation between individuals across collection sites. Our results revealed thatP. calleryanapopulations had differentiated shortly after the introduction to the US, most likely from specimens imported from Asia, consistent with historical records and our prior findings. The high invasive potential of the species is perhaps best underscored by transformation ofP. calleryanaspecimens introduced from Asia into escape populations at continental scale across the United States. Our data also provided novel insight into potential issues that could be problematic for the future asP. calleryanamay pose a potential threat to the economy, ecology, and native biodiversity in invaded areas.
Genome-wide Association Study Reveals New Loci Associated With Pyrethroid Resistance in Aedes aegypti
Authors: Cosme Luciano V. , Lima José Bento Pereira , Powell Jeffrey R. , Martins Ademir Jesus
Published: April 2022

Genome-wide association studies (GWAS) use genetic polymorphism across the genomes of individuals with distinct characteristics to identify genotype-phenotype associations. In mosquitoes, complex traits such as vector competence and insecticide resistance could benefit from GWAS. We used the Aedes aegypti 50k SNP chip to genotype populations with different levels of pyrethroid resistance from Northern Brazil. Pyrethroids are widely used worldwide to control mosquitoes and agricultural pests, and their intensive use led to the selection of resistance phenotypes in many insects including mosquitoes. For Ae. aegypti, resistance phenotypes are mainly associated with several mutations in the voltage-gated sodium channel, known as knockdown resistance (kdr). We phenotyped those populations with the WHO insecticide bioassay using deltamethrin impregnated papers, genotyped the kdr alleles using qPCR, and determined allele frequencies across the genome using the SNP chip. We identified single-nucleotide polymorphisms (SNPs) directly associated with resistance and one epistatic SNP pair. We also observed that the novel SNPs correlated with the known kdr genotypes, although on different chromosomes or not in close physical proximity to the voltage gated sodium channel gene. In addition, pairwise comparison of resistance and susceptible mosquitoes from each population revealed differentiated genomic regions not associated with pyrethroid resistance. These new bi-allelic markers can be used to genotype other populations along with kdr alleles to understand their worldwide distribution. The functional roles of the genes near the newly discovered SNPs require new studies to determine if they act synergistically with kdr alleles or reduce the fitness cost of maintaining resistant alleles.
Transcriptome Analysis of the Liver and Muscle Tissues of Dorper and Small-Tailed Han Sheep
Authors: Peng Hongyang , Hu Mingyue , Liu Zhengxi , Lai Weining , Shi Lulu , Zhao Zhongli , Ma Huihai , Li Yumei , Yan Shouqing
Published: April 2022

It is well known that Dorper (DP) is a full-bodied, fast-growing and high dressing percentage breed, while the production performance of Small-tailed Han sheep (STH) is not so excellent, in contrast to DP. Therefore, in this study, a comparative transcriptomic analysis of liver and muscle tissues from DP and STH breeds was carried out to find differentially expressed genes (DEGs) that affect their growth and meat quality traits. The results showed that the total number of DEGs was 2,188 in the two tissues. There were 950, 160 up-regulated and 1,007, 71 down-regulated genes in the liver and muscle, respectively. Several DEGs such as TGFB1, TGFB3, FABP3, LPL may be associated with growth and development in DP. Also, several GO terms were found to be associated with muscle growth and development, such as developmental growth (GO:0048589), and myofibril (GO:0030016). Further validation of eight genes (6 up-regulated, and 2 down-regulated) was performed using quantitative RT-PCR. These findings will provide valuable information for studying growth and development as well as meat quality traits in sheep.
DNA Repair–Related Gene Signature in Predicting Prognosis of Colorectal Cancer Patients
Authors: Lv Min-Yi , Wang Wei , Zhong Min-Er , Cai Du , Fan Dejun , Li Cheng-Hang , Kou Wei-Bin , Huang Ze-Ping , Duan Xin , Hu Chuling , Zhu Qiqi , He Xiaosheng , Gao Feng
Published: April 2022

Background: Increasing evidence have depicted that DNA repair–related genes (DRGs) are associated with the prognosis of colorectal cancer (CRC) patients. Thus, the aim of this study was to evaluate the impact of DNA repair–related gene signature (DRGS) in predicting the prognosis of CRC patients.

Method: In this study, we retrospectively analyzed the gene expression profiles from six CRC cohorts. A total of 1,768 CRC patients with complete prognostic information were divided into the training cohort (n = 566) and two validation cohorts (n = 624 and 578, respectively). The LASSO Cox model was applied to construct a prediction model. To further validate the clinical significance of the model, we also validated the model with Genomics of Drug Sensitivity in Cancer (GDSC) and an advanced clear cell renal cell carcinoma (ccRCC) immunotherapy data set.

Results: We constructed a prognostic DRGS consisting of 11 different genes to stratify patients into high- and low-risk groups. Patients in the high-risk groups had significantly worse disease-free survival (DFS) than those in the low-risk groups in all cohorts [training cohort: hazard ratio (HR) = 2.40, p < 0.001, 95% confidence interval (CI) = 1.67–3.44; validation-1: HR = 2.20, p < 0.001, 95% CI = 1.38–3.49 and validation-2 cohort: HR = 2.12, p < 0.001, 95% CI = 1.40–3.21). By validating the model with GDSC, we could see that among the chemotherapeutic drugs such as oxaliplatin, 5-fluorouracil, and irinotecan, the IC50 of the cell line in the low-risk group was lower. By validating the model with the ccRCC immunotherapy data set, we can clearly see that the overall survival (OS) of the objective response rate (ORR) with complete response (CR) and partial response (PR) in the low-risk group was the best.

Conclusions: DRGS is a favorable prediction model for patients with CRC, and our model can predict the response of cell lines to chemotherapeutic agents and potentially predict the response of patients to immunotherapy.
Integrative Analysis of Nanopore and Illumina Sequencing Reveals Alternative Splicing Complexity in Pig Longissimus Dorsi Muscle
Authors: Shu Ze , Wang Ligang , Wang Jinbu , Zhang Longchao , Hou Xinhua , Yan Hua , Wang Lixian
Published: April 2022

Alternative splicing (AS) is a key step in the post-transcriptional regulation of gene expression that can affect intramuscular fat (IMF). In this study, longissimus dorsi muscles from 30 pigs in high- and low- IMF groups were used to perform Oxford Nanopore Technologies (ONT) full-length sequencing and Illumina strand-specific RNA-seq. A total of 43,688 full-length transcripts were identified, with 4,322 novel genes and 30,795 novel transcripts. Using AStalavista, a total of 14,728 AS events were detected in the longissimus dorsi muscle. About 17.79% of the genes produced splicing isoforms, in which exon skipping was the most frequent AS event. By analyzing the expression differences of mRNAs and splicing isoforms, we found that differentially expressed mRNAs with splicing isoforms could participate in skeletal muscle development and fatty acid metabolism, which might determine muscle-related traits. SERBP1, MYL1, TNNT3, and TNNT1 were identified with multiple splicing isoforms, with significant differences in expression. AS events occurring in IFI6 and GADD45G may cause significant differences in gene expression. Other AS events, such as ONT.15153.3, may regulate the function of ART1 by regulating the expression of different transcripts. Moreover, co-expression and protein-protein interaction (PPI) analysis indicated that several genes (MRPL27, AAR2, PYGM, PSMD4, SCNM1, and HNRNPDL) may be related to intramuscular fat. The splicing isoforms investigated in our research provide a reference for the study of alternative splicing regulation of intramuscular fat deposition.
Subjective Birth Experience Predicts Mother–Infant Bonding Difficulties in Women With Mental Disorders
Authors: Junge-Hoffmeister Juliane , Bittner Antje , Garthus-Niegel Susan , Goeckenjan Maren , Martini Julia , Weidner Kerstin
Published: April 2022

Background

The subjective experience of giving birth to a child varies considerably depending on psychological, medical, situational, relational, and other individual characteristics. In turn, it may have an impact on postpartum maternal mental health and family relationships, such as mother–infant bonding. The objective of the study was to evaluate the relevance of the subjective birth experience (SBE) for mother–infant bonding difficulties (BD) in women with mental disorders.

Methods

This study used data from N = 141 mothers who were treated for postpartum mental disorders in the mother–baby day unit of the Psychosomatic University Clinic in Dresden, Germany. Patients' mental status at admission and discharge was routinely examined using a diagnostic interview (SCID I) and standard psychometric questionnaires (e.g., EPDS, BSI, PBQ). Both, the SBE (assessed by Salmon's Item List, SIL) as well as medical complications (MC) were assessed retrospectively by self-report. The predictive value of SBE, MC, as well as psychopathological symptoms for mother–infant BD were evaluated using logistic regression analyses.

Results

About half of this clinical sample (47.2%) reported a negative SBE; 56.8% of all mothers presented with severe mother–infant BD toward the baby. Mothers with BD showed not only significantly more depressiveness (EPDS: M = 16.6 ± 5.6 vs. 14.4 ± 6.2*), anxiety (STAI: M = 57.2 ± 10.6 vs. 51.4 ± 10.6***), and general psychopathology (BSI-GSI: M = 1.4 ± 0.7 vs. 1.1 ± 0.6**) compared to women without BD, but also a significantly more negative SBE (SIL: M = 79.3 ± 16.2 vs. 61.3 ± 22.9***). Moreover, the SBE was the most powerful predictor for BD in univariate and multiple logistic regression analyses [OR = 0.96*** (95% CI 0.94–0.98) vs. OR = 0.96** (95% CI 0.93–0.98)], even when univariate significant predictors (e.g., current psychopathology and MC during birth) were controlled.

Conclusions

A negative SBE is strongly associated with mother–infant bonding in patients with postpartum mental disorders. It needs to get targeted within postpartum treatment, preferably in settings including both mother and child, to improve distorted mother–infant bonding processes and prevent long-term risks for the newborn. Furthermore, the results highlight the importance of focusing on the specific needs of vulnerable women prior to and during birth (e.g., emotional safety, good communication, and support) as well as individual factors that might be predictive for a negative SBE.
Persistent Inflammation and Non-AIDS Comorbidities During ART: Coming of the Age of Monocytes
Authors: Bai Ruojing , Li Zhen , Lv Shiyun , Wang Ran , Hua Wei , Wu Hao , Dai Lili
Published: April 2022

Monocytes are innate immune cells that serve as the first line of defense against pathogens by engulfing and destroying pathogens or by processing and presenting antigens to initiate adaptive immunity and stimulate immunological responses. Monocytes are classified into three types: classical, intermediate, and non-classical monocytes, each of which plays a particular function in response to pathogens. Human immunodeficiency virus type 1 (HIV-1) infection disrupts the balance of monocyte subsets, and the quantity and function of monocytes will not fully recover even with long-term antiretroviral therapy (ART). Monocytes are vital for the establishment and maintenance of HIV-1 latent viral reservoirs and are closely related to immune dysfunction even after ART. Therefore, the present review focuses on the phenotypic function of monocytes and their functions in HIV-1 infection to elucidate their roles in HIV patients.
Identification of Anti-Collapsin Response Mediator Protein 2 Antibodies in Patients With Encephalitis or Encephalomyelitis
Authors: Xu Kaibiao , Wang Dongmei , He Yan , Wang Shengnan , Liu Guanghui , Pan Yue , Jiang Haishan , Peng Yu , Xiao Fenliang , Huang Yihua , Wang Qiqi , Wu Yongming , Pan Suyue , Hu Yafang
Published: April 2022

Background and Purpose

An increasing number of autoimmune encephalitis (AE)-associated autoantibodies have been successfully characterized. However, many cases of AE remain unexplained on account of unknown antibodies. The aim of the present study was to identify a novel antibody against collapsin response mediator protein 2 (CRMP2) in suspected AE patients.

Methods

A patient’s serum and cerebrospinal fluid samples tested negative for known AE antibodies; however, strong immunolabel signals were observed in the neuronal cytoplasm of the cortex, hippocampus, and Purkinje cells on rat brain sections. Immunoprecipitation from the rat brain protein lysate, followed by mass spectrometry analysis, was used to identify the targeting antigen. Western blotting and cell-based assay with antigen-overexpressing HEK293T cells were used for antibody specificity, epitope, IgG subtype determination, and retrospective study.

Results

An antibody against CRMP2, a synaptic protein involved in axon guidance, was identified. The immunostains of the patient’s samples on rat brain sections were eliminated by pre-absorption with HEK293T cells overexpressing CRMP2. The samples specifically immunoreacted with CRMP2, but not with CRMP1, CRMP3, CRMP4, and CRMP5. The C-terminus of CRMP2 with 536 amino acids contained the epitope for antibody binding. The subtype analysis showed that the anti-CRMP2 antibody was IgG4. Furthermore, a screening of 46 patients with neurological disoders and neuro-cytoplasm immunostainings on rat brain sections resulted in the identification of anti-CRMP2 antibodies in a case of encephalomyelitis. The two patients responded well to immunotherapies.

Conclusions

This study discovered that a novel anti-CRMP2 antibody was associated with suspected AE and thus should be included in the testing list for AE.
A Capsid Virus-Like Particle-Based SARS-CoV-2 Vaccine Induces High Levels of Antibodies and Protects Rhesus Macaques
Authors: Volkmann Ariane , Koopman Gerrit , Mooij Petra , Verschoor Ernst J. , Verstrepen Babs E. , Bogers Willy M. J. M. , Idorn Manja , Paludan Søren R. , Vang Søren , Nielsen Morten A. , Sander Adam F. , Schmittwolf Carolin , Hochrein Hubertus , Chaplin Paul
Published: April 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic. Here, we present non-human primate immunogenicity and protective efficacy data generated with the capsid virus-like particle (cVLP)-based vaccine ABNCoV2 that has previously demonstrated immunogenicity in mice. In rhesus macaques, a single vaccination with either 15 or 100 μg ABNCoV2 induced binding and neutralizing antibodies in a dose-dependent manner, at levels comparable to those measured in human convalescents. A second vaccine administration led to a >50-fold increase in neutralizing antibodies, with 2-log higher mean levels in the 100-μg ABNCoV2 group compared with convalescent samples. Upon SARS-CoV-2 challenge, a significant reduction in viral load was observed for both vaccine groups relative to the challenge control group, with no evidence of enhanced disease. Remarkably, neutralizing antibody titers against an original SARS-CoV-2 isolate and against variants of concern were comparable, indicating a potential for broad protection afforded by ABNCoV2, which is currently in clinical testing.
Research Trends and Most Influential Clinical Studies on Anti-PD1/PDL1 Immunotherapy for Cancers: A Bibliometric Analysis
Authors: Liu Yanhao , Xu Yan , Cheng Xi , Lin Yaru , Jiang Shu , Yu Haiming , Zhang Zhen , Lu Linlin , Zhang Xiaotao
Published: April 2022

In this study, a bibliometric analysis was carried out to identify the most influential clinical studies and research trends on anti-programmed cell death 1/programmed cell death 1 ligand 1 (anti-PD1/PDL1) immunotherapy. On January 1, 2022, we used Web of Science to identify the 100 most frequently cited papers on clinical studies investigating anti-PD1/PDL1 immunotherapy, and extracted the following data: publication year, source title, country/region, institution, and the total number of citations. The research design and area were classified independently by the authors. Subsequently, we carried out a bibliometric analysis to determine the trends and identify the major journals on anti-PD1/PDL1 immunotherapy. The authors analyzed the current research hotspots based on papers published in major journals from 2020 to 2021. These 100 papers were cited a total of 138,840 times, and the median number of citations was 899.5 (range: 341–7,983). “Safety, activity, and immune correlates of anti-PD-1 antibody in cancer” by Topalian et al. had the highest number of citations (7,983 times). New England Journal of Medicine had the highest number of top-cited papers (40 papers), average citations per paper (1,558.3 citations), and rate of top-cited papers (65.6%). Authors from the USA contributed most of the papers (76 papers). Lung cancer (30 papers, 46,422 citations) and melanoma (20 papers, 30,881 citations) were the most cited research areas. In summary, anti-PD1/PDL1 has become standard treatment for various cancer, while adjuvant anti-PD1/PDL1 therapy is currently a research hotspot. New England Journal of Medicine was identified as the most influential journal in this area. Non-small cell lung cancer and melanoma are the most well-studied cancers, while nivolumab and pembrolizumab are the most commonly investigated anti-PD1/PDL1 antibodies. Further studies are warranted to identify effective predictive biomarkers or models, clarify the molecular mechanism of combined therapy, and establish optimal therapeutic strategies. This study may assist researchers in obtaining a comprehensive impression of the landscape and current trends in anti-PD1/PDL1 immunotherapy and gain inspiration to conduct further studies.
CSF Biomarkers in COVID-19 Associated Encephalopathy and Encephalitis Predict Long-Term Outcome
Authors: Guasp Mar , Muñoz-Sánchez Guillermo , Martínez-Hernández Eugenia , Santana Daniel , Carbayo Álvaro , Naranjo Laura , Bolós Uma , Framil Mario , Saiz Albert , Balasa Mircea , Ruiz-García Raquel , Sánchez-Valle Raquel ,   The Barcelona Neuro-COVID Study Group
Published: April 2022

Patients with coronavirus disease 2019 (COVID-19) frequently develop acute encephalopathy and encephalitis, but whether these complications are the result from viral-induced cytokine storm syndrome or anti-neural autoimmunity is still unclear. In this study, we aimed to evaluate the diagnostic and prognostic role of CSF and serum biomarkers of inflammation (a wide array of cytokines, antibodies against neural antigens, and IgG oligoclonal bands), and neuroaxonal damage (14-3-3 protein and neurofilament light [NfL]) in patients with acute COVID-19 and associated neurologic manifestations (neuro-COVID). We prospectively included 60 hospitalized neuro-COVID patients, 25 (42%) of them with encephalopathy and 14 (23%) with encephalitis, and followed them for 18 months. We found that, compared to healthy controls (HC), neuro-COVID patients presented elevated levels of IL-18, IL-6, and IL-8 in both serum and CSF. MCP1 was elevated only in CSF, while IL-10, IL-1RA, IP-10, MIG and NfL were increased only in serum. Patients with COVID-associated encephalitis or encephalopathy had distinct serum and CSF cytokine profiles compared with HC, but no differences were found when both clinical groups were compared to each other. Antibodies against neural antigens were negative in both groups. While the levels of neuroaxonal damage markers, 14-3-3 and NfL, and the proinflammatory cytokines IL-18, IL-1RA and IL-8 significantly associated with acute COVID-19 severity, only the levels of 14-3-3 and NfL in CSF significantly correlated with the degree of neurologic disability in the daily activities at 18 months follow-up. Thus, the inflammatory process promoted by SARS-CoV-2 infection might include blood-brain barrier disruption in patients with neurological involvement. In conclusion, the fact that the levels of pro-inflammatory cytokines do not predict the long-term functional outcome suggests that the prognosis is more related to neuronal damage than to the acute neuroinflammatory process.
Distinct Role of TNFR1 and TNFR2 in Protective Immunity Against Orientia tsutsugamushi Infection in Mice
Authors: Liang Yuejin , Fisher James , Gonzales Casey , Trent Brandon , Card Galen , Sun Jiaren , Tumanov Alexei V. , Soong Lynn
Published: April 2022

Infection with Orientia tsutsugamushi, an obligate intracellular bacterium, can cause mild or severe scrub typhus. Some patients develop acute lung injury, multi-organ failure, and fatal infection; however, little is known regarding key immune mediators that mediate infection control or disease pathogenesis. Using murine models of scrub typhus, we demonstrated in this study the requirement of TNF-TNFR signaling in protective immunity against this infection. Mice lacking both TNF receptors (TNFR1 and TNFR2) were highly susceptible to O. tsutsugamushi infection, displaying significantly increased tissue bacterial burdens and succumbing to infection by day 9, while most wild-type mice survived through day 20. This increased susceptibility correlated with poor activation of cellular immunity in inflamed tissues. Flow cytometry of lung- and spleen-derived cells revealed profound deficiencies in total numbers and activation status of NK cells, neutrophils, and macrophages, as well as CD4 and CD8 T cells. To define the role of individual receptors in O. tsutsugamushi infection, we used mice lacking either TNFR1 or TNFR2. While deficiency in either receptor alone was sufficient to increase host susceptibility to the infection, TNFR1 and TNFR2 played a distinct role in cellular responses. TNF signaling through TNFR1 promoted inflammatory responses and effector T cell expansion, while TNFR2 signaling was associated with anti-inflammatory action and tissue homeostasis. Moreover, TNFRs played an intrinsic role in CD8+ T cell activation, revealing an indispensable role of TNF in protective immunity against O. tsutsugamushi infection.