bluuebunny/crossref_metadata_2025 huggingface dataset:
Design-Based Learning as a Pedagogical Approach in an Online Learning Environment for Science Undergraduate Students
Authors: Azizan Suzana Ariff , Abu Shamsi Nurulaini
Published: May 2022

Design-based learning (DBL) is a learning strategy that requires students to use their theoretical knowledge to develop an artifact or system to tackle a real-life problem. DBL has long been utilized in design-related curricula in higher education such as engineering, computer science, and architecture. However, little is known about how DBL in non-design-based courses enhances students’ learning experience, especially in recent years when the COVID-19 pandemic has compelled the worldwide education systems to adapt to online learning. Hence, this study aims to investigate the experience of science undergraduate students after one semester of participating in online DBL. The participants include 25 second-year science undergraduate students enrolling in the Managing New Technologies course. Using semi-structured interviews and thematic analysis, the findings of this study indicated that online DBL contributes to easy access to learning, enhances creativity, and allows students to think outside the box. Nevertheless, students highlighted online learning as an obstacle to their DBL experience. They claimed that online platforms as a means of communication are not practical due to insufficient interaction time and misunderstanding of information. In addition, some students stated that the online environment poses difficulties for collaborative learning.
Non-alcoholic Fatty Liver Disease Is Associated With Aortic Calcification: A Cohort Study With Propensity Score Matching
Authors: Zhu Rong-Rong , Gao Xu-Ping , Liao Min-Qi , Cui Yun-Feng , Tan Si-Xian , Zeng Fang-Fang , Lou Yan-Mei , Wang Chang-Yi , Xu Shan , Peng Xiao-Lin , Dai Shu-Hong , Zhao Dan , Wang Li , Ping Zhao , Dai Xiao-Yu , Feng Pin-Ning , Han Li-Yuan
Published: May 2022

Objectives

Non-alcoholic fatty liver disease (NAFLD) greatly affects cardiovascular disease, but evidence on the associations between NAFLD and markers of aortic calcification is limited. We aim to evaluate the association between NAFLD and aortic calcification in a cohort of Chinese adults using propensity score-matching (PSM) analysis.

Methods

This prospective cohort study involved adults who underwent health-screening examinations from 2009 to 2016. NAFLD was diagnosed by abdominal ultrasonography at baseline, and aortic calcification was identified using a VCT LightSpeed 64 scanner. Analyses included Cox proportional-hazards regression analysis and PSM with predefined covariates (age, gender, marital and smoking status, and use of lipid-lowering drugs) to achieve a 1:1 balanced cohort.

Results

Of the 6,047 eligible participants, 2,729 (45.13%) were diagnosed with NAFLD at baseline, with a median age of 49.0 years [interquartile range, 44.0–55.0]. We selected 2,339 pairs of participants with and without NAFLD at baseline for the PSM subpopulation. Compared with those without NAFLD, patients with NAFLD were at a higher risk of developing aortic calcification during follow-up; significant results were observed before and after matching, with the full-adjusted hazard ratios and corresponding 95% confidence intervals being 1.19 (1.02–1.38) and 1.18 (1.01–1.38), respectively (both p < 0.05). In subgroup analyses, no interaction was detected according to age, gender, smoking status, body mass index, total cholesterol, low-density lipoprotein cholesterol, use of lipid-lowering drugs, hypertension, or type 2 diabetes.

Conclusions

NAFLD may be independently associated with aortic calcification. Further studies are warranted to elucidate the possible underlying mechanisms.
Effective Conservation of Desert Riverscapes Requires Protection and Rehabilitation of In-Stream Flows With Rehabilitation Approaches Tailored to Water Availability
Authors: Pennock Casey A. , Budy Phaedra , Macfarlane William W.
Published: May 2022

Desert riverscape rehabilitation practitioners must contend with compounding effects of increasing human water demand, persistent drought, non-native species establishment, and climate change, which further stress desert riverine ecosystems such as rivers in the Colorado River basin, United States. Herein, we provide our perspective on the importance of natural flows, large floods in particular, for successful conservation and rehabilitation of riverscapes. We present ideas developed from our experience with rehabilitation projects across multiple desert tributary rivers with varying levels of habitat degradation and water abstraction. We propose spatially extensive measures such as protection of in-stream flows, tailoring rehabilitation efforts to available annual water availability, and working with nature using low-tech process-based techniques to more completely address the mechanisms of habitat degradation, such as flow reduction and vegetation-induced channel narrowing. Traditionally, rehabilitation efforts in the Colorado River basin take place at relatively small spatial extents, at convenient locations and, largely focus on reducing non-native plant and fish species. We suggest that we need to think more broadly and creatively, and that conservation or recovery of natural flow regimes is crucial to long-term success of almost all management efforts for both in-stream and riparian communities.
How to Control Coastal Zone Through Spatial Planning? Taking the Construction of the Spatial Monitoring Index System of the Coastal Zone in China as an Example
Authors: Guo Zelian , Hu Yecui , Bai Yuping , Yang Lei , Wang Jieyong
Published: May 2022

Due to its fragile ecological environment and superior natural and location conditions, coastal areas are receiving extensive attention all over the world. Scientific space control is needed to ensure the harmonious development of the “human-land-ocean” system in this region. The monitoring index system is a crucial grasp of the national territory use control; it is also one of the main contents in the reform of China’s planning system in the new era. Therefore, based on the strategic idea of land–sea overall management and the concept of “life community of human, mountains, rivers, forests, farmlands, lakes, grasslands, and ocean”, this study puts forward three connotations of the index system of coastal spatial planning from the perspective of “function-structure-elements.” Then, adopting the methods of “multiple planning integration” and expert consultation and using the research idea of “setting control objectives, contents, and indicators,” an index system suitable for coastal space control is constructed. The results show that the index system puts forward 33 sub-indexes for coastal ecological space, living space, and production space and provides a basis for the high-quality development of coastal space through the restrictions and requirements on the total amount, bottom line, boundary, conversion, and quality of various spatial elements. This study can provide a basis for formulation, implementation, and later monitoring of coastal spatial planning and provide an index reference for the management of coastal areas in other countries in the world.
The Distribution Characteristics and Human Health Risks of High- Fluorine Groundwater in Coastal Plain: A Case Study in Southern Laizhou Bay, China
Authors: Liu Sen , Liu Yanan , Wang Cong , Dang Xianzhang
Published: May 2022

High-F groundwater has caused serious human health problems worldwide. In this paper, a typical saline-fresh water mixing zone (SFMZ) in a coastal plain (south of Laizhou Bay, China) was chosen as an example to analyze and summarize the distribution characteristics and enrichment mechanism human health risks of high-fluorine groundwater. Thirty-two groundwater samples have F- concentrations that exceed the drinking water guideline value of the World Health Organization (WHO; 1.5 mg/L), Thirty-two groundwater samples exceeded the drinking water guideline value of the WHO (1.5 mg/L) and 43 groundwater samples exceeded the National Sanitary Standard for drinking water of China (1.0 mg/L), accounting for 68.1 and 91.5% of the total groundwater samples. The groundwater quality is relatively poor in this study area, and the water is unsuitable for human consumption. High-F groundwater is mainly found in the central and northern parts of the study area, and the concentrations increase in the direction of water flow. High-F groundwater is mainly found in the central and northern parts of the study area, and the concentrations increase in the direction of water flow. According to the analysis, the groundwater environment, saline water intrusion (SWI), evaporation and cation exchange are the main factors influencing the enrichment of F in the SFMZ. The neutral and weakly alkaline environment is conducive to the enrichment of F-. Cation exchange and evaporation are the most important factors in the enrichment of F. Human activity is not the main source of groundwater F. Na+ and HCO3− are adequately abundant in the groundwater environment in the study area, creating conditions that are conducive to the dissolution of fluorite and the release of F into the groundwater. An increase in the Na+ concentration and a decrease in the Ca2+ concentration can promote further dissolution of fluorite and other F-containing minerals, thereby releasing F- into the groundwater. Fluorite dissolution is prevalent in the groundwater environment, which can lead to an increase in the F concentration. This study is helpful to the development of strategies for the integrated management of high-F groundwater in coastal plains. The health risk assessment shows that long-term exposure to high-F groundwater can pose a great threat to four age clusters, especially for children and infants. The HQ values for shallow groundwater range from 0.32 to 2.89, 0.39 to 3.61, 0.56 to 5.11, and 0.42 to 3.85 for adults, teenagers, children and infants, respectively. The groundwater in this study area is not for irrigation and animal husbandry, which may indirectly affect human health.
The Competitiveness, Bargaining Power, and Contract Choice in Agricultural Water Markets in Pakistan: Implications for Price Discrimination and Environmental Sustainability
Authors: Razzaq Amar , Liu Hancheng , Zhou Yewang , Xiao Meizhen , Qing Ping
Published: May 2022

Pakistan is the world’s third-largest user of groundwater and the fourth-largest groundwater withdrawing country. The Indus Basin aquifer from where Pakistan withdraws its groundwater has become the world’s most “overstressed” groundwater aquifer. Given the growing shortages of surface and groundwater, the informal groundwater markets where farmers trade water have emerged in all provinces of Pakistan. Despite the considerable attention paid to the analysis of water markets in several countries, there is little evidence on the structure and implications of contractual agreements between the water users. This study includes buyers’ bargaining power in the contract choice model to estimate unbiased determinants of contract choice. The data was collected through a comprehensive survey of Punjab’s groundwater markets. Using several descriptive and econometric approaches, we find that the water markets in Pakistan are relatively competitive. A flat-rate water marketing contract is common in water-scarce regions, while a fuel-based contract is common in areas with large farmers. We find that buyers’ bargaining power is primarily determined by an agent’s ability to influence a joint decision between buyers and sellers. In addition, a seller’s landholding size also influences the choice of contract, as fuel-based contracts are more likely to be offered to large farmers. The relative bargaining power of buyers influences choice of fuel-based contracts, although this offers lower profits to sellers. We find evidence of price discrimination in which relatively well-off buyers with a long contractual history with sellers may receive discounts in the form of fuel-based contracts. As contract choice may also determine the extent of water use, these findings have implications for environmental sustainability. Policy intervention to standardize groundwater marketing contracts can help reduce overexploitation of groundwater and environmental externalities and promote sustainable development.
Genome-Wide Identification and Characterization of Long Non-Coding RNAs in Longissimus dorsi Skeletal Muscle of Shandong Black Cattle and Luxi Cattle
Authors: Liu Ruili , Han Mingxuan , Liu Xianxun , Yu Kun , Bai Xuejin , Dong Yajuan
Published: May 2022

There is an increasing understanding of the possible regulatory role of long non-coding RNAs (LncRNA). Studies on livestock have mainly focused on the regulation of cell differentiation, fat synthesis, and embryonic development. However, there has been little study of skeletal muscle of domestic animals and the potential role of lncRNA. In this study, the transcriptome numbers of longissimus muscle of different beef cattle (Shandong black catle and Luxi catlle) were used to construct muscle related lncRNAs-miRNA-mRNA interaction network through bioinformatics analysis. This is helpful to clarify the molecular mechanism of bovine muscle development, and can be used to promote animal husbandry and improve animal husbandry production. According to the screening criteria of |FC|≧2 and q < 0.05, a total of 1,415 transcripts (of which 480 were LncRNAs) were differentially expressed (q < 0.05) in the different breeds. Further, we found that the most differentially expressed LncRNAs were found on chromosome 9, in which the differentially expressed LncRNAs targeted 1,164 protein coding genes (MYORG, Wnt4, PAK1, ADCY7,etc) (upstream and downstream<50 Kb). In addition, Pearson’s correlation coefficients of co-expression levels indicated a potential trans regulatory relationship between the differentially expressed LncRNAs and 43844 mRNAs (r > 0.9). The identified co-expressed mRNAs (MYORG, Dll1, EFNB2, SOX6, MYOCD, and MYLK3) are related to the formation of muscle structure, and enriched in muscle system process, strained muscle cell differentiation, muscle cell development, striated muscle tissue development, calcium signaling, and AMPK signaling. Additionally, we also found that some LncRNAs (LOC112444238, LOC101903367, LOC104975788, LOC112441863, LOC112449549, and LOC101907194) may interact with miRNAs related to cattle muscle growth and development. Based on this, we constructed a LncRNAs-miRNA-mRNA interaction network as the putative basis for biological regulation in cattle skeletal muscle. Interestingly, a candidate differential LncRNA (LOC104975788) and a protein-coding gene (Pax7) contain miR-133a binding sites and binding was confirmed by luciferase reporter assay. LOC104975788 may combined miR-133a competitively with Pax7, thus relieving the inhibitory effect of miR-133a on Pax7 to regulate skeletal muscle development. These results will provide the theoretical basis for further study of LncRNA regulation and activity in different cattle breeds.
Case Report: Hemophagocytic Lymphohistiocytosis Prior to the Onset of Leukemia in a Boy With CDK13-Related Disorder
Authors: Cui Dongyan , Wang Songmi , Zhang Ai , Liu Aiguo , Hu Qun
Published: May 2022

Cardinal features of CDK13-related disorders are characterized by intellectual disability, developmental delay, dysmorphic facial features, structural heart defect and structural brain abnormality. A 9-year-old boy presented with intellectual disability, development delay, characteristic craniofacial features, brain malformation, cryptorchidism, autism spectrum disorder, and recently, recurrent hemophagocytic lymphohistiocytosis (HLH) in a half year period. Further investigation revealed the diagnosis of CDK13-related disorder. Finally, we found the underlying cause of HLH is acute lymphoblastic leukemia. Probably leukemia was a coincidental finding in this boy with CDK13-related disorder, but the case herein suggests that individuals with CDK13-related disorder also face risk of developing cancers. Further detailed information could enable us to clarify this presentation because of only limited investigation in affected cases.
2b-RAD Genotyping of the Seagrass Cymodocea nodosa Along a Latitudinal Cline Identifies Candidate Genes for Environmental Adaptation
Authors: Ruocco Miriam , Jahnke Marlene , Silva João , Procaccini Gabriele , Dattolo Emanuela
Published: May 2022

Plant populations distributed along broad latitudinal gradients often show patterns of clinal variation in genotype and phenotype. Differences in photoperiod and temperature cues across latitudes influence major phenological events, such as timing of flowering or seed dormancy. Here, we used an array of 4,941 SNPs derived from 2b-RAD genotyping to characterize population differentiation and levels of genetic and genotypic diversity of three populations of the seagrass Cymodocea nodosa along a latitudinal gradient extending across the Atlantic-Mediterranean boundary (i.e., Gran Canaria—Canary Islands, Faro—Portugal, and Ebro Delta—Spain). Our main goal was to search for potential outlier loci that could underlie adaptive differentiation of populations across the latitudinal distribution of the species. We hypothesized that such polymorphisms could be related to variation in photoperiod-temperature regime occurring across latitudes. The three populations were clearly differentiated and exhibited diverse levels of clonality and genetic diversity. Cymodocea nodosa from the Mediterranean displayed the highest genotypic richness, while the Portuguese population had the highest clonality values. Gran Canaria exhibited the lowest genetic diversity (as observed heterozygosity). Nine SNPs were reliably identified as outliers across the three sites by two different methods (i.e., BayeScan and pcadapt), and three SNPs could be associated to specific protein-coding genes by screening available C. nodosa transcriptomes. Two SNPs-carrying contigs encoded for transcription factors, while the other one encoded for an enzyme specifically involved in the regulation of flowering time, namely Lysine-specific histone demethylase 1 homolog 2. When analyzing biological processes enriched within the whole dataset of outlier SNPs identified by at least one method, “regulation of transcription” and “signalling” were among the most represented. Our results highlight the fundamental importance signal integration and gene-regulatory networks, as well as epigenetic regulation via DNA (de)methylation, could have for enabling adaptation of seagrass populations along environmental gradients.
Identification of Novel Characteristics in TP53-Mutant Hepatocellular Carcinoma Using Bioinformatics
Authors: Yang Yang , Qu Yajuan , Li Zhaopeng , Tan Zhiyong , Lei Youming , Bai Song
Published: May 2022

Background: TP53 mutations are the most frequent mutations in hepatocellular carcinoma (HCC) and affect the occurrence and development of this cancer type. Therefore, it is essential to clarify the function and mechanism of TP53 mutations in HCC.

Methods: We performed a sequence of bioinformatic analyses to elucidate the characteristics of TP53 mutations in HCC. We downloaded the data of hepatocellular carcinoma from The Cancer Genome Atlas database and used different R packages for serial analyses, including gene mutation analysis, copy number variation analysis, analysis of the tumor mutational burden and microsatellite instability, differential gene expression analysis, and functional enrichment analysis of TP53 mutations, and performed gene set enrichment analysis. We established a protein-protein interaction network using the STRING online database and used the Cytoscape software for network visualization, and hub gene screening. In addition, we performed anticancer drug sensitivity analysis using data from the Genomics of Drug Sensitivity in Cancer. Immune infiltration and prognosis analyses were also performed.

Results: Missense mutations accounted for a great proportion of HCC mutations, the frequency of single nucleotide polymorphisms was high, and C > T was the most common form of single nucleotide variations. TP53 had a mutation rate of 30% and was the most commonly mutated gene in HCC. In the TP53 mutant group, the tumor mutational burden (p < 0.001), drug sensitivity (p < 0.05), ESTIMATE score (p = 0.038), and stromal score (p < 0.001) dramatically decreased. The Cytoscape software screened ten hub genes, including CT45A1, XAGE1B, CT55, GAGE2A, PASD1, MAGEA4, CTAG2, MAGEA10, MAGEC1, and SAGE1. The prognostic model showed a poor prognosis in the TP53 mutation group compared with that in the wild-type group (overall survival, p = 0.023). Univariate and multivariate cox regression analyses revealed that TP53 mutation was an independent risk factor for the prognosis of HCC patients (p <0.05). The constructed prognostic model had a favorable forecast value for the prognosis of HCC patients at 1 and 3 years (1-year AUC = 0.752, 3-years AUC = 0.702).

Conclusion: This study further deepened our understanding of TP53-mutated HCC, provided new insights into a precise individualized therapy for HCC, and has particular significance for prognosis prediction.
Inter-Residue Distance Prediction From Duet Deep Learning Models
Authors: Zhang Huiling , Huang Ying , Bei Zhendong , Ju Zhen , Meng Jintao , Hao Min , Zhang Jingjing , Zhang Haiping , Xi Wenhui
Published: May 2022

Residue distance prediction from the sequence is critical for many biological applications such as protein structure reconstruction, protein–protein interaction prediction, and protein design. However, prediction of fine-grained distances between residues with long sequence separations still remains challenging. In this study, we propose DuetDis, a method based on duet feature sets and deep residual network with squeeze-and-excitation (SE), for protein inter-residue distance prediction. DuetDis embraces the ability to learn and fuse features directly or indirectly extracted from the whole-genome/metagenomic databases and, therefore, minimize the information loss through ensembling models trained on different feature sets. We evaluate DuetDis and 11 widely used peer methods on a large-scale test set (610 proteins chains). The experimental results suggest that 1) prediction results from different feature sets show obvious differences; 2) ensembling different feature sets can improve the prediction performance; 3) high-quality multiple sequence alignment (MSA) used for both training and testing can greatly improve the prediction performance; and 4) DuetDis is more accurate than peer methods for the overall prediction, more reliable in terms of model prediction score, and more robust against shallow multiple sequence alignment (MSA).
Integrated Analysis Reveals Critical Ferroptosis Regulators and FTL Contribute to Cancer Progression in Hepatocellular Carcinoma
Authors: Ke Shaoying , Wang Congren , Su Zijian , Lin Shaoze , Wu Gongle
Published: May 2022

Background: The carcinogenesis and prognosis of hepatocellular carcinoma (HCC) involve complex molecular mechanisms, and ferroptosis is related to the development and therapeutic efficacy of HCC, but the specific mechanism and prognostic role of ferroptosis-related genes in HCC have not been elucidated.

Methods: Differentially expressed gene analysis, Cox regression, and unsupervised consensus clustering were applied to identify crucial ferroptosis regulators and establish ferroptosis-related subtypes in HCC. Random forest analysis and survival analysis were adopted to confirm FTL as the hub prognostic and diagnostic ferroptosis regulator in HCC.

Results: The ferroptosis-related subtypes based on the crucial prognostic ferroptosis regulators showed that patients in fescluster A had a higher survival probability (p < 0.001) and better clinical characteristics than patients in fescluster B in the TCGA-LIHC cohort. Patients with a high tumor mutation burden (TMB) in fescluster B presented a significantly poorer prognosis. FTL was the core ferroptosis regulator, and its low expression revealed a significant survival advantage compared with its high expression (p = 0.03). The expression and predictive value of FTL were both closely related to the clinical features (p < 0.05). Expression of FTL accurately distinguished HCC from normal tissues in the TCGA-LIHC cohort, ICGC cohort, and GSE14520 dataset. In addition, higher infiltrating fractions of immune cells, such as activated CD8+ T cells and Gamma delta T cells, mainly enriched immune-related signaling pathways, including the IL2-STAT3 signaling pathway and interferon-gamma response signaling pathway, and higher expression of immune checkpoints, including PDCD1, CTLA4, TIGIT, and CD83, were presented in patients with high FTL expression (p < 0.05). Patients with high FTL were more sensitive to some targeted drugs, such as cisplatin, dasatinib, and sorafenib, than those with low FTL (p < 0.05). A nomogram based on FTL accurately predicted the prognosis of HCC. Further knockdown of FTL was determined to significantly inhibit cell proliferation and migration in HCC.

Conclusion: Our study validated ferroptosis-related subtypes and FTL with effective prognostic value in HCC and was beneficial for identifying candidates suitable for targeted drug therapy and immunotherapy, thereby offering further insight into individual treatment strategies to improve disease outcomes in HCC patients.
Identifying Functions of Proteins in Mice With Functional Embedding Features
Authors: Li Hao , Zhang ShiQi , Chen Lei , Pan Xiaoyong , Li ZhanDong , Huang Tao , Cai Yu-Dong
Published: May 2022

In current biology, exploring the biological functions of proteins is important. Given the large number of proteins in some organisms, exploring their functions one by one through traditional experiments is impossible. Therefore, developing quick and reliable methods for identifying protein functions is necessary. Considerable accumulation of protein knowledge and recent developments on computer science provide an alternative way to complete this task, that is, designing computational methods. Several efforts have been made in this field. Most previous methods have adopted the protein sequence features or directly used the linkage from a protein–protein interaction (PPI) network. In this study, we proposed some novel multi-label classifiers, which adopted new embedding features to represent proteins. These features were derived from functional domains and a PPI network via word embedding and network embedding, respectively. The minimum redundancy maximum relevance method was used to assess the features, generating a feature list. Incremental feature selection, incorporating RAndom k-labELsets to construct multi-label classifiers, used such list to construct two optimum classifiers, corresponding to two key measurements: accuracy and exact match. These two classifiers had good performance, and they were superior to classifiers that used features extracted by traditional methods.
Conservation and Diversity of miR166 Family Members From Highbush Blueberry (Vaccinium corymbosum) and Their Potential Functions in Abiotic Stress
Authors: Li Yuening , Wang Xianglong , Guo Qingxun , Zhang Xinsheng , Zhou Lianxia , Zhang Yang , Zhang Chunyu
Published: May 2022

MicroRNA166 (miR166) is highly conserved and has diverse functions across plant species. The highbush blueberry (Vaccinium corymbosum) genome is thought to harbor 10 miRNA166 loci (Vco-miR166), but the extent of their evolutionary conservation or functional diversification remains unknown. In this study, we identified six additional Vco-miR166 loci based on conserved features of the miR166 family. Phylogenetic analyses showed that mature Vco-miR166s and their precursor cluster in several clades are evolutionary conserved with diverse species. The cis-regulatory elements in the Vco-miR166 promoters indicated functions related to different phytohormones and defense responses. We also identified putative targets of vco-miR166s, which targeted the same gene families, suggesting the functional conservation and diversification of Vco-miR166 family members. Furthermore, we examined the accumulation patterns of six mature Vco-miR166s in response to abiotic stresses by stem-loop reverse RT-qPCR, which revealed their upregulation under freezing, cold, and heat stress, while they were downregulated by drought compared to control growth conditions. However, Vco-miR166 members showed different expression patterns when exposed to salt stress. These results showed that conserved Vco-miR166 family members display functional diversification but also coordinately influence plant responses to abiotic stress.
Microglia in the Neuroinflammatory Pathogenesis of Alzheimer’s Disease and Related Therapeutic Targets
Authors: Cai Yongle , Liu Jingliu , Wang Bin , Sun Miao , Yang Hao
Published: May 2022

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide, characterized by progressive neuron degeneration or loss due to excessive accumulation of β-amyloid (Aβ) peptides, formation of neurofibrillary tangles (NFTs), and hyperphosphorylated tau. The treatment of AD has been only partially successful as the majority of the pharmacotherapies on the market may alleviate some of the symptoms. In the occurrence of AD, increasing attention has been paid to neurodegeneration, while the resident glial cells, like microglia are also observed. Microglia, a kind of crucial glial cells associated with the innate immune response, functions as double-edge sword role in CNS. They exert a beneficial or detrimental influence on the adjacent neurons through secretion of both pro-inflammatory cytokines as well as neurotrophic factors. In addition, their endocytosis of debris and toxic protein like Aβ and tau ensures homeostasis of the neuronal microenvironment. In this review, we will systematically summarize recent research regarding the roles of microglia in AD pathology and latest microglia-associated therapeutic targets mainly including pro-inflammatory genes, anti-inflammatory genes and phagocytosis at length, some of which are contradictory and controversial and warrant to further be investigated.
Hyper-IgE and Carcinoma in CADINS Disease
Authors: Pietzsch Leonora , Körholz Julia , Boschann Felix , Sergon Mildred , Dorjbal Batsukh , Yee Debra , Gilly Vanessa , Kämmerer Eva , Paul Diana , Kastl Clemens , Laass Martin W. , Berner Reinhard , Jacobsen Eva Maria , Roesler Joachim , Aust Daniela , Lee-Kirsch Min A. , Snow Andrew L. , Schuetz Catharina
Published: May 2022

Background

Atopic dermatitis (AD) affects up to 25% of children and 10% of adults in Western countries. When severe or recurrent infections and exceedingly elevated serum IgE levels occur in AD patients, an inborn error of immunity (IEI) may be suspected. The International Union of Immunological Societies classification lists variants in different genes responsible for so-called Hyper-IgE syndromes. Diagnosing an underlying IEI may influence treatment strategies.

Methods

Clinical and diagnostic workup of family members are presented including a detailed immunological description and histology of the carcinoma. Functional testing of the novel variant in CARD11 underlying ‘CARD11-associated atopy with dominant interference of NF-kB signaling’ (CADINS) was performed.

Results

We report on an 18-year-old patient with a long-standing history of infections, accompanied by hypogammaglobulinemia, intermittent agranulocytosis, atopy, eosinophilia and colitis. The working diagnosis of common variable immunodeficiency was revised when a novel heterozygous CARD11 variant [c.223C>T; p.(Arg75Trp)] was identified. Functional studies confirmed this variant to have a dominant negative (DN) effect, as previously described in patients with CADINS. Five other family members were affected by severe atopy associated with the above variant, but not hypogammaglobulinemia. Malignancies occurred in two generations: an HPV-positive squamous cell carcinoma and a cutaneous T-cell lymphoma. So far, one patient is under treatment with dupilumab, which has shown marked benefit in controlling severe eczema.

Conclusion

The phenotypic spectrum associated with heterozygous CARD11 DN mutations is broad. Partial T-cell deficiency, diminished IFN-γ cytokine and increased IL-4 production, were identified as disease-causing mechanisms. Malignant disease associated with germline CARD11 DN variants has only been reported sporadically. HPV vaccination in teenage years, and cytology screening analogous with routine cervical swabs may be recommended. Treatment with dupilumab, a monoclonal antibody blocking interleukin-4- and interleukin-13 signaling, may be of benefit in controlling severe and extended AD for some patients as reported for STAT3 loss-of-function.
Granulocyte Colony-Stimulating Factor Accelerates the Recovery of Hepatitis B Virus-Related Acute-on-Chronic Liver Failure by Promoting M2-Like Transition of Monocytes
Authors: Tong Jingjing , Wang Hongmin , Xu Xiang , Wan Zhihong , Fang Hongbin , Chen Jing , Mu Xiuying , Liu Zifeng , Chen Jing , Su Haibin , Liu Xiaoyan , Li Chen , Huang Xiaowen , Hu Jinhua
Published: May 2022

Background and Aim

Acute-on-chronic liver failure (ACLF) has a high mortality rate. The role of granulocyte colony-stimulating factor (G-CSF) in ACLF remains controversial. Monocytes/macrophages are core immune cells, which are involved in the initiation and progression of liver failure; however, the effect of G-CSF on monocytes/macrophages is unclear. The study aimed to verify the clinical efficacy of G-CSF and explore the effect of it on monocytes in hepatitis B virus (HBV)-related ACLF (HBV-ACLF) paitents.

Methods

We performed a large randomized controlled clinical trial for the treatment of HBV-ACLF using G-CSF. A total of 111 patients with HBV-ACLF were prospectively randomized into the G-CSF group (5 μg/kg G-CSF every day for 6 days, then every other day until day 18) or the control group (standard therapy). All participants were followed up for at least 180 days. The relationship between monocyte count and mortality risk was analyzed. The effect of G-CSF on the phenotype and function of monocytes from patients with HBV-ACLF was evaluated using flow cytometry in vivo and in vitro experiments.

Results

The survival probability of the G-CSF group at 180 days was higher than that of the control group (72.2% vs. 53.8%, P = 0.0142). In the G-CSF-treated group, the monocyte counts on days 0 and 7 were independently associated with an evaluated mortality risk in the fully adjusted model (Model 3) [at day 0: hazard ratio (HR) 95% confidence interval (CI): 15.48 (3.60, 66.66), P = 0.0002; at day 7: HR (95% CI): 1.10 (0.50, 2.43), P=0.8080]. Further analysis showed that after treatment with G-CSF in HBV-ACLF patients, the expression of M1-like markers (HLA-DR and CD86) in monocytes decreased (HLA-DR: P = 0.0148; CD86: P = 0.0764). The expression of MerTK (M2-like marker) increased (P = 0.0002). The secretion of TNF-α, IL-6, and IL-10 from monocytes decreased without lipopolysaccharide (LPS) stimulation (TNF-α: P < 0.0001; IL-6: P= 0.0025; IL-10: P = 0.0004) or with LPS stimulation (TNF-α: P = 0.0439; P = 0.0611; IL-10: P = 0.0099). Similar effects were observed in vitro experiments.

Conclusion

G-CSF therapy confers a survival benefit to patients with HBV-ACLF. G-CSF can promote the anti-inflammatory/pro-restorative phenotype (M2-like) transition of monocytes, which may contribute to the recovery of ACLF.

Clinical Trial Registration Number

ClinicalTrials.gov, identifier (NCT02331745).
Safety and Efficacy of PD-1/PD-L1 Inhibitors in Cancer Patients With Preexisting Autoantibodies
Authors: Tang Hui , Geng Ruixuan , Xu Xiuxiu , Wang Yingyi , Zhou Jiaxin , Zhang Shulan , Zhao Lin , Guan Mei , Bai Chunmei
Published: May 2022

Background

Programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors therapy is now a routine scheme in cancers. However, the effect of preexisting autoantibodies on the safety and efficacy of PD-1/PD-L1 inhibitors in cancer patients is not well understood.

Methods

The present retrospective cohort study evaluated the safety and efficacy of PD-1/PD-L1 inhibitors in patients with preexisting autoantibodies. Patients who received PD-1/PD-L1 inhibitors in the Department of Medical Oncology, Peking Union Medical College Hospital between November 2017 and August 2021 were reviewed.

Results

67 (37.9%) of the 177 patients, 27 (20.3%) of the 133 patients, and 16 (11.0%) of 146 patients who received PD-1/PD-L1 inhibitors were positive for ANA, anti-Ro52, and antithyroid antibodies, respectively. Preexisting ANA and anti-Ro52 antibody were not associated with the increased risk of immune-related adverse events (irAEs), while thyroid dysfunction was more frequent in patients with positive antithyroid antibody (75.0% versus 13.8%, p < 0.001). The median progression-free survival (PFS, 13.1 versus 7.0 months, p = 0.015) was significantly longer in the ANA-positive patients, while the median overall survival (OS, 14.5 versus 21.8 months, p = 0.67) did not differ significantly between the ANA-positive and ANA-negative groups. Moreover, the preexisting anti-Ro52 and antithyroid antibodies were not significantly associated with PFS and OS.

Conclusions

The presence of ANA and anti-Ro52 antibody were not associated with a higher risk of irAEs, whereas patients positive for antithyroid antibody should monitor closely immune-related thyroid dysfunction. Preexisting ANA might be a predictor of longer PFS, while anti-Ro52 and antithyroid antibodies had no significant effect on survival outcomes in patients receiving PD-1/PD-L1 inhibitors therapy.
All About (NK Cell-Mediated) Death in Two Acts and an Unexpected Encore: Initiation, Execution and Activation of Adaptive Immunity
Authors: Ramírez-Labrada Ariel , Pesini Cecilia , Santiago Llipsy , Hidalgo Sandra , Calvo-Pérez Adanays , Oñate Carmen , Andrés-Tovar Alejandro , Garzón-Tituaña Marcela , Uranga-Murillo Iratxe , Arias Maykel A. , Galvez Eva M. , Pardo Julián
Published: May 2022

NK cells are key mediators of immune cell-mediated cytotoxicity toward infected and transformed cells, being one of the main executors of cell death in the immune system. NK cells recognize target cells through an array of inhibitory and activating receptors for endogenous or exogenous pathogen-derived ligands, which together with adhesion molecules form a structure known as immunological synapse that regulates NK cell effector functions. The main and best characterized mechanisms involved in NK cell-mediated cytotoxicity are the granule exocytosis pathway (perforin/granzymes) and the expression of death ligands. These pathways are recognized as activators of different cell death programmes on the target cells leading to their destruction. However, most studies analyzing these pathways have used pure recombinant or native proteins instead of intact NK cells and, thus, extrapolation of the results to NK cell-mediated cell death might be difficult. Specially, since the activation of granule exocytosis and/or death ligands during NK cell-mediated elimination of target cells might be influenced by the stimulus received from target cells and other microenvironment components, which might affect the cell death pathways activated on target cells. Here we will review and discuss the available experimental evidence on how NK cells kill target cells, with a special focus on the different cell death modalities that have been found to be activated during NK cell-mediated cytotoxicity; including apoptosis and more inflammatory pathways like necroptosis and pyroptosis. In light of this new evidence, we will develop the new concept of cell death induced by NK cells as a new regulatory mechanism linking innate immune response with the activation of tumour adaptive T cell responses, which might be the initiating stimulus that trigger the cancer-immunity cycle. The use of the different cell death pathways and the modulation of the tumour cell molecular machinery regulating them might affect not only tumour cell elimination by NK cells but, in addition, the generation of T cell responses against the tumour that would contribute to efficient tumour elimination and generate cancer immune memory preventing potential recurrences.
Seasonal Distribution of the Fin Whale (Balaenoptera physalus) in Antarctic and Australian Waters Based on Passive Acoustics
Authors: Aulich Meghan G. , McCauley Robert D. , Miller Brian S. , Samaran Flore , Giorli Giacomo , Saunders Benjamin J. , Erbe Christine
Published: May 2022

The fin whale is listed as globally vulnerable, with ongoing threats to their population, yet little is known about the distribution and movements of the Southern Hemisphere sub-species, Balaenoptera physalus quoyi. This study assesses fin whale distribution in the Southern Hemisphere analysing acoustic recordings from 15 locations in Antarctic and Australian waters from 2002 to 2019. A seasonal acoustic presence of fin whales in Antarctic waters from late austral summer to autumn (February to June) with long-term, consistent annual usage areas was identified at the Southern Kerguelen Plateau and Dumont d’Urville sites. In comparison, limited vocal presence of fin whales was observed at the Casey site. In Australian waters, fin whales were seasonally present from austral autumn to mid-spring (May to October) on east and west coasts, with a decadal pattern of acoustic presence observed at Cape Leeuwin, WA. Two migratory pathways are identified, from the Indian sector of Antarctica to the west coast of Australia and from the Pacific sector of Antarctica to the east coast of Australia. The identified seasonal distributions and migratory pathways provide valuable information to aid in monitoring the recovery of this vulnerable sub-species. We suggest the identified distribution and dispersal from the Southern Kerguelen Plateau and Dumont d’Urville sites to the west and east coasts of Australia respectively, as well as the spatial separation between Antarctic sites, provide preliminary evidence of separate sub-populations of the Southern Hemisphere sub-species of fin whale.
Seasonal, Annual, and Decadal Distribution of Three Rorqual Whale Species Relative to Dynamic Ocean Conditions Off Oregon, USA
Authors: Derville S. , Barlow D. R. , Hayslip C. , Torres L. G.
Published: May 2022

Whale populations recovering from historical whaling are particularly vulnerable to incidental mortality and disturbance caused by growing ocean industrialization. Several distinct populations of rorqual whales (including humpback, blue, and fin whales) migrate and feed off the coast of Oregon, USA where spatial overlap with human activities are on the rise. Effective mitigation of conflicts requires better foundational understanding of spatial and temporal habitat use patterns to inform conservation management. Based on a year-round, multi-platform distance sampling dataset (2016-2021, 177 survey days, 754 groups observed), this study generated density models to describe and predict seasonal distribution of rorqual whales in Oregon. Phenology analysis of sightings revealed a peak of humpback whale and blue whale density over the Oregon continental shelf in August and September respectively, and higher fin whale density in the winter (December). Additionally, we compared rorqual sighting rates across three decades of survey effort (since 1989) and demonstrate that rorqual whales are strikingly more prevalent in the current dataset, including distinct increases of blue and fin whales. Finally, density surface models relating whale densities to static and dynamic environmental variables acquired from data-assimilative ocean models revealed that summer and spring rorqual distribution were influenced by dynamic oceanographic features indicative of active upwelling and frontal zones (respectively 27% and 40% deviance explained). On the continental shelf, blue whales were predicted to occur closer to shore than humpback whales and in the more southern waters off Oregon. Summer and spring rorqual models, and humpback whale models, showed predictive performance suitable for management purposes, assessed through internal cross-validation and comparison to an external dataset (388 groups observed). Indeed, monthly hotspots of high predicted rorqual whale density across multiple years were validated by independent sightings (80% overlap in the summer model). These predictive models lay a robust basis for fine-scale dynamic spatial management to reduce impacts of human activities on endangered populations of rorqual whales in Oregon.
Accelerated Design of High γ′ Solvus Temperature and Yield Strength Cobalt-Based Superalloy Based on Machine Learning and Phase Diagram
Authors: Wang Cuiping , Chen Xin , Chen Yuechao , Yu Jinxin , Cai Wensu , Chen Zhongfeng , Yu Xiang , Li Yingju , Yang Yuansheng , Liu Xingjun
Published: May 2022

This study combines machine learning and a phase diagram to accelerate the design of a cobalt-based superalloy with a composition of Co-30Ni-10Al-6Ta (at%). The results show that Co-30Ni-10Al-6Ta alloy exhibits high γ′ solvus temperature (1,215 °C) and high yield strength (1,220 Mpa at 25 °C), which is comparable with commercial nickel-based polycrystalline superalloy M-Mar-247. Moreover, the wide processing window and excellent γ′ phase stability make it lucrative for further applications at high temperatures. Meanwhile, the alloy design method also provides a new idea for efficiently realizing the preparation of high-performance alloys.
Association of Myopia With Risk of Incident Metabolic Syndrome: Findings From the UK Biobank Study Cohort of 91,591 Participants
Authors: Chen Yanxian , Zhu Zhuoting , Wang Wei , Shang Xianwen , He Mingguang , Li Jinying
Published: May 2022

Purpose

To investigate the association between myopia and risk of metabolic syndrome (MetS) in a prospective cohort from the UK Biobank Study.

Methods

Volunteers (aged 40 years and above) free of baseline MetS and cataract included from the UK Biobank Study, a prospective follow-up cohort. Myopia was defined using uncycloplegic autorefraction, self-report-myopia, and medical records for refractive error at baseline. MetS as well as components of MetS were diagnosed based on health records, blood biochemistry, and questionnaires. Questionnaires determined the status of smoking, drinking, physical activity and dietary supplements, as well as ethnicity and education.

Results

A total of 91,591 participants were available in the analysis, with a mean age of 55.37 ± 8.07 years at baseline and a median follow-up years of 11.16 years. The proportion of myopia was 49.7%, and a total of 937 (1.0%) participants were identified as having incident MetS (0.09/100 person years). Subjects with myopia were more likely to have MetS compared with non-myopic subjects (0.82 vs. 0.21%, Log-rank testP< 0.001). Mopes had greater risk of incident MetS (Hazard ratio [HR] = 4.19, 95% confidence interval [CI] 3.57–4.93,P< 0.001) adjusting for baseline age, gender, education and ethnicity. After further controlling for lifestyle factors (smoking, drinking, physical activity, and fish oil supplement) or baseline metabolic disorders, the risk of incident MetS were 3.88- and 4.06-fold greater in myopic subjects than those without myopia, respectively (P< 0.001 for both models). The severity of myopia was not significantly correlated to incident MetS in multivariate-adjusted models.

Conclusions

An increased risk of incident MetS among the elderly is associated with myopia, but not the degree of myopia. These findings highlighted the need of prevention of MetS among older adults with myopia.