bluuebunny/crossref_metadata_2025 huggingface dataset:
Interdisciplinary Blockchain Education: Utilizing Blockchain Technology From Various Perspectives
Authors: Düdder Boris , Fomin Vladislav , Gürpinar Tan , Henke Michael , Iqbal Mubashar , Janavičienė Viktorija , Matulevičius Raimundas , Straub Natalia , Wu Haiqin
Published: January 2021

The early development of blockchain technology (BCT) has already demonstrated the technology's potential to serve the needs of different industries. BCT has also become established as a popular research topic in different scientific disciplines. This paper aims at introducing how several relevant scientific disciplines—supply chain management; management, economics and finance; computer science; security engineering—see the research and education perspectives for BCT. A field review is conducted to present challenges and opportunities of BCT, as well as suggestions for future research and education on the topic as seen from the selected different perspectives. The paper also presents methods for combining relevant disciplines in a modular online course to address the stated challenges and promote interdisciplinary blockchain education.
MICAL-L2 Is Essential for c-Myc Deubiquitination and Stability in Non-small Cell Lung Cancer Cells
Authors: Min Pengxiang , Zhang Lin , Wang Yueyuan , Qi Chenxiang , Song Yixuan , Bibi Maria , Zhang Yujie , Ma Yadong , Zhao Xuyang , Yu Minjie , Du Jun
Published: January 2021

Objectives: MICAL-L2, a member of the molecules interacting with the CasL (MICAL) family, was reported to be highly expressed in several types of cancers, however, the roles of MICAL-L2 in NSCLC pathogenesis remain to be explored. This study is designed to clarify the mechanisms by which MICAL-L2 participates in NSCLC cell proliferation.

Materials and Methods: The expression levels of MICAL-L2 in human lung cancer samples were assessed by immunohistochemical staining. Cells were transfected with siRNA or plasmids to regulate MICAL-L2 expression. Cell proliferation was measured by EdU staining and CCK-8 assays. MICAL-L2 and phosphorylated/total c-Myc expression were examined by Western blotting analysis. Interaction between MICAL-L2 and c-Myc was assessed by immunofluorescence staining, Western blotting and co-immunoprecipitation assays. Western blotting, polyubiquitylation detection and protein stability assays were used to assess whether MICAL-L2 exerts its oncogenic effect via c-Myc.

Results: We found that MICAL-L2 was highly expressed in human NSCLC. While overexpressing MICAL-L2 increased NSCLC cell proliferation, MICAL-L2 depletion decreased the proliferation of NSCLC cells, an effect that was linked to cell cycle arrest. MICAL-L2 physically interacted with the c-Myc protein and functioned to maintain nuclear c-Myc levels and prolonged its half-life. Knockdown of MICAL-L2 expression led to decreased c-Myc protein stability through accelerating polyubiquitylation of c-Myc and gave rise to c-Myc degradation. We further found that MICAL-L2 deubiquitinated c-Myc and blocked its degradation, presumably by inhibiting c-Myc phosphorylation at threonine residue 58.

Conclusions: These results indicate that MICAL-L2 is a key regulator of c-Myc deubiquitination and stability in the nucleus, and this activity may be involved in promoting NSCLC cell proliferation.
Role of Fibroblast Growth Factor 23 (FGF23) and αKlotho in Cancer
Authors: Ewendt Franz , Feger Martina , Föller Michael
Published: January 2021

Together with fibroblast growth factors (FGFs) 19 and 21, FGF23 is an endocrine member of the family of FGFs. Mainly secreted by bone cells, FGF23 acts as a hormone on the kidney, stimulating phosphate excretion and suppressing formation of 1,25(OH)2D3, active vitamin D. These effects are dependent on transmembrane protein αKlotho, which enhances the binding affinity of FGF23 for FGF receptors (FGFR). Locally produced FGF23 in other tissues including liver or heart exerts further paracrine effects without involvement of αKlotho. Soluble Klotho (sKL) is an endocrine factor that is cleaved off of transmembrane Klotho or generated by alternative splicing and regulates membrane channels, transporters, and intracellular signaling including insulin growth factor 1 (IGF-1) and Wnt pathways, signaling cascades highly relevant for tumor progression. In mice, lack of FGF23 or αKlotho results in derangement of phosphate metabolism and a syndrome of rapid aging with abnormalities affecting most organs and a very short life span. Conversely, overexpression of anti-aging factor αKlotho results in a profound elongation of life span. Accumulating evidence suggests a major role of αKlotho as a tumor suppressor, at least in part by inhibiting IGF-1 and Wnt/β-catenin signaling. Hence, in many malignancies, higher αKlotho expression or activity is associated with a more favorable outcome. Moreover, also FGF23 and phosphate have been revealed to be factors relevant in cancer. FGF23 is particularly significant for those forms of cancer primarily affecting bone (e.g., multiple myeloma) or characterized by bone metastasis. This review summarizes the current knowledge of the significance of FGF23 and αKlotho for tumor cell signaling, biology, and clinically relevant parameters in different forms of cancer.
The Lung Vasculature: A Driver or Passenger in Lung Branching Morphogenesis?
Authors: Kina Yelda Pakize , Khadim Ali , Seeger Werner , El Agha Elie
Published: January 2021

Multiple cellular, biochemical, and physical factors converge to coordinate organogenesis. During embryonic development, several organs such as the lung, salivary glands, mammary glands, and kidneys undergo rapid, but intricate, iterative branching. This biological process not only determines the overall architecture, size and shape of such organs but is also a pre-requisite for optimal organ function. The lung, in particular, relies on a vast surface area to carry out efficient gas exchange, and it is logical to suggest that airway branching during lung development represents a rate-limiting step in this context. Against this background, the vascular network develops in parallel to the airway tree and reciprocal interaction between these two compartments is critical for their patterning, branching, and co-alignment. In this mini review, we present an overview of the branching process in the developing mouse lung and discuss whether the vasculature plays a leading role in the process of airway epithelial branching.
Comparison of the Gut Microbiota Disturbance in Rat Models of Irritable Bowel Syndrome Induced by Maternal Separation and Multiple Early-Life Adversity
Authors: Enqi Wu , Jingzhu Song , Lingpeng Pei , Yaqin Ling
Published: January 2021

Background

The study aimed to identify the effects of modeling procedures on bacterial communities and to investigate whether different modeling procedures lead to consistent patterns of gut microbiome compositions.

Methods

Two irritable bowel syndrome (IBS) rat models maternal separation (MS) alone and multiple-early-adversity modeling (MAM) were established and the gut microbiome were analyzed using 16S-rRNA-based high-throughput sequencing methods.

Results

Rats from both models exhibited visceral hypersensitivity and the two model groups exhibited differences in the extent of visceral sensitivity and fecal water content. The microbial community structure of the two models exhibited significant differences compared to the controls, while the two model groups also exhibited significant differences between them. Furthermore, microbial community functional predictions suggested that the two models exhibited different abundances of metabolisms and pathways. Several common and distinct characteristic differences were also observed between the two model groups. Alloprevotella were more abundant in both model groups, while Butyricicoccus, Turicibacter, Ruminococcus, and Clostridium_sensu_stricto along with the family it belongs to were less abundant relative to controls. In addition, the abundance of Clostridium_IV, Corynebacterium, Rothia, Elusimicrobium, Romboutsia, Allobaculum, Parasutterella, and their related taxa were specifically associated with MS group, whereas Butyricimonas and Vampirovibrio along with its related taxa were specifically associated with MAM group. Among those, Butyricimonas, Butyricicoccus and Corynebacterium were found to partially mediate early adversity exposure-induced visceral hypersensitivity.

Conclusions

Our results highlight the importance in evaluating gut microbiota characteristics in IBS research while also systematically considering potential modeling procedural differences. The microbial compositional/functional differences identified in this study were suggestive to further investigation of mechanisms of early adversity induced IBS.
(−)-Epigallocatechin-3-Gallate Inhibits the Life Cycle of Pseudorabies Virus In Vitro and Protects Mice Against Fatal Infection
Authors: Huan Changchao , Xu Weiyin , Guo Tingting , Pan Haochun , Zou Hengyue , Jiang Luyao , Li Chengmin , Gao Song
Published: January 2021

A newly emerged pseudorabies virus (PRV) variant with enhanced pathogenicity has been identiﬁed in many PRV-vaccinated swine in China since 2011. The PRV variant has caused great economic cost to the swine industry, and measures for the effective prevention and treatment of this PRV variant are still lacking. (–)-Epigallocatechin-3-gallate (EGCG) exhibits antiviral activity against diverse viruses and thus in this study, we investigated the anti-PRV activity of EGCG in vitro and in vivo. EGCG significantly inhibited infectivity of PRV Ra and PRV XJ5 strains in PK15 B6 cells and Vero cells. The anti-PRV activity of EGCG was dose-dependent, and 50 μM EGCG could completely block viral infection at different multiplicities of infection. We next revealed that EGCG blocked PRV adsorption and entry to PK15 B6 cells in a dose-dependent manner, but inhibition of PRV entry by EGCG was not as efficient as its inhibition of PRV adsorption. PRV replication was suppressed in PK15 B6 cells treated with EGCG post-infection. However, EGCG did not affect PRV assembly and could promote PRV release. Furthermore, 40 mg/kg EGCG provided 100% protection in BALB/c mice challenged with PRV XJ5, when EGCG was administrated both pre- and post-challenge. These results revealed that EGCG exhibits antiviral activity against PRV mainly by inhibiting virus adsorption, entry and replication in vitro. Meanwhile, EGCG increased the survival of mice challenged with PRV. Therefore, EGCG might be a potential antiviral agent against PRV infection.
Comparison of Experimental Rat Models in Donation After Circulatory Death (DCD): in-situ vs. ex-situ Ischemia
Authors: Arnold Maria , Méndez-Carmona Natalia , Wyss Rahel K. , Joachimbauer Anna , Casoni Daniela , Carrel Thierry , Longnus Sarah
Published: January 2021

Introduction: Donation after circulatory death (DCD) could substantially improve donor heart availability. However, warm ischemia prior to procurement is of particular concern for cardiac graft quality. We describe a rat model of DCD with in-situ ischemia in order to characterize the physiologic changes during the withdrawal period before graft procurement, to determine effects of cardioplegic graft storage, and to evaluate the post-ischemic cardiac recovery in comparison with an established ex-situ ischemia model.

Methods: Following general anesthesia in male, Wistar rats (404 ± 24 g, n = 25), withdrawal of life-sustaining therapy was simulated by diaphragm transection. Hearts underwent no ischemia or 27 min in-situ ischemia and were explanted. Ex situ, hearts were subjected to a cardioplegic flush and 15 min cold storage or not, and 60 min reperfusion. Cardiac recovery was determined and compared to published results of an entirely ex-situ ischemia model (n = 18).

Results: In donors, hearts were subjected to hypoxia and hemodynamic changes, as well as increased levels of circulating catecholamines and free fatty acids prior to circulatory arrest. Post-ischemic contractile recovery was significantly lower in the in-situ ischemia model compared to the ex-situ model, and the addition of cardioplegic storage improved developed pressure-heart rate product, but not cardiac output.

Conclusion: The in-situ model provides insight into conditions to which the heart is exposed before procurement. Compared to an entirely ex-situ ischemia model, hearts of the in-situ model demonstrated a lower post-ischemic functional recovery, potentially due to systemic changes prior to ischemia, which are partially abrogated by cardioplegic graft storage.
Seafloor Pressure Change Excited at the Northwest Corner of the Shikoku Basin by the Formation of the Kuroshio Large-Meander in September 2017
Authors: Nagano Akira , Yamashita Yusuke , Ariyoshi Keisuke , Hasegawa Takuya , Matsumoto Hiroyuki , Shinohara Masanao
Published: January 2021

The Kuroshio takes a greatly southward displaced path called a large-meander (LM) path off the southern coast of Japan on interannual to decadal time scales. The transition of the current path from a non-large-meander path to an LM path is the most salient ocean current variation south of Japan. The change in pressure on the seafloor due to the formation of the LM path in September 2017 is of critical importance to understand the dynamics of the LM path and to distinguish the change due to the Kuroshio path variation from changes due to crustal deformation. Hence, we examined the seafloor pressure across the continental slope off the eastern coast of Kyushu for the period March 2014 to April 2019. The pressure and its cross-slope gradient over the continental slope shallower than 3,000 m beneath near the Kuroshio are invariable. As a mesoscale current path disturbance, called a small meander, passed over the observation stations, the pressure decreased by approximately 0.1 dbar on the continental slope deeper than 3000 m and was kept low until the end of the observation period (April 2019). The pressure decrease is consistent with the changes in sea surface height and subsurface water density and is caused by the baroclinic enhancement of the Shikoku Basin local recirculation. This seafloor pressure change implies a strengthening of the deep southwestward current, possibly as a part of a deep cyclonic circulation in the Shikoku Basin. The present study demonstrated that, in addition to altimetric sea surface height data, hydrographic data are useful to distinguish the ocean variation in seafloor pressure from the variation due to crustal deformation, and vice versa.
Using Machine Learning to Make Computationally Inexpensive Projections of 21st Century Stratospheric Column Ozone Changes in the Tropics
Authors: Keeble James , Yiu Yu Yeung Scott , Archibald Alexander T. , O’Connor Fiona , Sellar Alistair , Walton Jeremy , Pyle John A.
Published: January 2021

Stratospheric ozone projections in the tropics, modeled using the UKESM1 Earth system model, are explored under different Shared Socioeconomic Pathways (SSPs). Consistent with other studies, it is found that tropical stratospheric column ozone does not return to 1980s values by the end of the 21st century under any SSP scenario as increased ozone mixing ratios in the tropical upper stratosphere are offset by continued ozone decreases in the tropical lower stratosphere. Stratospheric column ozone is projected to be largest under SSP scenarios with the smallest change in radiative forcing, and smallest for SSP scenarios with larger radiative forcing, consistent with a faster Brewer-Dobson circulation at high greenhouse gas loadings. This study explores the use of machine learning (ML) techniques to make accurate, computationally inexpensive projections of tropical stratospheric column ozone. Four ML techniques are investigated: Ridge regression, Lasso regression, Random Forests and Extra Trees. All four techniques investigated here are able to make projections of future tropical stratospheric column ozone which agree well with those made by the UKESM1 Earth system model, often falling within the ensemble spread of UKESM1 simulations for a broad range of SSPs. However, all techniques struggle to make accurate projects for the final decades of the SSP5-8.5 scenario. Accurate projections can only be achieved when the ML methods are trained on sufficient data, including both historical and future simulations. When trained only on historical data, the projections made using models based on ML techniques fail to accurately predict tropical stratospheric ozone changes. Results presented here indicate that, when sufficiently trained, ML models have the potential to make accurate, computationally inexpensive projections of tropical stratospheric column ozone. Further development of these models may reduce the computational burden placed on fully coupled chemistry-climate and Earth system models and enable the exploration of tropical stratospheric column ozone recovery under a much broader range of future emissions scenarios.
Triple Water Vapour–Isotopologues Record from Chhota Shigri, Western Himalaya, India: A Unified Interpretation based on δ17O, δ18O, δD and Comparison to Meteorological Parameters
Authors: Ranjan S. , Ramanathan AL. , Keesari Tirumalesh , Singh Virendra B. , Kumar Naveen , Pandey Manish , Leuenberger Markus C.
Published: January 2021

The objective of this study is to investigate and understand the source and transportation of water vapour in the western Himalayan region—that is still missing—using water vapour stable isotopologues and air mass trajectory diagnostics. We report the first-time triple oxygen isotopic compositions of water vapour from high altitude western Himalaya (Chhota Shigri, India) and compare them with meteorological conditions at the site of investigation as well as tracked backwards through the Lagrangian air mass trajectory diagnostics. A total of 21 water vapour samples were collected using a quantitative cryogenic method. δ17O and δ18O values show a significant correlation coefficient of 0.999 (p <0.01). The temporal variations of δ17O, δ18O, δD, D-excess and 17O-excess are 1.2, 2.3, 17.3, 11.6 and 39‰ permeg, respectively. δ17O and δ18O exhibit significant (p < 0.05) diurnal variations along with meteorological parameters. Chhota Shigri vapour isotopic results show a clear difference in the 17O-excess value compared to near the south Indian Ocean and the Southern Ocean regions, reflecting the influence of local moisture recycling at the continental site. NCEP/NCAR reanalyses show lower Specific Humidity during the sampling period (September, ending month of the Indian summer monsoon) favouring evaporative conditions which are further corroborated through the Lagrangian moisture diagnostics suggesting frequent moisture uptake and moisture loss in specific regions.
Earthquake Analysis Suggests Dyke Intrusion in 2019 Near Tarawera Volcano, New Zealand
Authors: Benson Thomas W. , Illsley-Kemp Finnigan , Elms Hannah C. , Hamling Ian J. , Savage Martha K. , Wilson Colin J. N. , Mestel Eleanor R. H. , Barker Simon J.
Published: January 2021

Tarawera volcano (New Zealand) is volumetrically dominated by rhyolitic lavas and pyroclastic deposits, but the most recent event in AD 1886 was a basaltic Plinian fissure eruption. In March 2019 a swarm of at least 64 earthquakes occurred to the NE of Tarawera volcano, as recorded by the New Zealand Geohazard Monitoring Network (GeoNet). We use seismological analysis to show that this swarm was most likely caused by a dyke that intruded into the brittle crust between depths of 8–10 km and propagated toward Tarawera volcano for 2 km at a rate of 0.3–0.6 m s−1. We infer that this was a dyke of basaltic composition that was stress-guided toward Tarawera volcano by the topographic load of the volcanic edifice. Dyke intrusions of this nature are most likely a common occurrence but a similar process may have occurred during the 1886 eruption with a dyke sourced from some lateral distance away from the volcano. The 2019 intrusion was not detected by InSAR geodesy and we use synthetic models to show that geodetic monitoring could only detect a ≥6 m wide dyke at these depths. Improvements to geodetic monitoring, combined with detailed seismological analysis, could better detect future magmatic intrusions in the region and serve to help assess ongoing changes in the magmatic system and the associated possibilities of a volcanic event.
Role of Hydrogen in a Low-Carbon Electric Power System: A Case Study
Authors: Schulthoff Michael , Rudnick Ivan , Bose Abhishek , Gençer Emre
Published: January 2021

The European Union set a 2050 decarbonization target in the Paris Agreement to reduce carbon emissions by 90–95% relative to 1990 emission levels. The path toward achieving those deep decarbonization targets can take various shapes but will surely include a portfolio of economy-wide low-carbon energy technologies/options. The growth of the intermittent renewable power sources in the grid mix has helped reduce the carbon footprint of the electric power sector. Under the need for decarbonizing the electric power sector, we simulated a low-carbon power system. We investigated the role of hydrogen for future electric power systems under current cost projections. The model optimizes the power generation mix economically for a given carbon constraint. The generation mix consists of intermittent renewable power sources (solar and wind) and dispatchable gas turbine and combined cycle units fueled by natural gas with carbon capture and sequestration, as well as hydrogen. We created several scenarios with battery storage options, pumped hydro, hydrogen storage, and demand-side response (DSR). The results show that energy storage replaces power generation, and pumped hydro entirely replaces battery storage under given conditions. The availability of pumped hydro storage and demand-side response reduced the total cost as well as the combination of solar photovoltaic and pumped hydro storage. Demand-side response reduces relatively costly dispatchable power generation, reduces annual power generation, halves the shadow carbon price, and is a viable alternative to energy storage. The carbon constrain defines the generation mix and initializes the integration of hydrogen (H2). Although the model rates power to gas with hydrogen as not economically viable in this power system under the given conditions and assumptions, hydrogen is important for hard-to-abate sectors and enables sector coupling in a real energy system. This study discusses the potential for hydrogen beyond this model approach and shows the differences between cost optimization models and real-world feasibility.
The Impact Study of El Niño-Southern Oscillation to the Wind and Solar Data in Malaysia Using the Wavelet Analysis
Authors: Albani Aliashim , Ibrahim Mohd Zamri , Abdul Ghani Siti Syazwani , Mat Rofi Muhammad Zulkifli , Taslin Puteri Nurfarah Adawiyah
Published: January 2021

Malaysia has launched initiatives for utilizing renewable energy (RE) as a source of electricity since 2011 by establishing renewable energy-related laws and policies. Malaysia's geographical location and climate have led to a limited amount of intermittent RE resources. Thus, a more thorough study of the various factors affecting the RE-based electricity generation is needed for energy output optimization. This article aims to understand the impact of El Niño-Southern Oscillation (ENSO) events on wind and solar reanalysis datasets using the Wavelet Transform. The thirty-year ERA5 solar and wind datasets were used in the study, together with the multivariate ENSO Index (MEI). As a result, the selected sites experienced an increase in solar irradiation during moderate to very strong El Niño and a decrease during the La Niña period. The wind speed increases during La Niña and decreases during El Niño, with the exception of the high wind speed during the Northeast monsoon season. Also, there was a significant coherence relationship between the wind and solar datasets with the ENSO index at a specified period. Therefore, the ENSO is essential as an input factor for future development plans for wind and solar power, energy predictions, and risk assessment.
Financial Speculation or Capital Investment? Evidence From Relationship Between Corporate Financialization and Green Technology Innovation
Authors: Huang Zhehao , Li Xue , Chen Shuanglian
Published: January 2021

In this paper, 3,493 non-financial listed companies in China from 2007 to 2018 are selected as samples to study the impact of corporate financialization on green technology innovation through the panel regression model as well as the mediating effect model, so as to identify whether enterprises tend to financial speculation or capital investment. The main conclusions are as follows. First, corporate financialization has a speculative tendency instead of strategic capital investment. Second, corporate financialization shows heterogeneous impact on green technology innovation, which is dominated by capital expenditure. Third, the heterogeneity is reflected in two aspects: attribute characteristics and external environment. The attribute characteristics of the enterprise includes whether the industry belongs to pollution industry and the ownership structure. The external environment includes the location of enterprise and the degree of financing constraints. Fourth, there are significant differences between attribute characteristics and external environment of enterprises in the impact of financialization decision-making behavior. The deviation caused by enterprise attributes is less than 10%, but the deviation caused by external environment is close to 80%.
Phenotypic Clumping Decreases With Flock Richness in Mixed-Species Bird Flocks
Authors: Bangal Priti , Sridhar Hari , Shanker Kartik
Published: January 2021

Animals that live in groups may experience positive interactions such as cooperative behavior or negative interactions such as competition from group members depending on group size and similarity between individuals. The effect of group size and phenotypic and ecological similarity on group assembly has not been well-studied. Mixed-species flocks are important subsets of bird communities worldwide. We examined associations within these in relation to flock size, to understand rules of flock assembly, in the Western Ghats of India. We examined the relationship between phenotypic clumping and flock richness using four variables—body size, foraging behavior, foraging height and taxonomic relatedness. Using a null model approach, we found that small flocks were more phenotypically clumped for body size than expected by chance; however, phenotypic clumping decreased as flocks increased in size and approached expected phenotypic variation in large flocks. This pattern was not as clear for foraging height and foraging behavior. We then examined a dataset of 55 flock matrices from 24 sites across the world. We found that sites with smaller flocks had higher values of phenotypic clumping for body size and sites with larger flocks were less phenotypically clumped. This relationship was weakly negative for foraging behavior and not statistically significant for taxonomic relatedness. Unlike most single-species groups, participants in mixed-species flocks appear to be able to separate on different axes of trait similarity. They can gain benefits from similarity on one axis while mitigating competition by dissimilarity on others. Consistent with our results, we speculate that flock assembly was deterministic up to a certain point with participants being similar in body size, but larger flocks tended to approach random phenotypic assemblages of species.
What Would a Tree Say About Its Size?
Authors: Larjavaara Markku
Published: January 2021

When developing theories, designing studies, and interpreting the results, researchers are influenced by their perception of tree size. For example, we may compare two trees of the same size belonging to different species, and attribute any differences to dissimilarities between the species. However, the meaning of “same size” depends on the measures of size used. Wood density influences certain measures, such as biomass, but does not influence e.g., trunk diameter. Therefore, the choice of the measure of size can reverse any conclusions. Hence, it is import to consider which measure of size should be used. I argue that the most common measure of size, i.e., trunk diameter, is often a bad choice when wood density varies, as diameter is then not directly related to processes important in evolution. When trees with equal diameters but differing wood densities are compared, the tree with denser wood is larger if the measure of size is related to construction cost or trunk strength, a proxy of leaf area. From this perspective, the comparison is then conducted between a biologically larger heavy-wooded tree and a smaller light-wooded tree, and the differences between the trees may be caused by size instead of wood density. Therefore, trunk biomass and strength may often be more suitable measures of size, as they reflect the construction cost and biomechanical potency linked to leaf area crown height, often too challenging to estimate more directly. To assess how commonly inadequate measures of tree size have been used, I reviewed 10 highly cited journal articles. None of these 10 articles discussed the impact of wood density on biological size, and instead based the analyses on diameters or basal areas. This led to conclusions that could change or even reverse in an analysis based on biomass or strength. Overall, I do not suggest avoiding the use of diameter, but I recommend considering result sensitivity to the measure of size, particularly in studies ones with variable wood densities.
Genome-Wide Association Study of Maize Aboveground Dry Matter Accumulation at Seedling Stage
Authors: Lu Xianju , Wang Jinglu , Wang Yongjian , Wen Weiliang , Zhang Ying , Du Jianjun , Zhao Yanxin , Guo Xinyu
Published: January 2021

Dry matter accumulation and partitioning during the early phases of development could significantly affect crop growth and productivity. In this study, the aboveground dry matter (DM), the DM of different organs, and partition coefficients of a maize association mapping panel of 412 inbred lines were evaluated at the third and sixth leaf stages (V3 and V6). Further, the properties of these phenotypic traits were analyzed. Genome-wide association studies (GWAS) were conducted on the total aboveground biomass and the DM of different organs. Analysis of GWAS results identified a total of 1,103 unique candidate genes annotated by 678 significant SNPs (Pvalue < 1.28e–6). A total of 224 genes annotated by SNPs at the top five of each GWAS method and detected by multiple GWAS methods were regarded as having high reliability. Pathway enrichment analysis was also performed to explore the biological significance and functions of these candidate genes. Several biological pathways related to the regulation of seed growth, gibberellin-mediated signaling pathway, and long-day photoperiodism were enriched. The results of our study could provide new perspectives on breeding high-yielding maize varieties.
Caspase 4 Overexpression as a Prognostic Marker in Clear Cell Renal Cell Carcinoma: A Study Based on the Cancer Genome Atlas Data Mining
Authors: Meng Lingfeng , Tian Zijian , Long Xingbo , Diao Tongxiang , Hu Maolin , Wang Miao , Zhang Wei , Zhang Yaoguang , Wang Jianye , He Yuhui
Published: January 2021

The dysregulation of caspase 4 (CASP4) expression is related to the occurrence, development, and outcome of many malignant tumors; however, its role in clear cell renal cell carcinoma (ccRCC) remains unclear. Herein, we investigated the expression of CASP4 in tumor tissues and its relationship with clinical prognosis, immune infiltration, and drug sensitivity status of ccRCC patients. Oncomine and The Cancer Genome Atlas (TCGA) databases were used to determine CASP4 mRNA expression in ccRCC patients. The correlation between CASP4 expression and disease prognosis was evaluated using Kaplan–Meier analysis. Related pathways were obtained from TCGA database via gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA). Meanwhile, genes co-expressing with CASP4 in ccRCC were investigated. Finally, we analyzed the proportion of tumor-infiltrating immune cells (TICs) using the CIBERSORT computational method and assessed CASP4 methylation and its relationship with drug sensitivity. Immunohistochemical analysis of 30 paired ccRCC and adjacent normal tissues confirmed the in silico results. CASP4 mRNA expression in ccRCC was significantly higher than that in the normal tissues, positively correlated with clinicopathological features (clinical stage and pathological grade), and negatively correlated with patient overall survival (OS). GSEA and GSVA showed that the genes in the CASP4-high expression group were primarily enriched in immune-related activities. Moreover, CIBERSORT analysis of TIC proportions revealed that activated CD4 memory T cells were positively correlated with CASP4 expression. Notably, methylation analysis revealed that the abnormal upregulation of CASP4 might be caused by hypomethylation. Finally, we found that the abnormal expression of CASP4 may be related to tumor drug resistance. Overall, our study shows that CASP4 is overexpressed in ccRCC and is an important factor affecting disease prognosis. Hence, CASP4 may serve as a potential prognostic biomarker and therapeutic target in ccRCC.
Generating Ensembles of Gene Regulatory Networks to Assess Robustness of Disease Modules
Authors: Lim James T. , Chen Chen , Grant Adam D. , Padi Megha
Published: January 2021

The use of biological networks such as protein–protein interaction and transcriptional regulatory networks is becoming an integral part of genomics research. However, these networks are not static, and during phenotypic transitions like disease onset, they can acquire new “communities” (or highly interacting groups) of genes that carry out cellular processes. Disease communities can be detected by maximizing a modularity-based score, but since biological systems and network inference algorithms are inherently noisy, it remains a challenge to determine whether these changes represent real cellular responses or whether they appeared by random chance. Here, we introduce Constrained Random Alteration of Network Edges (CRANE), a method for randomizing networks with fixed node strengths. CRANE can be used to generate a null distribution of gene regulatory networks that can in turn be used to rank the most significant changes in candidate disease communities. Compared to other approaches, such as consensus clustering or commonly used generative models, CRANE emulates biologically realistic networks and recovers simulated disease modules with higher accuracy. When applied to breast and ovarian cancer networks, CRANE improves the identification of cancer-relevant GO terms while reducing the signal from non-specific housekeeping processes.
New QTLs for Spot Blotch Disease Resistance in Wheat (Triticum aestivum L.) Using Genome-Wide Association Mapping
Authors: Tomar Vipin , Singh Daljit , Dhillon Guriqbal Singh , Singh Ravi Prakash , Poland Jesse , Joshi Arun Kumar , Singh Pawan Kumar , Bhati Pradeep Kumar , Kumar Suneel , Rahman Mokhlesur , Tiwari Budhi Sagar , Kumar Uttam
Published: January 2021

Spot blotch disease caused by Bipolaris sorokiniana is a major constraint for wheat production in tropics and subtropics. The introgression of spot blotch resistance alleles to the disease susceptible lines is critical to securing the wheat production in these regions. Although genome-wide association studies (GWASs) for spot blotch were attempted earlier, the present study focused on identifying new quantitative trait loci (QTLs) for spot blotch under natural disease pressure in diverse field conditions. A total of 139 advanced spring wheat lines were evaluated in three environments (three years and two locations) in India and Bangladesh. The GWAS using 14,063 polymorphic genotyping-by-sequencing (GBS) markers identified eight QTLs associated with spot blotch disease resistance belonging to eight chromosomes across the wheat genome. Here, we report the identified marker–trait associations (MTAs), along with the allele effects associated with the disease. The functional annotation of the significant markers identified NBS-LRR, MADS-box transcription factor, and 34 other plant-related protein families across multiple chromosomal regions. The results indicate four promising new QTLs on chromosomes 1A (497.2 Mb), 1D (89.84 Mb), 2B (421.92 Mb), and 6D (6.84 Mb) associated with several disease resistance protein families. These results provide insights into new genomic regions associated with spot blotch disease, and with additional validation, could be utilized in disease resistance breeding efforts in wheat development.
Extracellular Vesicles in Rheumatoid Arthritis and Systemic Lupus Erythematosus: Functions and Applications
Authors: Zhang Bo , Zhao Ming , Lu Qianjin
Published: January 2021

In the last two decades, extracellular vesicles (EVs) have aroused wide interest among researchers in basic and clinical research. EVs, small membrane vesicles are released by almost all kinds of cells into the extracellular environment. According to many recent studies, EVs participate in immunomodulation and play an important role in the pathogenesis of autoimmune diseases. In addition, EVs have great potential in the diagnosis and therapy of autoimmune diseases. Here, we reviewed the latest research advances on the functions and mechanisms of EVs and their roles in the pathogenesis, diagnosis, and treatment of rheumatoid arthritis and systemic lupus erythematosus.
IFIH1 Contributes to M1 Macrophage Polarization in ARDS
Authors: Zhang Shi , Chu Cuilin , Wu Zongsheng , Liu Feng , Xie Jianfeng , Yang Yi , Qiu Haibo
Published: January 2021

Accumulated evidence has demonstrated that the macrophage phenotypic switch from M0 to M1 is crucial in the initiation of the inflammatory process of acute respiratory distress syndrome (ARDS). Better insight into the molecular control of M1 macrophages in ARDS may identify potential therapeutic targets. In the current study, 36 candidate genes associated with the severity of ARDS and simultaneously involved in M1-polarized macrophages were first screened through a weighted network algorithm on all gene expression profiles from the 26 ARDS patients and empirical Bayes analysis on the gene expression profiles of macrophages. STAT1, IFIH1, GBP1, IFIT3, and IRF1 were subsequently identified as hub genes according to connectivity degree analysis and multiple external validations. Among these candidate genes, IFIH1 had the strongest connection with ARDS through the RobustRankAggreg algorithm. It was selected as a crucial gene for further investigation. For in vitro validation, the RAW264.7 cell line and BMDMs were transfected with shIFIH1 lentivirus and plasmid expression vectors of IFIH1. Cellular experimental studies further confirmed that IFIH1 was a novel regulator for promoting M1 macrophage polarization. Moreover, gene set enrichment analysis (GSEA) and in vitro validations indicated that IFIH1 regulated M1 polarization by activating IRF3. In addition, previous studies demonstrated that activation of IFIH1-IRF3 was stimulated by viral RNAs or RNA mimics. Surprisingly, the current study found that LPS could also induce IFIH1-IRF3 activation via a MyD88-dependent mechanism. We also found that only IFIH1 expression without LPS or RNA mimic stimulation could not affect IRF3 activation and M1 macrophage polarization. These findings were validated on two types of macrophages, RAW264.7 cells and BMDMs, which expanded the knowledge on the inflammatory roles of IFIH1 and IRF3, suggesting IFIH1 as a potential target for ARDS treatment.
Tissue Resident Memory γδT Cells in Murine Uterus Expressed High Levels of IL-17 Promoting the Invasion of Trophocytes
Authors: Kang Shuangpeng , Wu Qiongli , Huang Jun , Yang Binyan , Liang Changyan , Chi Peidong , Wu Changyou
Published: January 2021

γδT cells are non-conventional T cells and serve as the bridge for connecting the innate and adaptive immune systems. γδT cells form a substantial population at barrier sites and play an important role in the development of physiology, inflammation, autoimmune diseases and tumors. γδT cells not only distribute in the maternal-fetal interface during pregnancy but also in non-pregnant uterus. However, the phenotypes and functions of γδT cells in uterus were not clear. In the current study, we found that the percentages of γδT cells were significantly higher in uterus than peripheral blood and most of γδT cells in uterus were distributed in endometrium. Further studies indicated that the majority of γδT cells in uterus were memory cells with higher expression of CD44 and CD27 but lower expression of CD62L and CCR7 compared to those in blood. In addition, we found that γδT cells in uterus were tissue resident memory γδT cells expressing CD69, expressed high levels of CCR6, GranzymeB and CD107a. Moreover, γδT cells in uterus were activated and fully expressed transcription factor RORγt. After short time of activation, γδT cells in uterus significantly expressed high levels of IL-17 but not IFN-γ, which promotes the invasion of murine trophocytes. Taken together, our study will lay the foundation for future research on uterine γδT cells in pregnancy and autoimmune disease.
Vagus Nerve Stimulation Decreases Pancreatitis Severity in Mice
Authors: Zhang Luyao , Wu Zhiyang , Tong Zhihui , Yao Qi , Wang Ziyu , Li Weiqin
Published: January 2021

Background

Vagus nerve stimulation (VNS) is effective in reducing inflammation in various diseases, such as rheumatoid arthritis, colitis and acute kidney injury. The anti-inflammatory effect of vagus nerve in these diseases necessitates the interactions of neural activation and α7 nicotinic acetylcholine receptors (α7nAChRs) on splenic macrophages. In this study, we aimed to investigate the effect of VNS on severity in experimental acute pancreatitis (AP).

Methods

Two independent AP models were used, which induced in ICR mice with caerulein or pancreatic duct ligation (PDL). Thirty minutes after modeling, the left cervical carotid sheath containing the vagus nerve was electrically stimulated for 2 min. Plasma lipase and amylase activities, TNF-α levels and pancreas histologic damage were evaluated. In caerulein mice, the percentages of α7nAChR+ macrophage in pancreas and spleen were assessed by flow cytometry. Furthermore, splenectomy and adoptive transfer of VNS-conditioned α7nAChR splenocytes were performed in caerulein mice to evaluate the role of spleen in the protective effect of VNS.

Results

VNS reduced plasma lipase and amylase activities, blunted the concentrations of TNF-α and protected against pancreas histologic damage in two AP models. Survival rates were improved in the PDL model after VNS. In caerulein AP mice, VNS increased the percentages of α7nAChR+ macrophages in pancreas and spleen. Adoptive transfer of VNS-treated α7nAChR splenocytes provided protection against pancreatitis in recipient mice. However, splenectomy did not abolish the protective effect of VNS.

Conclusions

VNS reduces disease severity and attenuates inflammation in AP mice. This effect is independent of spleen and is probably related to α7nAChR on macrophage.
Immune Checkpoint Molecules—Inherited Variations as Markers for Cancer Risk
Authors: Wagner Marta , Jasek Monika , Karabon Lidia
Published: January 2021

In recent years, immunotherapy has been revolutionized by a new approach that works by blocking receptors called immune checkpoints (IC). These molecules play a key role in maintaining immune homeostasis, mainly by suppressing the immune response and by preventing its overactivation. Since inhibition of the immune response by IC can be used by cancer to avoid recognition and destruction by immune system, blocking them enhances the anti-tumor response. This therapeutic approach has brought spectacular clinical effects. The ICs present heterogeneous expression patterns on immune cells, which may affect the effectiveness of immunotherapy. The inherited genetic variants in regulatory regions of ICs genes can be considered as potential factors responsible for observed inter-individual differences in ICs expression levels on immune cells. Additionally, polymorphism located in exons may introduce changes to ICs amino acid sequences with potential impact on functional properties of these molecules. Since genetic variants may affect both expression and structure of ICs, they are considered as risk factors of cancer development. Inherited genetic markers such as SNPs may also be useful in stratification patients into groups which will benefit from particular immunotherapy. In this review, we have comprehensively summarized the current understanding of the relationship between inherited variations ofCTLA-4, PDCD1,PD-L1, BTLA,TIM-3, andLAG-3genes in order to select SNPs which can be used as predictive biomarkers in personalized evaluation of cancer risk development and outcomes as well as possible response to immunotherapy.
Local Stabilization of Hypoxia-Inducible Factor-1α Controls Intestinal Inflammation via Enhanced Gut Barrier Function and Immune Regulation
Authors: Kim Young-In , Yi Eun-Je , Kim Young-Dae , Lee A Reum , Chung Jiwoung , Ha Hae Chan , Cho Joong Myung , Kim Seong-Ryeol , Ko Hyun-Jeong , Cheon Jae-Hee , Hong Yong Rae , Chang Sun-Young
Published: January 2021

Intestinal epithelial cells are adapted in mucosal hypoxia and hypoxia-inducible factors in these cells can fortify barrier integrity to support mucosal tissue healing. Here we investigated whether hypoxia-related pathways could be proposed as potential therapeutic targets for inflammatory bowel disease. We developed a novel hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, CG-598 which stabilized HIF-1α in the gut tissue. Treatment of CG-598 did not affect extra-intestinal organs or cause any significant adverse effects such as erythropoiesis. In the experimental murine colitis model, CG-598 ameliorated intestinal inflammation with reduction of inflammatory lesions and pro-inflammatory cytokines. CG-598 treatment fortified barrier function by increasing the expression of intestinal trefoil factor, CD73, E-cadherin and mucin. Also, IL-10 and IL-22 were induced from lamina propria CD4+ T-cells. The effectiveness of CG-598 was comparable to other immunosuppressive therapeutics such as TNF-blockers or JAK inhibitors. These results suggest that CG-598 could be a promising therapeutic candidate to treat inflammatory bowel disease.