bluuebunny/crossref_metadata_2025 huggingface dataset:
PTH, FGF-23, Klotho and Vitamin D as regulators of calcium and phosphorus: Genetics, epigenetics and beyond
Authors: Portales-Castillo Ignacio , Simic Petra
Published: September 2022

The actions of several bone-mineral ion regulators, namely PTH, FGF23, Klotho and 1,25(OH)2 vitamin D (1,25(OH)2D), control calcium and phosphate metabolism, and each of these molecules has additional biological effects related to cell signaling, metabolism and ultimately survival. Therefore, these factors are tightly regulated at various levels – genetic, epigenetic, protein secretion and cleavage. We review the main determinants of mineral homeostasis including well-established genetic and post-translational regulators and bring attention to the epigenetic mechanisms that affect the function of PTH, FGF23/Klotho and 1,25(OH)2D. Clinically relevant epigenetic mechanisms include methylation of cytosine at CpG-rich islands, histone deacetylation and micro-RNA interference. For example, sporadic pseudohypoparathyroidism type 1B (PHP1B), a disease characterized by resistance to PTH actions due to blunted intracellular cAMP signaling at the PTH/PTHrP receptor, is associated with abnormal methylation at the GNAS locus, thereby leading to reduced expression of the stimulatory G protein α-subunit (Gsα). Post-translational regulation is critical for the function of FGF-23 and such modifications include glycosylation and phosphorylation, which regulate the cleavage of FGF-23 and hence the proportion of available FGF-23 that is biologically active. While there is extensive data on how 1,25(OH)2D and the vitamin D receptor (VDR) regulate other genes, much more needs to be learned about their regulation. Reduced VDR expression or VDR mutations are the cause of rickets and are thought to contribute to different disorders. Epigenetic changes, such as increased methylation of the VDR resulting in decreased expression are associated with several cancers and infections. Genetic and epigenetic determinants play crucial roles in the function of mineral factors and their disorders lead to different diseases related to bone and beyond.
A prior knowledge-embedded reinforcement learning method for real-time active power corrective control in complex power systems
Authors: Xu Peidong , Zhang Jun , Lu Jixiang , Zhang Haoran , Gao Tianlu , Chen Siyuan
Published: September 2022

With the increasing uncertainty and complexity of modern power grids, the real-time active power corrective control problem becomes intractable, bringing significant challenges to the stable operation of future power systems. To promote effective and efficient active power corrective control, a prior knowledge-embedded reinforcement learning method is proposed in this paper, to improve the performance of the deep reinforcement learning agent while maintaining the real-time control manner. The system-level feature is first established based on prior knowledge and cooperating with the equipment-level features, to provide a thorough description of the power network states. A global-local network structure is then constructed to integrate the two-level information accordingly by introducing the graph pooling method. Based on the multi-level representation of power system states, the Deep Q-learning from Demonstrations method is adopted to guide the deep reinforcement learning agent to learn from the expert policy along with the interactive improving process. Considering the infrequent corrective control actions in practice, the double-prioritized training mechanism combined with the λ-return is further developed to help the agent lay emphasis on learning from critical control experience. Simulation results demonstrate that the proposed method prevails over the conventional deep reinforcement learning methods in training efficiency and control effects, and has the potential to solve the complex active power corrective control problem in the future.
Multiple objective optimization based on particle swarm algorithm for MMC-MTDC system
Authors: Qian Wenyan , Cao Siyuan , Zhang Yuanshi , Hu Qinran , Li Hengyu , Li Yang
Published: September 2022

Multi-terminal high voltage DC (MTDC) network is an effective technology to integrate large-scale offshore wind energy sources into conventional AC grids and improve the stability and flexibility of the power system. In this paper, firstly, an analytical model of a general applicable MTDC system integrated with several isolated AC grids is established. Then, an improved AC-DC power flow algorithm is used to eliminate the additional DC slack bus or droop bus iteration (SBI/DBI) step of the conventional AC-DC sequential power flow. A multi-objective optimal power flow (MOPF) algorithm is proposed to minimize two optimization targets, i.e., overall active power loss and generation costs of the system. To increase the degree of freedom, adaptive droop control is used in the proposed optimization algorithm in which the voltage references and droop coefficients of the modular multilevel converters (MMCs) are control variables. A multiple objective particle swarm optimization (MOPSO) method is applied to solve the MOPF problem and achieve the Pareto front. A technique for order of preference by similarity to ideal solution (TOPSIS) is incorporated in the decision analysis section and helps the decision maker to identify the best compromise solution.
A novel chaotic flower pollination algorithm for function optimization and constrained optimal power flow considering renewable energy sources
Authors: Daqaq Fatima , Ouassaid Mohammed , Kamel Salah , Ellaia Rachid , El-Naggar Mohamed F.
Published: September 2022

This study presents an improved chaotic flower pollination algorithm (CFPA) with a view to handle the optimal power flow (OPF) problem integrating a hybrid wind and solar power and generate the optimal settings of generator power, bus voltages, shunt reactive power, and tap setting transformers. In spite of the benefits of FPA, it encounters two problems like other evolutionary algorithms: entrapment in local optima and slow convergence speed. Thus, to deal with these drawbacks and enhance the FPA searching accuracy, a hybrid optimization approach CFPA which combines the stochastic algorithm FPA that simulates the flowering plants process with the chaos methodology is applied in this manuscript. Therefore, owing to the various nonlinear constraints in OPF issue, a constraint handling technique named superiority of feasible solutions (SF) is embedded into CFPA. To confirm the performance of the chaotic FPA, a set of different well-known benchmark functions were employed for ten diverse chaotic maps, and then the best map is tested on IEEE 30-bus and IEEE 57-bus test systems incorporating the renewable energy sources (RESs). The obtained results are analyzed statistically using non-parametric Wilcoxon rank-sum test in view of evaluating their significance compared to the outcomes of the state-of-the-art meta-heuristic algorithms such as ant bee colony (ABC), grasshopper optimization algorithm (GOA), and dragonfly algorithm (DA). From this study, it may be established that the suggested CFPA algorithm outperforms its meta-heuristic competitors in most benchmark test cases. Additionally, the experimental results regarding the OPF problem demonstrate that the integration of RESs decreases the total cost by 12.77% and 33.11% for the two systems, respectively. Thus, combining FPA with chaotic sequences is able to accelerate the convergence and provide better accuracy to find optimal solutions. Furthermore, CFPA (especially with the Sinusoidal map) is challenging in solving complex real-world problems.
A SEM-based research on influencing factors of team situation awareness in nuclear power plants
Authors: Wang Ru , Wen Jing , Li Pengcheng
Published: September 2022

Team situation awareness (TSA) is one of the key factors that affect team decision-making and implementation. TSA is influenced by performance shaping factors (PSFs) in digital nuclear power plants (NPPs). In order to identify the influencing relationships and extent between TSA and PSFs, a model is needed to describe and correlate them. Firstly, based on TSA cognitive process, the main PSFs influencing the level of TSA are identified, including team knowledge and experience level, information display quality, attention and attitude, and team stress level. Then a conceptual model of TSA influencing factors is proposed to explore the path relationships and influencing mechanism between TSA and PSFs, and a structural equation model (SEM) that relates TSA to its PSFs is developed subsequently. Finally, by analyzing human factor events and small deviation reports, data from 178 samples were obtained and substituted into the structural equation model to analyze and identify the relationships between the PSFs. The results show that the preceding PSFs have significant effects on TSA. Based on path coefficients, positive effects were: team knowledge and experience level (0.504), information display quality (0.370), attention and attitude (0.249). Negative effect was: team stress level (−0.384). The results of this study can provide a theoretical basis for the prevention and control of TSA errors, and a qualitative analysis model for the quantitative evaluation of TSA reliability.
Analysis of the coupling coordinated development and evolutionary trend of digital economy and ecological environment
Authors: Fu Lianyan , Liu Bo , Zhu Zhichuan , Cao Jianhong , Sun Congting , Yu Zhuoxi
Published: September 2022

In order to clarify the coordinated development status between the digital economy and the ecological environment in the context of rapid development of the digital economy and frequent ecological environment problems, we constructed an evaluation system using data related to the digital economy and the ecological environment in China from 2011 to 2019. And the level of coordinated development is calculated with the help of entropy method and the Coupling Coordinated Development (CCD) model. Further, we analyzed the spatial and temporal evolutionary trends of their coordinated development levels with the kernel density analysis and the Dagum Gini coefficient decomposition. The results of the entropy method and CCD show that both the level of digital economy, the level of ecological environment and the level of coupling coordination between the two have increased. And the level of coordinated development shows regional heterogeneity, with the highest in the eastern region, followed by the central region, and the lowest in the western region. The results of the kernel density analysis show that there is heterogeneity in the development process of CCD scores over time across regions. The results of the Dagum Gini coefficient decomposition show that the overall inter-regional differences, as well as intra-regional differences, are fluctuating and decreasing. And the overall imbalance mainly comes from the differences in development levels between regions. The analysis of the above methods provides a basis for understanding the spatial and temporal evolution characteristics of the coordinated development of China’s digital economy and ecological environment. And it also provides relevant policy recommendations for promoting coordinated and sustainable development among regions.
The relationship between school districts and parental commuting behavior: Analysis of gender differences in the Chinese context
Authors: Jiang Huaxiong , Liu Qingfang , Li Yongling , Guo Kaifei , Guo Yuanyuan
Published: September 2022

The distribution of school districts would largely influence people’s commuting distance, but this association is hardly examined. This study applies the 2015 Xiamen household travel survey to investigate the associations between the school district and parental commuting behavior. The results showed that school districts mainly affect the parents’ commuting distance when the interaction effects between gender and commuting distance are considered. Specifically, the school district is positively associated with commuting distances for males, whereas the opposite trend is observed for females. Then, variations exist in the effects of the school district on parental commuting distance between respondents with different levels of education. The school district quality is positively associated with the commuting distance for respondents without college degrees, especially male respondents, whereas no significant association was found for more respondents with college degrees. Male respondents, especially those without college degrees, suffer higher costs and longer commuting distances than their female counterparts. This study highlights that urban planners and policy makers should consider the impact of school districts and rethink the most effective distribution of high-quality primary schools to reduce socio-spatial inequality (e.g., disadvantage of males in commuting).
Strategies of property developers and governments under carbon tax and subsidies
Authors: Yao Qingzhen , Shao Liangshan , Yin Zimin , Wang Junmei , Lan Yue
Published: September 2022

Implementing low-carbon houses is inseparable from the carbon tax and subsidy policies. Appropriate carbon taxes and subsidies can help to reduce household carbon emissions. This study aims to identify a suitable carbon tax and subsidy policy and investigate how this policy will affect the adoption of low-carbon housing. We classify programs including carbon taxes and subsidies into four categories: static carbon tax static subsidy, static carbon tax dynamic subsidy, dynamic carbon tax dynamic subsidy, and dynamic carbon tax static subsidy. Additionally, under various carbon tax and subsidy systems, the evolutionary stability strategies (ESS) of real estate developers and governments will be examined using evolutionary game theory. The case simulation results show that static carbon tax and dynamic subsidies are the best strategies. Government regulation is essential for the implementation of low-carbon housing. The higher the carbon tax and the property developer’s profit, the higher the willingness of property developers to implement low-carbon houses and the higher the willingness of government regulation. Appropriate low-carbon subsidies will help property developers implement low-carbon houses. However, after reaching a certain point, low-carbon subsidies will make property developers less inclined to build low-carbon houses. The higher the cost of government regulation, the lower the probability of the low-carbon strategy of property developers, but the cost of government regulation has little impact on the government’s regulation strategy.
Spatial and temporal heterogeneity of tropical cyclone precipitation over China from 1959 to 2018
Authors: Xu Wanling , Zhang Meng , Hu Zengyun , Guan Xiaojun , Jiang Lizhi , Bao Ruijuan , Wei Yingying , Ma Miaomiao , Wei Jianhui , Gao Lu
Published: September 2022

Tropical cyclone precipitation (TCP) can cause serious floods and urban waterlogs as well as cause various secondary disasters, such as landslides and debris flows, which negatively affect human lives and the sustainable development of the economy. This study applied the prewhitening Mann-Kendall test, empirical orthogonal function, and continuous wavelet transform to investigate the long-term trend, spatiotemporal pattern, and periodicity of TCP at monthly, interannual, and interdecadal timescales over China. The recurrence risks of extreme TCP were analyzed using the return period estimation model. The results showed that 1) TCP displayed a significant increasing trend, especially in eastern China, inland areas, and Guangxi Province. The TCP periodicities were 2.5 and 4.9 years across all of China. However, TCP cycles had large discrepancies in the time and frequency domains in different subregions. 2) Monthly TCP demonstrated a decreasing trend in May and an increasing trend from June to October in all of China. The TCP in northeastern China and southern China tended to decrease in July and August, respectively. 3) TCP demonstrated a decreasing tendency from the 1960s–1980s followed by a rebounding trend in the 1990s–2010s. In addition, TCP showed a dipole mode in the 1970s and 2000s. 4) There was an increasing recurrence risk of extreme TCP in the Yangtze River Delta, Hainan Province, southeastern Guangxi Province, and southwestern Guangdong Province. It is therefore necessary to improve forecasting of extreme TCP events to improve risk management and prevention capacity of natural disasters, especially in regions with high population and economy exposure.
Research on the impacts of dual environmental regulation on regional carbon emissions under the goal of carbon neutrality-the intermediary role of green technology innovation
Authors: Dong Xueqin , Zhong Yuan , Liu Mengkai , Xiao Wei , Qin Chuan
Published: September 2022

As an important means to promote regional low-carbon development, environmental regulation has great theoretical and practical significance for achieving the goal of carbon-neutral development in China. Based on the panel data of 30 provinces and cities in China from 2005 to 2019, this paper first uses the intermediary effect model to analyze the impact of the implementation of environmental regulation policies on regional carbon emissions, discusses the relationship between environmental regulation, green technology innovation and carbon emissions, and further uses the threshold effect model to discuss the nonlinear relationship between environmental regulation and regional carbon emissions. The results show that: the improvement of formal and informal environmental regulation can play a role in “forced emission reduction”; Green technology innovation plays a complete intermediary role in the impact of environmental regulation on regional carbon emissions; At the same time, the impact of formal and informal environmental regulation on regional carbon emissions has a threshold effect. Among them, formal environmental regulation has a double threshold effect, the threshold values are 0.429 and 0.502 respectively, while informal environmental regulation has a single threshold effect, the threshold value is 1.803. The results of heterogeneity analysis show that there are obvious differences in the implementation effects of environmental regulation policies under different economic development levels and industrialization development stages. Therefore, we should pay attention to the mutual promotion effect of different types of environmental regulation, strengthen the collaborative emission reduction of environmental regulation and green technology innovation, and improve the level of regional green technology innovation, so as to better promote the realization of regional carbon neutrality goals.
Effects of multiple cropping of farmland on the welfare level of farmers: Based on the perspective of poverty vulnerability
Authors: Peng Jiquan , Chen Lili , Yu Bingwen , Zhang Xiaohan , Huo Zenghui
Published: September 2022

This paper aims to explore the impact of multiple cropping on farmers’ welfare level and provide the theoretical and empirical basis for solving relative poverty in rural areas in the future. The paper uses data from the field survey of 1,120 farmers in Hubei in 2018 and uses the Endogenous Transformation Regression Model (ESR) and generalized propensity score matching (GPSM) model to construct a counterfactual framework. The paper analyses the effect of multiple cropping on farmers’ relative poverty and examines its mechanism. The result shows that: Multiple cropping of farmland can reduce the relative poverty of farmers through the mechanism of yield improvement path and factor intensification path. Under the counterfactual hypothesis, the relative poverty of farmers would increase by 28.43% if the farmers who participated in the multiple cropping did not; and that the relative poverty of the farmers would decrease by 29.57% if the farmers who did not participate in the multiple cropping participated. From the perspective of multiple cropping, the poverty reduction effect of multiple cropping in paddy fields is higher than that of dry land. From the perspective of the degree of multiple cropping, the poverty reduction effects of paddy fields and dryland will experience an increasing return to scale as the multiple cropping index increases. When the household equivalent scale adjustment coefficient is not used to eliminate the impact of family population structure on the “family per capita comparable income,” the artificially high results estimated by the model cannot truly reflect the poverty-reducing effect of multi-cropping of farmland. This paper argues that the government can guide farmers to choose the suitable mode of multiple cropping to reduce farmers’ vulnerability to relative poverty.
Pre-Columbian cultivation of vegetatively propagated and fruit tree tropical crops in the Atacama Desert
Authors: Capriles José M. , García Magdalena , Valenzuela Daniela , Domic Alejandra I. , Kistler Logan , Rothhammer Francisco , Santoro Calogero M.
Published: September 2022

South America is a megadiverse continent that witnessed the domestication, translocation and cultivation of various plant species from seemingly contrasting ecosystems. It was the recipient and supplier of crops brought to and from Mesoamerica (such as maize and cacao, respectively), and Polynesia to where the key staple crop sweet potato was exported. Not every instance of thetrans-ecological expansion of cultivated plants (both domesticated and wild), however, resulted in successful farming. Here, we review the transregional circulation and introduction of five food tropical crops originated in the tropical and humid valleys of the eastern Andes—achira, cassava,ahipa, sweet potato, and pacay—to the hyper-arid coastal valleys of the Atacama Desert of northern Chile, where they have been found in early archeological sites. By means of an evaluation of the contexts of their deposition and supported by direct radiocarbon dating, stable isotopes analyses, and starch grain analysis, we evaluate different hypotheses for explaining their introduction and adaptation to the hyper-arid soils of northern Chile, by societal groups that after the introduction of cultigens still retained a strong dependence on marine hunting, gathering and fishing ways of life based on wide variety of marine coast resources. Many of the studied plants were part of a broader package of introduced goods and technological devices and procedures, linked to food, therapeutic medicine, social and ritual purposes that transformed previous hunter-gatherer social, economic, and ideological institutions. Based on archeological data, we discuss some of the possible socio-ecological processes involved in the development of agricultural landscapes including the adoption of tropical crops originated several hundred kilometers away from the Atacama Desert during the Late Holocene.
Root traits rather than functional diversity of soil microorganisms respond to drought and plant species composition in Mediterranean shrubland species
Authors: Shihan Ammar , Hättenschwiler Stephan , Fromin Nathalie
Published: September 2022

Belowground responses are critical in understanding how plants cope with the predicted increase in drought intensity and frequency in the Mediterranean region, because plant root systems compete with each other and interact with soil microbial communities under limiting water availability. However, the combined responses of plant roots and soil microorganisms to drought are not well understood. Using an experimental approach, we addressed the question of how recurrent drought and different combinations of two individuals from three common Mediterranean plant species (Quercus coccifera, Cistus albidus, and Brachypodium retusum) affect root characteristics and soil microbial activity. We hypothesized that drought effects on root characteristics and associated soil microbial communities are stronger when plant individuals of the same species compete for limiting water compared to inter-specific competition. Root morphological traits were more affected by the species identity of the neighbor individual than by recurrent severe drought, particularly in B. retusum, which may in part explain the higher survival previously observed for this species. On the other hand, drought and plant composition had little effect on root-associated soil microbes’ ability to use a wide range of different carbon substrates. Overall, our results did not confirm stronger effects of intra- compared to interspecific competition on the root and microbial responses, but showed strong species identity effects.
Evaluating the impact of different afforestation timescales on the soil quality in a typical watershed valley using the criteria importance through intercriteria correlation method and gray target model
Authors: Yin Huiyan , Yu Bo , Zhang Zhiwei , Jia Lizhi , Xue Jie , Chen Xiaoqiang , Wang Shunke , Han Jiahua , Xing Zhen
Published: September 2022

Soil quality evaluation is the foundation for understanding the current situation of soil quality and promoting the sustainable utilization of land resources. However, the evaluation of the impacts of the different long-term afforestation timescales on the soil quality in a typical watershed valley area is still insufficient. Here, based on the soil samples collected from different afforestation years of 2, 5, 11, 15, and 31 years and natural sample plots with similar site conditions in the same region, the gray target model and criteria importance through intercriteria correlation (CRITIC) method are used in this study to evaluate the soil quality of the sample plots with different afforestation years and the corresponding natural sample plots in the Tibet Plateau. Results show that: (1) The most positive soil physical and chemical indexes increase with the increase in afforestation years based on the analysis of the characteristics, variation, and fertility grade of 13 soil physical and chemical indexes in different areas. The content of most soil physical and chemical indexes is greater than that in the corresponding natural sample plots in 31 years of afforestation. (2) The bullseye degree of the soil quality in the study area is divided into five grades according to the principle of equal division and integration. The soil quality grade of the corresponding sample plot after 15 years of afforestation is grade 4. The other plots are grade 5. (3) The soil quality index (SQI) generally increases with the increase of in forestation years. The different afforestation years indicate SQI (0.709) of 15 years > SQI (0.662) of 31 years > SQI (0.426) of 11 years > SQI (0.348) of 2 years > SQI (0.309) of 5 years. (4) The full data set method verifies the effectiveness of the gray target model. The two soil quality evaluation methodologies are consistent and can verify each other’s accuracy. The correlation coefficient of the two results reaches 0.957. This study finds that the long-term afforestation timescales have improved the soil quality of watershed valley. Available phosphorus, silt, soil water content are the main factors impacting the soil quality in the afforestation timescales.
Deep_KsuccSite: A novel deep learning method for the identification of lysine succinylation sites
Authors: Liu Xin , Xu Lin-Lin , Lu Ya-Ping , Yang Ting , Gu Xin-Yu , Wang Liang , Liu Yong
Published: September 2022

Identification of lysine (symbol Lys or K) succinylation (Ksucc) sites centralizes the basis for disclosing the mechanism and function of lysine succinylation modifications. Traditional experimental methods for Ksucc site ientification are often costly and time-consuming. Therefore, it is necessary to construct an efficient computational method to prediction the presence of Ksucc sites in protein sequences. In this study, we proposed a novel and effective predictor for the identification of Ksucc sites based on deep learning algorithms that was termed as Deep_KsuccSite. The predictor adopted Composition, Transition, and Distribution (CTD) Composition (CTDC), Enhanced Grouped Amino Acid Composition (EGAAC), Amphiphilic Pseudo-Amino Acid Composition (APAAC), and Embedding Encoding methods to encode peptides, then constructed three base classifiers using one-dimensional (1D) convolutional neural network (CNN) and 2D-CNN, and finally utilized voting method to get the final results. K-fold cross-validation and independent testing showed that Deep_KsuccSite could serve as an effective tool to identify Ksucc sites in protein sequences. In addition, the ablation experiment results based on voting, feature combination, and model architecture showed that Deep_KsuccSite could make full use of the information of different features to construct an effective classifier. Taken together, we developed Deep_KsuccSite in this study, which was based on deep learning algorithm and could achieved better prediction accuracy than current methods for lysine succinylation sites. The code and dataset involved in this methodological study are permanently available at the URL https://github.com/flyinsky6/Deep_KsuccSite.
Genome-wide identification and expression analysis of glutathione S-transferase gene family to reveal their role in cold stress response in cucumber
Authors: Duan Xiaoyu , Yu Xuejing , Wang Yidan , Fu Wei , Cao Ruifang , Yang Lu , Ye Xueling
Published: September 2022

The plant glutathione S-transferases (GSTs) are versatile proteins encoded by several genes and play vital roles in responding to various physiological processes. Members of plant GSTs have been identified in several species, but few studies on cucumber (Cucumis sativus L.) have been reported. In this study, we identified 46 GST genes, which were divided into 11 classes. Chromosomal location and genome mapping revealed that cucumber GSTs (CsGSTs) were unevenly distributed in seven chromosomes, and the syntenic regions differed in each chromosome. The conserved motifs and gene structure of CsGSTs were analyzed using MEME and GSDS 2.0 online tools, respectively. Transcriptome and RT-qPCR analysis revealed that most CsGST members responded to cold stress. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses for differentially expressed CsGSTs under cold stress revealed that these genes responded to cold stress probably through “glutathione metabolism.” Finally, we screened seven candidates that may be involved in cold stress using Venn analysis, and their promoters were analyzed using PlantCARE and New PLACE tools to predict the factors regulating these genes. Antioxidant enzyme activities were increased under cold stress conditions, which conferred tolerance against cold stress. Our study illustrates the characteristics and functions of CsGST genes, especially in responding to cold stress in cucumber.
Analysis and identification of the necroptosis landscape on therapy and prognosis in bladder cancer
Authors: Zhao Zihan , Jiang Ning , Zhang Yulin , Bai Yuhao , Liu Tianyao , Li Tianhang , Guo Hongqian , Yang Rong
Published: September 2022

Bladder cancer (BLCA) is one of the most common malignant tumors of the urinary system, but the current therapeutic strategy based on chemotherapy and immune checkpoint inhibitor (ICI) therapy cannot meet the treatment needs, mainly owing to the endogenous or acquired apoptotic resistance of cancer cells. Targeting necroptosis provides a novel strategy for chemotherapy and targeted drugs and improves the efficacy of ICIs because of strong immunogenicity of necroptosis. Therefore, we systemically analyzed the necroptosis landscape on therapy and prognosis in BLCA. We first divided BLCA patients from The Cancer Genome Atlas (TCGA) database into two necroptosis-related clusters (C1 and C2). Necroptosis C2 showed a significantly better prognosis than C1, and the differential genes of C2 and C1 were mainly related to the immune response according to GO and KEGG analyses. Next, we constructed a novel necroptosis-related gene (NRG) signature consisting of SIRT6, FASN, GNLY, FNDC4, SRC, ANXA1, AIM2, and IKBKB to predict the survival of TCGA-BLCA cohort, and the accuracy of the NRG score was also verified by external datasets. In addition, a nomogram combining NRG score and several clinicopathological features was established to more accurately and conveniently predict the BLCA patient’s survival. We also found that the NRG score was significantly related to the infiltration levels of CD8 T cells, NK cells, and iDC cells, the gene expression of CTLA4, PD-1, TIGIT, and LAG3 of TME, and the sensitivity to chemotherapy and targeted agents in BLCA patients. In conclusion, the NRG score has an excellent performance in evaluating the prognosis, clinicopathologic features, tumor microenvironment (TME), and therapeutic sensitivity of BLCA patients, which could be utilized as a guide for chemotherapy, ICI therapy, and combination therapy.
Structural changes and adaptative evolutionary constraints in FLOWERING LOCUS T and TERMINAL FLOWER1-like genes of flowering plants
Authors: Almeida de Jesus Deivid , Batista Darlisson Mesquista , Monteiro Elton Figueira , Salzman Shayla , Carvalho Lucas Miguel , Santana Kauê , André Thiago
Published: September 2022

Regulation of flowering is a crucial event in the evolutionary history of angiosperms. The production of flowers is regulated through the integration of different environmental and endogenous stimuli, many of which involve the activation of different genes in a hierarchical and complex signaling network. The FLOWERING LOCUS T/TERMINAL FLOWER 1 (FT/TFL1) gene family is known to regulate important aspects of flowering in plants. To better understand the pivotal events that changed FT and TFL1 functions during the evolution of angiosperms, we reconstructed the ancestral sequences of FT/TFL1-like genes and predicted protein structures through in silico modeling to identify determinant sites that evolved in both proteins and allowed the adaptative diversification in the flowering phenology and developmental processes. In addition, we demonstrate that the occurrence of destabilizing mutations in residues located at the phosphatidylcholine binding sites of FT structure are under positive selection, and some residues of 4th exon are under negative selection, which is compensated by the occurrence of stabilizing mutations in key regions and the P-loop to maintain the overall protein stability. Our results shed light on the evolutionary history of key genes involved in the diversification of angiosperms.
Development of a prognostic prediction model based on a combined multi-omics analysis of head and neck squamous cell carcinoma cell pyroptosis-related genes
Authors: Chen Bin , Luo Yuanbo , Kang Xueran , Sun Yuxing , Jiang Chenyan , Yi Bin , Yan Xiaojun , Chen Yisheng , Shi Runjie
Published: September 2022

This study aimed to understand the prognosis of patients with head and neck squamous cell carcinoma (HNSCC) and to develop and validate a prognostic model for HNSCC based on pyroptosis-associated genes (PAGs) in nasopharyngeal carcinoma. The Cancer Genome Atlas database was used to identify differentially expressed PAGs. These genes were analyzed using the Kyoto Encyclopedia of Genes and Genomes functional annotation analyses and Gene Ontology analyses. The NLR family pyrin domain containing 1 (NLRP1) gene, charged multivesicular body protein 7 (CHMP7) gene, and cytochrome C (CYCS) gene were used to create a prognostic model for HNSCC. The results of the Kaplan-Meier (K-M) and Cox regression analyses indicated that the developed model served as an independent risk factor for HNSCC. According to the K-M analysis, the overall survival of high-risk patients was lower than that of low-risk patients. The hazard ratios corresponding to the risk scores determined using the multivariate and univariate Cox regression analyses were 1.646 (95% confidence interval (CI): 1.189–2.278) and 1.724 (95% CI: 1.294–2.298), respectively, and the area under the receiver operator characteristic curve was 0.621. The potential mechanisms associated with the functions of the identified genes were then identified, and the tumor microenvironment and levels of immune cell infiltration achieved were analyzed. The immune infiltration analysis revealed differences in the distribution of Th cells, tumor-infiltrating lymphocytes, regulatory T cells, follicular helper T cells, adipose-derived cells, interdigitating dendritic cells, CD8+ T cells, and B cells. However, validating bioinformatics analyses through biological experiments is still recommended. This study developed a prognostic model for HNSCC that included NLRP1, CHMP7, and CYCS.
Two subtypes of cutaneous melanoma with distinct mutational signatures and clinico-genomic characteristics
Authors: Kim Yoon-Seob , Lee Minho , Chung Yeun-Jun
Published: September 2022

Background: To decipher mutational signatures and their associations with biological implications in cutaneous melanomas (CMs), including those with a low ultraviolet (UV) signature.

Materials and Methods: We applied non-negative matrix factorization (NMF) and unsupervised clustering to the 96-class mutational context of The Cancer Genome Atlas (TCGA) cohort (N = 466) as well as other publicly available datasets (N = 527). To explore the feasibility of mutational signature-based classification using panel sequencing data, independent panel sequencing data were analyzed.

Results: NMF decomposition of the TCGA cohort and other publicly available datasets consistently found two mutational signatures: UV (SBS7a/7b dominant) and non-UV (SBS1/5 dominant) signatures. Based on mutational signatures, TCGA CMs were classified into two clusters: UV-high and UV-low. CMs belonging to the UV-low cluster showed significantly worse overall survival and landmark survival at 1-year than those in the UV-high cluster; low or high UV signature remained the most significant prognostic factor in multivariate analysis. The UV-low cluster showed distinct genomic and functional characteristic patterns: low mutation counts, increased proportion of triple wild-type and KIT mutations, high burden of copy number alteration, expression of genes related to keratinocyte differentiation, and low activation of tumor immunity. We verified that UV-high and UV-low clusters can be distinguished by panel sequencing.

Conclusion: Our study revealed two mutational signatures of CMs that divide CMs into two clusters with distinct clinico-genomic characteristics. Our results will be helpful for the clinical application of mutational signature-based classification of CMs.
Combination treatment of radiofrequency ablation and peptide neoantigen vaccination: Promising modality for future cancer immunotherapy
Authors: Shou Jiawei , Mo Fan , Zhang Shanshan , Lu Lantian , Han Ning , Liu Liang , Qiu Min , Li Hongseng , Han Weidong , Ma Dongying , Guo Xiaojie , Guo Qianpeng , Huang Qinxue , Zhang Xiaomeng , Ye Shengli , Pan Hongming , Chen Shuqing , Fang Yong
Published: September 2022

Background

The safety and immunogenicity of a personalized neoantigen-based peptide vaccine, iNeo-Vac-P01, was reported previously in patients with a variety of cancer types. The current study investigated the synergistic effects of radiofrequency ablation (RFA) and neoantigen vaccination in cancer patients and tumor-bearing mice.

Methods

Twenty-eight cancer patients were enrolled in this study, including 10 patients who had received RFA treatment within 6 months before vaccination (Cohort 1), and 18 patients who had not (Cohort 2). Individualized neoantigen peptide vaccines were designed, manufactured, and subcutaneously administrated with GM-CSF as an adjuvant for all patients. Mouse models were employed to validate the synergistic efficacy of combination treatment of RFA and neoantigen vaccination.

Results

Longer median progression free survival (mPFS) and median overall survival (mOS) were observed in patients in Cohort 1 compared to patients in Cohort 2 (4.42 and 20.18 months vs. 2.82 and 10.94 months). The results of ex vivo IFN-γ ELISpot assay showed that patients in Cohort 1 had stronger neoantigen-specific immune responses at baseline and post vaccination. Mice receiving combination treatment of RFA and neoantigen vaccines displayed higher antitumor immune responses than mice receiving single modality. The combination of PD-1 blockage with RFA and neoantigen vaccines further enhanced the antitumor response in mice.

Conclusion

Neoantigen vaccination after local RFA treatment could improve the clinical and immune response among patients of different cancer types. The synergistic antitumor potentials of these two modalities were also validated in mice, and might be further enhanced by immune checkpoint inhibition. The mechanisms of their synergies require further investigation.

Clinical trial registration

https://clinicaltrials.gov/, identifier NCT03662815.
Sterile protection and transmission blockade by a multistage anti-malarial vaccine in the pre-clinical study
Authors: Iyori Mitsuhiro , Blagborough Andrew M. , Mizuno Tetsushi , Abe Yu-ichi , Nagaoka Mio , Hori Naoto , Yamagoshi Iroha , Da Dari F. , Gregory William F. , Hasyim Ammar A. , Yamamoto Yutaro , Sakamoto Akihiko , Yoshida Kunitaka , Mizukami Hiroaki , Shida Hisatoshi , Yoshida Shigeto
Published: September 2022

The Malaria Vaccine Technology Roadmap 2013 (World Health Organization) aims to develop safe and effective vaccines by 2030 that will offer at least 75% protective efficacy against clinical malaria and reduce parasite transmission. Here, we demonstrate a highly effective multistage vaccine against both the pre-erythrocytic and sexual stages of Plasmodium falciparum that protects and reduces transmission in a murine model. The vaccine is based on a viral-vectored vaccine platform, comprising a highly-attenuated vaccinia virus strain, LC16m8Δ (m8Δ), a genetically stable variant of a licensed and highly effective Japanese smallpox vaccine LC16m8, and an adeno-associated virus (AAV), a viral vector for human gene therapy. The genes encoding P. falciparum circumsporozoite protein (PfCSP) and the ookinete protein P25 (Pfs25) are expressed as a Pfs25–PfCSP fusion protein, and the heterologous m8Δ-prime/AAV-boost immunization regimen in mice provided both 100% protection against PfCSP-transgenic P. berghei sporozoites and up to 100% transmission blocking efficacy, as determined by a direct membrane feeding assay using parasites from P. falciparum-positive, naturally-infected donors from endemic settings. Remarkably, the persistence of vaccine-induced immune responses were over 7 months and additionally provided complete protection against repeated parasite challenge in a murine model. We propose that application of the m8Δ/AAV malaria multistage vaccine platform has the potential to contribute to the landmark goals of the malaria vaccine technology roadmap, to achieve life-long sterile protection and high-level transmission blocking efficacy.
Decreased peripheral basophil counts in urticaria and mouse model of oxazolone-induced hypersensitivity, the latter suggesting basopenia reflecting migration to skin
Authors: Kishimoto Izumi , Ma Ni , Takimoto-Ito Riko , Nakashima Chisa , Otsuka Atsushi , Walls Andrew F. , Tanizaki Hideaki , Kambe Naotomo
Published: September 2022

A decrease in the number of basophils in the peripheral blood, or basopenia, has been noted, reflecting the activity of chronic spontaneous urticaria (CSU). Infiltration of basophils into the skin has also been reported, but the mechanism of basopenia in CSU has not been clarified. The phenomenon of basopenia during the active phase of urticaria was confirmed, and basophil numbers increased following symptom improvement in 15 out of 17 patients treated with omalizumab and in 13 of 15 patients treated with antihistamines. Our examination by immunostaining also revealed basophil infiltration of the CSU lesions, as in previous reports, but since most of our patients were already taking oral steroids, it was not considered appropriate to examine the relationship between basophil numbers in tissue and peripheral blood. Then, we used mouse model of contact hypersensitivity with a single application of oxazolone, which is known to stimulate basophil infiltration, and investigated basophil counts in the skin, peripheral blood, and bone marrow. In this model, a decrease in peripheral blood basophil numbers was observed one day after challenge, but not after 2 days, reflecting supplementation from the bone marrow. Indeed, when cultured basophils expressing GFP were transplanted into the peripheral blood, GFP-positive basophil numbers in the peripheral blood remained low even after 2 days of challenge. Despite differences among species and models, these results suggest that one reason for the decrease of basophils in the peripheral blood in CSU may involve migration of circulating basophils into the skin.
Immunological study of COVID-19 vaccine candidate based on recombinant spike trimer protein from different SARS-CoV-2 variants of concern
Authors: Rudi Erika , Martin Aispuro Pablo , Zurita Eugenia , Gonzalez Lopez Ledesma Maria M. , Bottero Daniela , Malito Juan , Gabrielli Magali , Gaillard Emilia , Stuible Matthew , Durocher Yves , Gamarnik Andrea V. , Wigdorovitz Andrés , Hozbor Daniela
Published: September 2022

The emergency of new SARS-CoV-2 variants that feature increased immune escape marks an urgent demand for better vaccines that will provide broader immunogenicity. Here, we evaluated the immunogenic capacity of vaccine candidates based on the recombinant trimeric spike protein (S) of different SARS-CoV-2 variants of concern (VOC), including the ancestral Wuhan, Beta and Delta viruses. In particular, we assessed formulations containing either single or combined S protein variants. Our study shows that the formulation containing the single S protein from the ancestral Wuhan virus at a concentration of 2µg (SW2-Vac 2µg) displayed in the mouse model the highest IgG antibody levels against all the three (Wuhan, Beta, and Delta) SARS-CoV-2 S protein variants tested. In addition, this formulation induced significantly higher neutralizing antibody titers against the three viral variants when compared with authorized Gam-COVID-Vac-rAd26/rAd5 (Sputnik V) or ChAdOx1 (AstraZeneca) vaccines. SW2-Vac 2µg was also able to induce IFN-gamma and IL-17, memory CD4 populations and follicular T cells. Used as a booster dose for schedules performed with different authorized vaccines, SW2-Vac 2µg vaccine candidate also induced higher levels of total IgG and IgG isotypes against S protein from different SARS-CoV-2 variants in comparison with those observed with homologous 3-dose schedule of Sputnik V or AstraZeneca. Moreover, SW2-Vac 2µg booster induced broadly strong neutralizing antibody levels against the three tested SARS-CoV-2 variants. SW2-Vac 2µg booster also induced CD4+ central memory, CD4+ effector and CD8+ populations. Overall, the results demonstrate that SW2-Vac 2 µg is a promising formulation for the development of a next generation COVID-19 vaccine.