bluuebunny/crossref_metadata_2025 huggingface dataset:
Vitamin D Trajectories and Cardiometabolic Risk Factors During Childhood: A Large Population-Based Prospective Cohort Study
Authors: Xiao Pei , Cheng Hong , Li Haibo , Zhao Xiaoyuan , Hou Dongqing , Xie Xianghui , Mi Jie
Published: March 2022

Background and Objectives

Vitamin D has been indicated to play an important role in the optimal function of the cardiovascular system. However, with limited evidence, it remains unclear whether vitamin D status transition during childhood would affect cardiometabolic risk factors. Thus, we aimed to identify the associations of the longitudinal trajectory of vitamin D status with cardiometabolic risk factors in children.

Methods

A total of 10,482 participants with complete follow-up records from a large population-based prospective cohort study were included in this analysis. The 25-hydroxyvitamin D [25(OH)D] concentrations, blood pressure, blood lipids, and fasting blood glucose were determined. Vitamin D deficiency was defined as serum 25(OH)D concentrations below 30 nmol/L according to the Institute of Medicine recommendations. Based on the vitamin D status at baseline and follow-up, we identified four possible trajectories: (1) persistent non-deficiency (reference); (2) baseline non-deficiency to follow-up deficiency; (3) baseline deficiency to follow-up non-deficiency; (4) persistent deficiency. The relationships between cardiometabolic risk factors and vitamin D trajectories were evaluated using adjusted risk ratios (RRs).

Results

Overall, 35.1 and 24.2% of participants had vitamin D deficiency at the baseline and follow-up, respectively, and 15.1% were under the condition of persistent vitamin D deficiency. Compared to children with persistent non-deficiency, those who shifted from non-deficiency at baseline to deficiency at follow-up had a 2.09-fold (95% CI: 1.36, 3.23) increased risk of high triglyceride (TG). Besides, children with altered vitamin D status from deficiency to non-deficiency during follow-up were still at a significantly higher risk of high total cholesterol (TC) than the reference group [RR (95% CI): 1.39 (1.04, 1.86)]. Finally, children with persistent vitamin D deficiency were at the highest risks of high TC [RR (95% CI): 1.61 (1.18, 2.19), Ptrend < 0.001], high low-density lipoprotein cholesterol (LDL-C) [RR (95% CI): 1.53 (1.04, 2.27), Ptrend = 0.046], and high TG [RR (95% CI): 1.96 (1.34, 2.87), Ptrend = 0.003].

Conclusion

Our results suggest that persistent vitamin D deficiency might increase the risk of dyslipidemia in children, and vitamin D deficiency could have has short- and long-term effects on TG and TC, respectively.
High Rank Coal Pore Fracture Structure and its Impact on Reservoir Characteristics in the Southern Qinshui Basin
Authors: Ji Changjiang , Li Guofu , Hao Haijin , Song Zhimin , Guo Dingding
Published: March 2022

Although the southern Qinshui Basin is the most successful area for coalbed methane (CBM) development in China, the production of CBM wells in different blocks in the area is significantly different. One of the key reasons is the difference in pore structure in various-ranked coal. In this study, No. 3 coal seam of Sihe and Zhaozhuang blocks in southern Qinshui Basin was selected as the research object to investigate the high rank coal pore fracture structure and its impact on reservoir characteristics. Mercury intrusion porosimetry (MIP), low-temperature liquid nitrogen adsorption (LTN2A), scanning electron microscopy (SEM), and isothermal adsorption tests were conducted. The results show that the Sihe No.3 coal seam was mainly composed of open cylindrical and flat pores with a high proportion of transition pores (10–100 nm), large specific surface area, good connectivity, strong adsorption capacity, high gas content, and reservoir energy. Zhaozhuang No.3 coal had high proportion of mesopores (100–1,000 nm), small specific surface area, poor pores connectivity, weak adsorption capacity, poor gas content, low reservoir energy, and critical desorption pressure. The proportion of cylindrical pores, parallel plate pores, and wedge-shaped pores closed at one end was high. The anomalies in pore morphology and pore structure characteristics of coal reservoir were the main factors that caused variation in gas production of No.3 coal seam in Sihe and Zhaozhuang blocks.
Association of Organochlorine Pesticides With Genetic Markers of Endoplasmic Reticulum Stress in Type 2 Diabetes Mellitus: A Case–Control Study Among the North-Indian Population
Authors: Tawar Neha , Banerjee Basu Dev , Madhu Sri Venkata , Agrawal Vivek , Gupta Sanjay
Published: March 2022

Background

Organochlorine pesticides (OCPs) have been long linked to type 2 diabetes mellitus (T2DM); however, this relation at the molecular level has not been explored yet. Endoplasmic reticulum (ER) stress and pro-inflammatory pathways are considered vital ones in the pathogenesis of T2DM. We aimed to investigate the existence of any association between OCPs, ER stress, and pro-inflammatory pathways in subjects with known T2DM.

Methods

Seventy subjects each with T2DM and normal glucose tolerance were recruited from the surgery department. Their visceral adipose tissue was collected intraoperatively. OCP concentration, ER stress, and pro-inflammatory markers were analyzed and compared between two study groups.

Results

We found 18 OCPs and their metabolites in visceral adipose tissue samples of study participants. The levels of δ-HCH, heptachlor, endrin, and p,p′DDT were significantly higher in the T2DM group and were also positively correlated with fasting and postprandial plasma glucose levels (p < 0.01). We observed a positive association of δ-HCH (p < 0.01), heptachlor (p < 0.05), and endrin (p < 0.05) with central adiposity and ER stress markers. However, we failed to establish the correlation of OCPs with any of the pro-inflammatory markers.

Conclusion

The existence and simultaneous complex correlation of OCPs with ER stress may explain their role in the pathogenesis of T2DM, revealing the persistence of the gene–environment interaction in the etiology of T2DM.
Long-Term Oral Administration of Salidroside Alleviates Diabetic Retinopathy in db/db Mice
Authors: Yao Fei , Jiang Xinyi , Qiu Ling , Peng Zixuan , Zheng Wei , Ding Lexi , Xia Xiaobo
Published: March 2022

Diabetic retinopathy (DR), a microvascular complication of diabetes mellitus, is the leading cause of vision loss in the working-age population worldwide. Unfortunately, current clinical treatments cannot completely prevent the occurrence and development of DR. Salidroside (Sal) is a medicinal supplement that has antioxidative and cytoprotective properties. This study aimed to investigate the therapeutic effect of Sal on DR. Briefly, Sal treatment was applied to wide-type mice and db/db mice (a widely used diabetic mice) at 25 mg/kg by oral gavage once daily from 8 weeks to 20 weeks. Mice’s bodyweight, blood glucose, total cholesterol, triglyceride, high density lipoprotein and low density lipoprotein were recorded and analyzed. Retinal trypsin digestion and evans blue dye assay were used to detect retinal microvessel changes and function. Retinal glutathione and malondialdehyde content measurements were applied to assess retinal oxidative stress. Full-length transcriptome analysis was performed to explore the underlying mechanisms of Sal protection. Our results found that Sal treatment could successfully relieve blood glucose and blood lipid abnormalities, and reduce retinal oxidative stress level in diabetic mice. Also, Sal treatment repaired the abnormal transcriptome caused by diabetes, alleviated the microvascular lesion of the fundus in diabetic mice, and protected retinal normal barrier function. This study enriches the indications of Sal in the treatment of diabetic diseases, providing practical research ideas for the comprehensive preventions and treatments of DR.
Multiterminal Hybrid DC Line Protection Based on Intrinsic Mode Energy Entropy
Authors: Xing Chao , Li Pengsong , Bi Guihong , Chen Shilong , Chen Junhao , Zhang Zihang
Published: March 2022

In view of the UHV multiterminal hybrid DC transmission system, the DC line protection with universal applicability, fast response speed, stability, and reliability is particularly important for its safe and economic operation. In this article, the boundary frequency characteristics of the UHV multiterminal hybrid DC transmission system are analyzed by considering the DC boundary of the rectifier side and inverter side, line frequency variation, and other factors. According to the fact that the boundary of the fault line has a strong attenuation effect on the high-frequency component of the transient current, a protection method based on the intrinsic mode energy entropy is proposed to distinguish the faults inside and outside. The criterion to initiate the protection is constructed by using the amplitude of the transient power; the fault direction criterion is constructed by using the positive and negative characteristics of the transient energy of the fault power detected by power direction elements on both sides of the T-zone; the fault pole selection criterion is constructed by using the ratio of low-frequency transient power changes of positive and negative poles. Finally, the Kun–Liu–Long line UHV three-terminal hybrid DC transmission system model is built on the PSCAD/EMTDC simulation platform, and a large number of simulation examples verify that the protection can operate reliably under different fault poles, fault positions, and transition resistances.
Control Strategy of Distributed Energy Micro-Grid Involving Distribution System Resilience
Authors: Wu Jun , Qiu Rui , Wang Mingyue , Han Rui , Huang Wenxin , Guo Zihui
Published: March 2022

To realize low-carbon energy systems, distributed energy storage systems and flexible loads have been integrated into power grids. System reliability, economy, and resilience, therefore, face significant challenges. This article presents modeling of a distributed energy micro-grid including wind turbines, micro gas turbines, waste heat recovery devices, electric boilers, direct-fired boilers, battery energy storage, interruptible loads, and transferable loads. At the same time, the optimal configuration of energy storage and the demand-side response modeling are studied, and the combined optimization control strategy of the two is demonstrated. The simulation results indicate that the proposed control strategy has better performance than the traditional operation. In addition, this article also clarifies the impact of control strategy on distribution system resilience. The results show that the control strategy proposed in this article can achieve the resource complementarity of demand-side response and energy storage, and realize the integrated coordination of source, network, load, and storage. The distributed energy micro-grid under this control strategy has the best overall economic benefit and the best capacity to accommodate load growth.
Restoring Rivers and Floodplains for Habitat and Flood Risk Reduction: Experiences in Multi-Benefit Floodplain Management From California and Germany
Authors: Serra-Llobet Anna , Jähnig Sonja C. , Geist Juergen , Kondolf G. Mathias , Damm Christian , Scholz Mathias , Lund Jay , Opperman Jeff J. , Yarnell Sarah M. , Pawley Anitra , Shader Eileen , Cain John , Zingraff-Hamed Aude , Grantham Theodore E. , Eisenstein William , Schmitt Rafael
Published: March 2022

Conventional flood control has emphasized structural measures such as levees, reservoirs, and engineered channels—measures that typically simplify river channels and cut them off from their floodplain, both with adverse environmental consequences. Structural measures tend to be rigid and not easily adapted to increased flooding regimes resulting from environmental change. Such actions also limit the natural hydrologic benefits of floodplains such as storing floodwaters, improving water quality, providing habitat for invertebrates and fish during periods of inundation, and supporting a multitude of cultural services. As these benefits are more widely recognized, policies are being adopted to encourage projects that reduce flood risks and restore floodplain ecosystems, while acknowledging the social-ecological context. The number of such projects, however, remains small. We assessed four multi-benefit floodplain projects (two in California, United States, and two in Germany) and characterized their drivers, history, and measures implemented. In both United States cases, the dominant driver behind the project was flood risk reduction, and ecosystem restoration followed, in one case inadvertently, in the other as a requirement to receive a subsidy for a flood risk reduction project. One German case was motivated by ecosystem restoration, but it was more widely accepted because it also offered flood management benefits. The fourth case was conceived in terms of balanced goals of flood risk reduction, ecosystem restoration, and recreation. We conclude that projects that both reduce flood risk and restore ecosystems are clearly possible and often cost-effective, and that they could be more widely implemented. The principal barriers are often institutional and regulatory, rather than technical.
Predictable NHEJ Insertion and Assessment of HDR Editing Strategies in Plants
Authors: Molla Kutubuddin A. , Shih Justin , Wheatley Matthew S. , Yang Yinong
Published: March 2022

Canonical CRISPR-Cas9 genome editing technique has profoundly impacted the fields of plant biology, biotechnology, and crop improvement. Since non-homologous end joining (NHEJ) is usually considered to generate random indels, its high efficiency mutation is generally not pertinent to precise editing. Homology-directed repair (HDR) can mediate precise editing with supplied donor DNA, but it suffers from extreme low efficiency in higher plants. Therefore, precision editing in plants will be facilitated by the ability to predict NHEJ repair outcome and to improve HDR efficiency. Here, we report that NHEJ-mediated single nucleotide insertion at different rice genes is predictable based on DNA sequences at the target loci. Three mutation prediction tools (inDelphi, FORECasT, and SPROUT) have been validated in the rice plant system. We also evaluated the chimeric guide RNA (cgRNA) and Cas9-Retron precISe Parallel Editing via homologY (CRISPEY) strategies to facilitate donor template supply for improving HDR efficiency in Nicotiana benthamiana and rice. However, neither cgRNA nor CRISPEY improved plant HDR editing efficiency in this study. Interestingly, our data indicate that tethering of 200–250 nucleotides long sequence to either 5′ or 3′ ends of guide RNA did not significantly affect Cas9 cleavage activity.
Dynamic Changes in the Quantitative Electroencephalographic Spectrum During Attention Tasks in Patients With Prader–Willi Syndrome
Authors: Tsai Li-Ping , Wang Syu-Siang , Chee Siew-Yin , Wong Shi-Bing
Published: March 2022

Introduction: Attention problems are frequently observed in patients with Prader–Willi syndrome (PWS); however, only few studies have investigated the severity and mechanisms of attention problems in them. In this study, we aim to evaluate dynamic changes in the quantitative electroencephalographic (EEG) spectrum during attention tasks in patients with PWS.

Method: From January to June 2019, 10 patients with PWS and 10 age-matched neurotypical control participants were recruited at Taipei Tzu Chi Hospital. Each participant completed Conners’ continuous performance test, third edition (CPT-3), tasks with simultaneous EEG monitoring. The dynamic changes in the quantitative EEG spectrum between the resting state and during CPT-3 tasks were compared.

Results: Behaviorally, patients with PWS experienced significant attention problems, indicated by the high scores for several CPT-3 variables. The theta/beta ratio of the resting-state EEG spectrum revealed no significant differences between the control participants and patients with PWS. During CPT-3 tasks, a significant decrease in the alpha power was noted in controls compared with that in patients with PWS. The attention-to-resting alpha power ratio was positively correlated with many CPT-3 variables. After adjusting for genotype, age, intelligence, and body mass index, the attention-to-resting alpha power ratio was still significantly correlated with participants’ commission errors.

Conclusion: This study provides evidence that attention problems are frequently observed in patients with PWS, while attention impairment can be demonstrated by dynamic changes in the quantitative EEG spectrum.
SNP-Based Genome-Wide Association Mapping of Pollen Viability Under Heat Stress in Tropical Zea mays L. Inbred Lines
Authors: Ahmed Zubair , Khalid Maria , Ghafoor Abdul , Shah Muhammad Kausar Nawaz , Raja Ghazala Kaukab , Rana Rashid Mehmood , Mahmood Tahir , Thompson Addie M.
Published: March 2022

Global environmental changes with more extreme episodes of heat waves are major threats to agricultural productivity. Heat stress in spring affects the reproductive stage of maize, resulting in tassel blast, pollen abortion, poor pollination, reduced seed set, barren ears and ultimately yield loss. As an aneamophelous crop, maize has a propensity for pollen abortion under heat stress conditions. To overcome the existing challenges of heat stress and pollen abortion, this study utilized a broad genetic base of maize germplasm to identify superior alleles to be utilized in breeding programs. A panel of 375 inbred lines was morpho-physiologically screened under normal and heat stress conditions in two locations across two consecutive planting seasons, 2017 and 2018. The exposure of pollen to high temperature showed drastic decline in pollen germination percentage. The average pollen germination percentage (PGP) at 35 and 45°C was 40.3% and 9.7%, respectively, an average decline of 30.6%. A subset of 275 inbred lines were sequenced using tunable genotyping by sequencing, resulting in 170,098 single nucleotide polymorphisms (SNPs) after filtration. Genome wide association of PGP in a subset of 122 inbred lines resulted in ten SNPs associated with PGP35°C (p ≤ 10−5), nine with PGP45°C (p ≤ 10−6–10−8) and ten SNPs associated with PGP ratio (p ≤ 10−5). No SNPs were found to be in common across PGP traits. The number of favorable alleles possessed by each inbred line for PGP35°C, PGP45°C, and the PGP ratio ranged between 4 and 10, 3–13 and 5–13, respectively. In contrast, the number of negative alleles for these traits ranged between 2 and 8, 3–13 and 3–13, respectively. Genetic mapping of yield (adjusted weight per plant, AWP−1) and flowering time (anthesis-silking interval, ASI) in 275 lines revealed five common SNPs: three shared for AWP−1 between normal and heat stress conditions, one for ASI between conditions, and one SNP, CM007648.1-86615409, was associated with both ASI and AWP−1. Variety selection can be performed based on these favorable alleles for various traits. These marker trait associations identified in the diversity panel can be utilized in breeding programs to improve heat stress tolerance in maize.
Effects of IL-6 Polymorphisms on Individual Susceptibility to Allergic Diseases: A Systematic Review and Meta-Analysis
Authors: Yang Ying , Xiao Jingxin , Tang Lingling , Wang Bohan , Sun Xianhong , Xu Zhongchi , Liu Li , Shi Suofang
Published: March 2022

Background: Many studies have assessed the potential link between interleukin-6 polymorphisms and susceptibility to allergic diseases. However, the results are still conflicting. Therefore, a comprehensive meta-analysis can not only resolve differences but also provide clues for future projects.

Methods: A systematic electronic search was conducted on the databases of Web of Science, PubMed, and Cochrane Library to retrieve all published studies. Revman and Stata software were used for statistical analysis.

Results: This meta-analysis included 11 studies. The results revealed that there was a statistically significant association between IL-6 rs1800795 polymorphism and the risk of asthma and allergic rhinitis in the general population. Subgroup analyses demonstrated that rs1800795 affected allergic diseases risk in different populations.

Conclusion: Our findings suggested that IL-6 rs1800795 was associated with allergic diseases susceptibility among Asians and Caucasians in opposite trends, and it might influence the risk of asthma and allergic rhinitis. None of the IL-6 polymorphisms were shared risk variants of allergic diseases.
One Ferroptosis-Related Gene-Pair Signature Serves as an Original Prognostic Biomarker in Lung Adenocarcinoma
Authors: Li Lei , Wang Buhai
Published: March 2022

Lung adenocarcinoma is the most common histological subtype of lung cancer which causes the largest number of deaths worldwide. Exploring reliable prognostic biomarkers based on biological behaviors and molecular mechanisms is essential for predicting prognosis and individualized treatment strategies. Ferroptosis is a recently discovered type of regulated cell death. We downloaded ferroptosis-related genes from the literature and collected transcriptome profiles of lung adenocarcinoma from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to construct ferroptosis-related gene-pair matrixes. Then, we performed the least absolute shrinkage and selection operator regression to build our prognostic ferroptosis-related gene-pair index (FRGPI) in TCGA training matrix. Our study validated FRGPI through ROC curves, Kaplan–Meier methods, and Cox hazard analyses in TCGA and GEO cohorts. The optimal cut-off 0.081 stratified patients into low- and high-FRGPI groups. Also, the low-FRGPI group had a significantly better prognosis than the high-FRGPI group. For further study, we analyzed differentially expressed ferroptosis-related genes between high- and low-FRGPI groups. Gene set enrichment analysis (GSEA) enrichment maps indicated that “cell cycle,” “DNA replication,” “proteasome,” and “the p53 signaling pathway” were significantly enriched in the high-FRGPI group. The high-FRGPI group also presented higher infiltration of M1 macrophages. Meanwhile, there were few differences in adaptive immune responses between high- and low-FRGPI groups. In conclusion, FRGPI was an independent prognostic biomarker which might be beneficial for guiding individualized tumor therapy.
Pre-Transplant Expression of CCR-2 in Kidney Transplant Recipients Is Associated With the Development of Delayed Graft Function
Authors: Pontrelli Paola , Simone Simona , Rascio Federica , Pesce Francesco , Conserva Francesca , Infante Barbara , Castellano Giuseppe , Sallustio Fabio , Fiorentino Marco , Zaza Gianluigi , Gallone Anna , Battaglia Michele , Ditonno Pasquale , Stallone Giovanni , Gesualdo Loreto , Grandaliano Giuseppe
Published: March 2022

Background

Delayed graft function (DGF) leads to a reduced graft survival. Donors’ features have been always considered as key pathogenic factors in this setting. The aim of our study was to evaluate the recipients’ characteristics in the development of DGF.

Methods

We enrolled 932 kidney graft recipients from 466 donors; 226 recipients experienced DGF. In 290 donors, both recipients presented with early graft function (EGF, group A), in 50 both recipients experienced DGF (group B), and in 126 one recipient presented with DGF and the other with EGF (group C). In group C, we selected 7 couples of DGF/EGF recipients and we evaluated the transcriptomic profile by microarray on circulating mononuclear cells harvested before transplantation. Results were validated by qPCR in an independent group of 25 EGF/DGF couples.

Findings

In the whole study group, DGF was associated with clinical characteristics related to both donors and recipient. In group C, DGF was significantly associated with body mass index, hemodialysis, and number of mismatches. In the same group, we identified 411 genes differently expressed before transplantation between recipients discordant for the transplant outcome. Those genes were involved in immune dysfunction and inflammation. In particular, we observed a significant increase in DGF patients in the expression of C–C chemokine receptor type 2 (CCR2), the monocyte chemoattractant protein-1 (MCP-1) receptor. CCR-2 upregulation was confirmed in an independent cohort of patients.

Conclusions

Our results suggest that recipients’ clinical/immunological features, potentially modulated by dialysis, are associated with the development of DGF independently of donors’ features.
Multiple SARS-CoV-2 Variants Exhibit Variable Target Cell Infectivity and Ability to Evade Antibody Neutralization
Authors: Tang Haijun , Gao Long , Wu Zhao , Meng Fang , Zhao Xin , Shao Yun , Hou Guocun , Du Xiaohong , Qin F. Xiao-Feng
Published: March 2022

The continuous emergence of SARS-coronavirus 2 (SARS-CoV-2) variants, especially the variants of concern (VOC), exacerbated the impact of the coronavirus disease 2019 (COVID-19) pandemic. As the key of viral entry into host cells, the spike (S) protein is the major target of therapeutic monoclonal antibodies (mAbs) and polyclonal antibodies elicited by infection or vaccination. However, the mutations of S protein in variants may change the infectivity and antigenicity of SARS-CoV-2, leading to the immune escape from those neutralizing antibodies. To characterize the mutations of S protein in newly emerging variants, the proteolytic property and binding affinity with receptor were assessed, and the vesicular stomatitis virus (VSV)-based pseudovirus system was used to assess the infectivity and immune escape. We found that some SARS-CoV-2 variants have changed significantly in viral infectivity; especially, B.1.617.2 is more likely to infect less susceptible cells than D614G, and the virus infection process can be completed in a shorter time. In addition, neutralizing mAbs and vaccinated sera partially or completely failed to inhibit host cell entry mediated by the S protein of certain SARS-CoV-2 variants. However, SARS-CoV-2 variant S protein-mediated viral infection can still be blocked by protease inhibitors and endocytosis inhibitors. This work provides a deeper understanding of the rise and evolution of SARS-CoV-2 variants and their immune evasion.
Targeting NK Cells for HIV-1 Treatment and Reservoir Clearance
Authors: Duan Siqin , Liu Shuwen
Published: March 2022

Combined antiretroviral therapy (cART) can inhibit the replication of human immunodeficiency virus type 1 (HIV-1) and reduce viral loads in the peripheral blood to undetectable levels. However, the presence of latent HIV-1 reservoirs prevents complete HIV-1 eradication. Several drugs and strategies targeting T cells are now in clinical trials, but their effectiveness in reducing viral reservoirs has been mixed. Interestingly, innate immune natural killer (NK) cells, which are promising targets for cancer therapy, also play an important role in HIV-1 infection. NK cells are a unique innate cell population with features of adaptive immunity that can regulate adaptive and innate immune cell populations; therefore, they can be exploited for HIV-1 immunotherapy and reservoir eradication. In this review, we highlight immunotherapy strategies for HIV infection that utilize the beneficial properties of NK cells.
CD90 Marks a Mesenchymal Program in Human Thymic Epithelial Cells In Vitro and In Vivo
Authors: Sun Shicheng , Li Jacky Y. , Nim Hieu T. , Piers Adam , Ramialison Mirana , Porrello Enzo R. , Konstantinov Igor E. , Elefanty Andrew G. , Stanley Edouard G.
Published: March 2022

Thymic epithelium is critical for the structural integrity of the thymus and for T cell development. Within the fully formed thymus, large numbers of hematopoietic cells shape the thymic epithelium into a scaffold-like structure which bears little similarity to classical epithelial layers, such as those observed in the skin, intestine or pancreas. Here, we show that human thymic epithelial cells (TECs) possess an epithelial identity that also incorporates the expression of mesenchymal cell associated genes, whose expression levels vary between medullary and cortical TECs (m/cTECs). Using pluripotent stem cell (PSC) differentiation systems, we identified a unique population of cells that co-expressed the master TEC transcription factorFOXN1, as well as the epithelial associated marker EPCAM and the mesenchymal associated gene CD90. Using the same serum free culture conditions, we also observed co-expression of EPCAM and CD90 on cultured TECs derived from neonatal human thymusin vitro. Single cell RNA-sequencing revealed these cultured TECs possessed an immature mTEC phenotype and expressed epithelial and mesenchymal associated genes, such asEPCAM,CLDN4,CD90andCOL1A1. Importantly, flow cytometry and single cell RNA-sequencing analysis further confirmed the presence of an EPCAM+CD90+ population in the CD45- fraction of neonatal human thymic stromal cellsin vivo. Using the human thymus cell atlas, we found that cTECs displayed more pronounced mesenchymal characteristics than mTECs during embryonic development. Collectively, these results suggest human TECs possess a hybrid gene expression program comprising both epithelial and mesenchymal elements, and provide a basis for the further exploration of thymus development from primary tissues and from thein vitrodifferentiation of PSCs.
Alum Adjuvant and Built-in TLR7 Agonist Synergistically Enhance Anti-MUC1 Immune Responses for Cancer Vaccine
Authors: Zhou Shi-Hao , Li Yu-Ting , Zhang Ru-Yan , Liu Yan-Ling , You Zi-Wei , Bian Miao-Miao , Wen Yu , Wang Jian , Du Jing-Jing , Guo Jun
Published: March 2022

The tumor-associated antigen mucin 1 (MUC1) is an attractive target of antitumor vaccine, but its weak immunogenicity is a big challenge for the development of vaccine. In order to enhance immune responses against MUC1, herein, we conjugated small molecular toll-like receptor 7 agonist (TLR7a) to carrier protein BSA via MUC1 glycopeptide to form a three-component conjugate (BSA-MUC1-TLR7a). Furthermore, we combined the three-component conjugate with Alum adjuvant to explore their synergistic effects. The immunological studies indicated that Alum adjuvant and built-in TLR7a synergistically enhanced anti-MUC1 antibody responses and showed Th1-biased immune responses. Meanwhile, antibodies elicited by the vaccine candidate effectively recognized tumor cells and induced complement-dependent cytotoxicity. In addition, Alum adjuvant and built-in TLR7a synergistically enhanced MUC1 glycopeptide-specific memory CD8+ T-cell immune responses. More importantly, the vaccine with the binary adjuvant can significantly inhibit tumor growth and prolong the survival time of mice in the tumor challenge experiment. This novel vaccine construct provides an effective strategy to develop antitumor vaccines.
Identification and Characterization of BmNPV m6A Sites and Their Possible Roles During Viral Infection
Authors: Zhang Xing , Zhang Yaxin , Pan Jun , Gong Chengliang , Hu Xiaolong
Published: March 2022

Bombyx mori nucleopolyhedrovirus (BmNPV) is one of the most serious pathogens and causes serious economic losses in sericulture. At present, there is no epigenetic modification of BmNPV transcripts, especially of m6A, and this modification mediates diverse cellular and viral functions. This study showed that m6A modifications are widespread in BmNPV transcripts in virally infected cells and the identified m6A peaks with a conserved RRACH sequence. m6A sites predominantly appear in the coding sequences (CDS) and the 3′-end of CDS. About 37% of viral genes with m6A sites deleted from the viral genome did not produce any infectious virions in KOV-transfected cells. Among the viral genes related to replication and proliferation, ie-1 mRNA was identified with a higher m6A level than other viral genes. The m6A sites in the ie-1 mRNA may be negatively related to the protein expression. Viral replication was markedly inhibited in cells overexpressed with BmYTHDF3 in a dose-dependent manner, and a contrary effect was found in si-BmYTHDF3-transfected cells. Collectively, the identification of putative m6A modification in BmNPV transcripts provides a foundation for comprehensively understanding the viral infection, replication, and pathobiology in silkworms.
Taxonomy and Phylogeny of Two Spirotrichean Ciliates (Alveolata, Protista, and Ciliophora) From a Plateau Saline–Alkaline Lake in Tibet, China, Including Description of a New Species
Authors: Kouser Farzana , Song Wenya , Jiang Limin , Zhuang Wenbao , Wang Congcong , Wu Tong , Hu Xiaozhong
Published: March 2022

There are few researches concerning ciliates from “extreme” environments such as plateau salt lakes; nevertheless, such a faunistic survey is of great significance for understanding the diversity and biogeography of these microeukaryotes. In this study, two ciliates, namely, Hemiurosomoida tibetensis sp. nov. and Euplotes euryhalinusValbonesi and Luporini, 1990, isolated from Kyêbxang Co, a Tibet Plateau saline-alkaline lake, China, were investigated based on observations of live and silver-stained specimens, and 18S rDNA sequences were analyzed. The new species can be characterized by having a size of 60–95 × 20–40 μm in vivo, an elongate elliptical body, colorless cortical granules mainly grouped around cirri and dorsal bristles, about 21 adoral membranelles, 20 cirri on each marginal row, and two macronuclear nodules and two micronuclei. The Chinese population of E. euryhalinus corresponds well with the original one. Phylogenetic analyses show that Hemiurosomoida is non-monophyletic, H. tibetensis sp. nov. has a closer relationship with H. longa within this genus, and that Euplotes euryhalinus presents a wide geographic distribution. This study first reveals the ciliature, morphogenesis, and rRNA gene sequence data for H. tibetensis sp. nov. and the Chinese population of E. euryhalinus, which thus increases our knowledge about the diversity of ciliates at high altitudes.
Digital Twins for Materials
Authors: Kalidindi Surya R. , Buzzy Michael , Boyce Brad L. , Dingreville Remi
Published: March 2022

Digital twins are emerging as powerful tools for supporting innovation as well as optimizing the in-service performance of a broad range of complex physical machines, devices, and components. A digital twin is generally designed to provide accurate in-silico representation of the form (i.e., appearance) and the functional response of a specified (unique) physical twin. This paper offers a new perspective on how the emerging concept of digital twins could be applied to accelerate materials innovation efforts. Specifically, it is argued that the material itself can be considered as a highly complex multiscale physical system whose form (i.e., details of the material structure over a hierarchy of material length) and function (i.e., response to external stimuli typically characterized through suitably defined material properties) can be captured suitably in a digital twin. Accordingly, the digital twin can represent the evolution of structure, process, and performance of the material over time, with regard to both process history and in-service environment. This paper establishes the foundational concepts and frameworks needed to formulate and continuously update both the form and function of the digital twin of a selected material physical twin. The form of the proposed material digital twin can be captured effectively using the broadly applicable framework of n-point spatial correlations, while its function at the different length scales can be captured using homogenization and localization process-structure-property surrogate models calibrated to collections of available experimental and physics-based simulation data.
Dry Textile Forming Simulations: A Benchmarking Exercise
Authors: Sun Xiaochuan , Belnoue Jonathan P.-H. , Thompson Adam , Said Bassam El , Hallett Stephen R.
Published: March 2022

In this study, four representative finite element (FE) based modelling techniques and an analytical solution for the prediction of 2D woven fabrics’ deformation during forming are compared back-to-back. Ordered from high to low fidelity they are: 1/a Multi-Filament (MF) method that sits between micro- and meso-scale that uses multiple beam element chains to represent each fibre yarn; 2/a meso-scale 3D representation (3D-Shell method) that uses 2D structural shell elements to model each fibre yarn; 3/a 2D continuum element approach that uses coincident membrane and shell elements with user defined material properties to capture the deformation response of textiles in an homogenised sense at the macro-scale; 4/pin-jointed net (PJN) models where the reinforcement directions are represented by extendable 1D elements, pin-jointed at the elements’ crossover points. These modelling approaches are systematically compared for identical forming processes with identical process and material parameters such as boundary conditions, weave architecture and tooling geometries. For completeness and to highlight the importance of considering inter-yarn and preform-to-tool interactions, a kinematic drape algorithm (based on geometrical mapping) is also considered. An attempt is made to visualise the overall modelling performance and computational cost of all representative modelling approaches by simplified metrics.
Performance Assessment of Two Different Approaches of Measuring Skeletonized Radial Peripapillary Capillary Vessel Density in Glaucoma Patients
Authors: Guo Yiqin , Sun Yunxiao , Zhang Xueyuan , Wang Ningli
Published: March 2022

Objective

To compare performance assessment of two methods of measuring radial peripapillary capillary (RPC) vessel density (VD) after skeletonization using MATLAB and Image J in glaucoma clinical setting.

Methods

Seventy-three eyes of 73 glaucoma patients from Beijing Tongren Hospital were included in this prospective study. Original images of RPC were obtained using optical coherence tomography angiography. Two approaches were executed before measuring. Method 1 (M1) required image sharpening, removal of big vessels, and skeletonization. Method 2 (M2) required skeletonization and removal of major vessels. Each method was executed twice. Repeatability and correlations with glaucomatous parameters were assessed. Factors associated with retinal nerve fiber layer thickness (RNFLT) and visual field mean deviation (MD) were analyzed.

Results

Average VD was 13.86 ± 2.73 and 7.50 ± 2.50% measured by M1 and M2. Percentage of total elimination of the major vessels was 36.99 and 100% by M1 and M2, respectively. The intrasession and intersession reproducibility was higher by M2 (ICC = 0.979, ICC = 0.990) than by M1 (ICC = 0.930, ICC = 0.934). VD measured by M2 showed stronger correlations with glaucomatous parameters than by M1. By stepwise multiple linear regression, thinner RNFLT was associated with smaller VD measured by M2 (B = 4.643, P < 0.001). Worse MD was associated with smaller VD measured by M1 (B = 1.079, P = 0.015).

Conclusion

The VD measured by M2 showed better reproducibility and higher correlation with glaucomatous structural parameters. Image sharpning helps display of hazy vasculature in glaucoma, which may reflect visual function better. Researchers should carefully choose image processing methods according to their research object.
Tissue Damage, Not Infection, Triggers Hepatic Unfolded Protein Response in an Experimental Rat Peritonitis Model
Authors: Müllebner Andrea , Herminghaus Anna , Miller Ingrid , Kames Martina , Luís Andreia , Picker Olaf , Bauer Inge , Kozlov Andrey V. , Duvigneau Johanna Catharina
Published: March 2022

Background

Abdominal surgery is an efficient treatment of intra-abdominal sepsis. Surgical trauma and peritoneal infection lead to the activation of multiple pathological pathways. The liver is particularly susceptible to injury under septic conditions. Liver function is impaired when pathological conditions induce endoplasmic reticulum (ER) stress. ER stress triggers the unfolded protein response (UPR), aiming at restoring ER homeostasis, or inducing cell death. In order to translate basic knowledge on ER function into the clinical setting, we aimed at dissecting the effect of surgery and peritoneal infection on the progression of ER stress/UPR and inflammatory markers in the liver in a clinically relevant experimental animal model.

Methods

Wistar rats underwent laparotomy followed by colon ascendens stent peritonitis (CASP) or surgery (sham) only. Liver damage (aspartate aminotransferase (AST), alanine aminotransferase (ALT) and De Ritis values), inflammatory and UPR markers were assessed in livers at 24, 48, 72, and 96 h postsurgery. Levels of inflammatory (IL-6, TNF-α, iNOS, and HO-1), UPR (XBP1, GRP78, CHOP), and apoptosis (BAX/Bcl-XL) mRNA were determined by qPCR. Splicing of XBP1 (XBP1s) was analyzed by gel electrophoresis, p-eIF2α and GRP78 protein levels using the western blots.

Results

Aspartate aminotransferase levels were elevated 24 h after surgery and thereafter declined with different kinetics in sham and CASP groups. Compared with sham De Ritis ratios were significantly higher in the CASP group, at 48 and 96 h. CASP induced an inflammatory response after 48 h, evidenced by elevated levels of IL-6, TNF-α, iNOS, and HO-1. In contrast, UPR markers XBP1s, p-eIF2α, GRP78, XBP1, and CHOP did not increase in response to infection but paralleled the kinetics of AST and De Ritis ratios. We found that inflammatory markers were predominantly associated with CASP, while UPR markers were associated with surgery. However, in the CASP group, we found a stronger correlation between XBP1s, XBP1 and GRP78 with damage markers, suggesting a synergistic influence of inflammation on UPR in our model.

Conclusion

Our results indicate that independent mechanisms induce ER stress/UPR and the inflammatory response in the liver. While peritoneal infection predominantly triggers inflammatory responses, the conditions associated with organ damage are predominant triggers of the hepatic UPR.
Systemic Immune-Inflammation Index Predicts Contrast-Induced Acute Kidney Injury in Patients Undergoing Coronary Angiography: A Cross-Sectional Study
Authors: Jiang Hangpan , Li Duanbin , Xu Tian , Chen Zhezhe , Shan Yu , Zhao Liding , Fu Guosheng , Luan Yi , Xia Shudong , Zhang Wenbin
Published: March 2022

Background and Aims

Systemic immune-inflammation index (SII) is an emerging indicator and correlated to the incidence of cardiovascular diseases. This study aimed to explore the association between SII and contrast-induced acute kidney injury (CI-AKI).

Methods

In this retrospective cross-sectional study, 4,381 subjects undergoing coronary angiography (CAG) were included. SII is defined as neutrophil count × platelet count/lymphocyte count. CI-AKI was determined by the elevation of serum creatinine (Scr). Multivariable linear and logistic regression analysis were used to determine the relationship of SII with Scr and CI-AKI, respectively. Receiver operator characteristic (ROC) analysis, structural equation model analysis, and subgroup analysis were also performed.

Results

Overall, 786 (17.9%) patients suffered CI-AKI after the intravascular contrast administration. The subjects were 67.1 ± 10.8 years wold, with a mean SII of 5.72 × 1011/L. Multivariable linear regression analysis showed that SII linearly increased with the proportion of Scr elevation (β [95% confidence interval, CI] = 0.315 [0.206 to 0.424], P < 0.001). Multivariable logistic regression analysis demonstrated that higher SII was associated with an increased incidence of CI-AKI ([≥12 vs. <3 × 1011/L]: odds ratio, OR [95% CI] = 2.914 [2.121 to 4.003], P < 0.001). Subgroup analysis showed consistent results. ROC analysis identified a good predictive value of SII on CI-AKI (area under the ROC curve [95% CI]: 0.625 [0.602 to 0.647]). The structural equation model verified a more remarkable direct effect of SII (β = 0.102, P < 0.001) on CI-AKI compared to C-reactive protein (β = 0.070, P < 0.001).

Conclusions

SII is an independent predictor for CI-AKI in patients undergoing CAG procedures.
Epithelial Abnormalities in the Small Intestine of Zambian Children With Stunting
Authors: Mulenga Chola , Sviben Sanja , Chandwe Kanta , Amadi Beatrice , Kayamba Violet , Fitzpatrick James A. J. , Mudenda Victor , Kelly Paul
Published: March 2022

Background

Environmental enteropathy (EE) contributes to impaired linear growth (stunting), in millions of children worldwide. We have previously reported that confocal laser endomicroscopy (CLE) shows fluorescein leaking from blood to gut lumen in vivo in adults and children with EE. We set out to identify epithelial lesions which might explain this phenomenon in Zambian children with stunting non-responsive to nutritional support.

Methods

We performed confocal laser endomicroscopy (CLE) in 75 children and collected intestinal biopsies for histology in 91 children. CLE videos were evaluated, employing the Watson score to determine severity of leakiness. Morphometry was carried out on well-orientated mucosa and 3 biopsies were examined by electron microscopy.

Results

Confocal laser endomicroscopy demonstrated substantial leakage from circulation to gut lumen in 73 (97%) children. Histology consistently showed characteristic changes of EE: villus blunting, lamina propria and epithelial inflammation, and depletion of secretory cells (Paneth cells and goblet cells). Epithelial abnormalities included marked variability in epithelial height, disorganised and shortened microvilli, dilated intercellular spaces, pseudostratification, formation of synechiae between epithelium on adjacent villi, crypt destruction, and abundant destructive lesions which may correspond to the microerosions identified on CLE.

Conclusion

Epithelial abnormalities were almost universal in Zambian children with non-responsive stunting, including epithelial microerosions, cell-cell adhesion anomalies, and defects in secretory cells which may all contribute to impairment of mucosal barrier function and microbial translocation.
From Macroscopy to Ultrastructure: An Integrative Approach to Pulmonary Pathology
Authors: Verleden Stijn E. , Braubach Peter , Werlein Christopher , Plucinski Edith , Kuhnel Mark P. , Snoeckx Annemiek , El Addouli Haroun , Welte Tobias , Haverich Axel , Laenger Florian P. , Dettmer Sabine , Pauwels Patrick , Verplancke Veronique , Van Schil Paul E. , Lapperre Therese , Kwakkel-Van-Erp Johanna M. , Ackermann Maximilian , Hendriks Jeroen M. H. , Jonigk Danny
Published: March 2022

Pathology and radiology are complimentary tools, and their joint application is often crucial in obtaining an accurate diagnosis in non-neoplastic pulmonary diseases. However, both come with significant limitations of their own: Computed Tomography (CT) can only visualize larger structures due to its inherent–relatively–poor resolution, while (histo) pathology is often limited due to small sample size and sampling error and only allows for a 2D investigation. An innovative approach of inflating whole lung specimens and subjecting these subsequently to CT and whole lung microCT allows for an accurate matching of CT-imaging and histopathology data of exactly the same areas. Systematic application of this approach allows for a more targeted assessment of localized disease extent and more specifically can be used to investigate early mechanisms of lung diseases on a morphological and molecular level. Therefore, this technique is suitable to selectively investigate changes in the large and small airways, as well as the pulmonary arteries, veins and capillaries in relation to the disease extent in the same lung specimen. In this perspective we provide an overview of the different strategies that are currently being used, as well as how this growing field could further evolve.