bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental Study on the Evolution of Dynamic Pore Pressure and Unidirectional and Bidirectional Vibrations of Phosphogypsum
Authors: Kang Fuqi , Wang Guangjin , Liu Wenlian , Zhao Kui , Wang Menglai , Li Xiaoshuang , Zhong Wen , Dong Zhicheng
Published: June 2022

Under seismic action, the stock of phosphogypsum (PG) affects the security risk significantly, so it is crucial to study the dynamic characteristics of PG. In this article, unidirectional and bidirectional vibration tests on typical PG in Yunnan under different consolidation-confining pressure and vibration conditions were carried out using a dynamic triaxial apparatus that can be used for bidirectional vibration. The results show that the pore pressure growth of PG under both unidirectional and bidirectional vibrations has obvious stages and can be fitted by the BiDoseResp function. The dynamic strength of PG does not increase monotonically with the increase in consolidation-confining pressure and dynamic stress under the same cyclic stress ratio (CSR) but varies under a specific critical condition. The dynamic strength of PG decreases significantly with the increase in CSR under unidirectional and bidirectional vibrations. The number of vibrations required for liquefaction by bidirectional vibrations is much larger than that by unidirectional vibrations under the same CSR conditions, and the specimens have significant softening characteristics after liquefaction by bidirectional vibrations. The study results can provide theoretical references for studying the dynamic stability of PG reservoirs under seismic action.
Teaching of Human Parasitology During the COVID-19 Pandemic in China
Authors: Deng Sheng-Qun , He Mu-Zi , Wang Wei , Zhang Chao , Shen Ji-Jia , Shen Ji-Long , Du Yi-Nan , Liu Miao
Published: June 2022

Since the coronavirus disease 2019 (COVID-19) pandemic, human parasitology education has been exceedingly disrupted. To deliver human parasitology knowledge, medical universities in China have employed multiple measures, some of which have had positive outcomes that have not yet been summarized. The objective of this review is to share the Chinese experience as the human parasitology teaching methods were transformed. In general, we adopted a fully online teaching model under urgent pandemic control measures based on a well-structured teaching model that integrated the course preview, live lecture, review, and assessment. Combinations were attempted of COVID-19 and parasitology teaching contents. Some active learning models, such as case-based e-learning and flipped classrooms, were proposed for offline and online blended teaching during the normalization stage of the pandemic. Meanwhile, we discuss both the strengths and flaws of online and blended teaching. Some useful assessment tools are presented for reference purposes. In conclusion, this transition to online and online-offline blended human parasitology teaching in China has boosted innovative teaching activities and may continue to catalyze the transformation of medical education.
Mental Health in Postoperative Thyroid Patients During the COVID-19 Pandemic
Authors: Yang Shijie , Xu Xiequn
Published: June 2022

Background

Little is known about mental health in patients after thyroid surgery during the peak of the COVID-19 pandemic in China. This study aimed to assess the mental health of postoperative thyroid patients and to explore potential factors associated with psychological symptoms.

Methods

In this study, we surveyed 241 patients who underwent thyroid surgery at Peking Union Medical College Hospital. Insomnia, anxiety, depression, and posttraumatic stress symptoms (PTSS) were measured using the Insomnia Severity Index (ISI), Generalized Anxiety Disorder Questionnaire (GAD-7), Patient Health Questionnaire (PHQ-9), and Impact of Event Scale-Revised (IES-R), respectively.

Results

A significant proportion of postoperative patients reported experiencing insomnia, anxiety, depression, and PTSS. Patients that were older, single/divorced/widowed, and less educated; had lower income and poor general health; had undergone surgery within the past six months; had disrupted follow-up, and; searched social media for COVID-19-related information were associated with worse mental health.

Conclusions

During the COVID-19 pandemic, postoperative thyroid patients tended to develop mental health problems and have less psychological support, emphasizing the importance of patient education and psychological interventions.
Novel Nomograms to Predict Delayed Hyponatremia After Transsphenoidal Surgery for Pituitary Adenoma
Authors: Lin Kunzhe , Zeng Ran , Mu Shuwen , Lin Yinghong , Wang Shousen
Published: June 2022

Objective

This study aimed to develop a nomogram of clinical variables and magnetic resonance imaging scans to predict delayed hyponatremia after transsphenoidal surgery for pituitary adenoma.

Methods

Patients who underwent transsphenoidal surgery for pituitary adenoma in Fuzong Clinical Medical College of Fujian Medical University between January 2012 and December 2020 were retrospectively investigated. Medical records, MRI findings, and laboratory examination results were recorded as candidate variable predictors of delayed hyponatremia. A nomogram to predict delayed hyponatremia was formulated based on the multivariable model of risk factors. The predictive accuracy and discriminative ability of the nomogram were assessed using the receiver operating characteristic (ROC) curve, calibration plot, and decision curve analyses. The model underwent prospective validation in three medical centers with patients who underwent transsphenoidal surgery for pituitary adenoma between January 2021 and February 2022.

Results

The model that incorporated the postoperative length of “measurable pituitary stalk,” pituitary stalk deviation angle difference, postoperative diabetes insipidus, sinking depth of diaphragma sellae, and blood sodium level on the second postoperative day was developed and presented as the nomogram of the training cohort. The nomogram achieved area under the ROC curve (AUCs) of 0.806 and 0.849 for the training cohort and the testing cohort, respectively, and displayed good calibration. Decision curve analysis showed that the nomogram was clinically useful when the threshold probability was 13–96%.

Conclusions

We developed a nomogram to evaluate the individualized prediction of delayed hyponatremia after transsphenoidal surgery for pituitary adenomas.
Latent Autoimmune Diabetes in Adults and Metabolic Syndrome—A Mini Review
Authors: Pan Niansi , Yang Shimei , Niu Xiaohong
Published: June 2022

Latent autoimmune diabetes in adults (LADA) is a heterogeneous subtype of diabetes characterized by islet cell destruction mediated by islet autoimmunity and insulin resistance. Metabolic syndrome (MetS) is a state in which many risk factors for metabolic and cardiovascular diseases accumulate in an individual. Based on clinical data, this review covers the prevalence of MetS in LADA, focusing on the risk associated with and the role of insulin resistance in the development of LADA from the perspective of inflammatory factors, environmental factors, and the gut microbiota, aiming to improve our understanding of this condition.
pH-Dependence of Glucose-Dependent Activity of Beta Cell Networks in Acute Mouse Pancreatic Tissue Slice
Authors: Postić Sandra , Gosak Marko , Tsai Wen-Hao , Pfabe Johannes , Sarikas Srdjan , Stožer Andraž , Korošak Dean , Yang Shi-Bing , Slak Rupnik Marjan
Published: June 2022

Extracellular pH has the potential to affect various aspects of the pancreatic beta cell function. To explain this effect, a number of mechanisms was proposed involving both extracellular and intracellular targets and pathways. Here, we focus on reassessing the influence of extracellular pH on glucose-dependent beta cell activation and collective activity in physiological conditions. To this end we employed mouse pancreatic tissue slices to perform high-temporally resolved functional imaging of cytosolic Ca2+ oscillations. We investigated the effect of either physiological H+ excess or depletion on the activation properties as well as on the collective activity of beta cell in an islet. Our results indicate that lowered pH invokes activation of a subset of beta cells in substimulatory glucose concentrations, enhances the average activity of beta cells, and alters the beta cell network properties in an islet. The enhanced average activity of beta cells was determined indirectly utilizing cytosolic Ca2+ imaging, while direct measuring of insulin secretion confirmed that this enhanced activity is accompanied by a higher insulin release. Furthermore, reduced functional connectivity and higher functional segregation at lower pH, both signs of a reduced intercellular communication, do not necessary result in an impaired insulin release.
Cellular Senescence and Regulated Cell Death of Tubular Epithelial Cells in Diabetic Kidney Disease
Authors: Shen Shuang , Ji Chuanyuan , Wei Kaifeng
Published: June 2022

Cellular senescence is frequently evident at etiologic sites of chronic diseases and involves essentially irreversible arrest of cell proliferation, increased protein production, resistance to apoptosis, and altered metabolic activity. Regulated cell death plays a vital role in shaping fully functional organs during the developmental process, coordinating adaptive or non-adaptive responses, and coping with long-term harmful intracellular or extracellular homeostasis disturbances. In recent years, the concept of ‘diabetic tubulopathy’ has emerged. tubular epithelial cells are particularly susceptible to the derangements of diabetic state because of the virtue of the high energy requirements and reliance on aerobic metabolism render. Hyperglycemia, oxidative stress, persistent chronic inflammation, glucose toxicity, advanced glycation end-products (AGEs) accumulation, lipid metabolism disorders, and lipotoxicity contribute to the cellular senescence and different patterns of regulated cell death (apoptosis, autophagic cell death, necroptosis, pyroptosis, and ferroptosis) in tubular epithelial cells. We now explore the ‘tubulocentric’ view of diabetic kidney disease(DKD). And we summarize recent discoveries regarding the development and regulatory mechanisms of cellular senescence, apoptosis, autophagic cell death, necroptosis, pyroptosis, and ferroptosis in the pathogenesis of DKD. These findings provide new perspectives on the mechanisms of DKD and are useful for designing novel therapeutic approaches for the treatment of DKD.
Muscle Fat Content Is Strongly Associated With Hyperuricemia: A Cross-Sectional Study in Chinese Adults
Authors: Chen Ningxin , Han Tingting , Liu Hongxia , Cao Jie , Liu Wenwen , Zuo Didi , Zhang Ting , Lan Xiucai , Jin Xian , Weng Yurong , Hu Yaomin
Published: June 2022

Studies have indicated that the skeletal muscle mass and strength was related to serum uric acid (UA), but there is a lack of research on the association of skeletal muscle fat content with UA. The purpose of this cross-sectional study is to investigate the correlation of skeletal muscle fat index (SMFI) and hyperuricemia (HUA) in Chinese adults. 500 subjects (306 men and 194 women) were included in the study. The participants were divided into four groups according to SMFI quartiles. Pearson’s correlations between SMFI and metabolic variables were calculated. Logistic regression analysis was used to estimate the association between the quartiles of SMFI and risk of hyperuricemia. UA showed a positive association with SMFI after adjusted for BMI, age and gender. A significant association between the SMFI and risk of HUA was found, the OR for HUA was 2.79 (95% CI 1.18-6.59, p<0.05) in Q2, 2.41(95% CI 1.00-5.81, p<0.05) in Q3, and 2.63 (95% CI 1.03-6.72, p<0.05) in Q4, after adjusted for BMI. In conclusion, the SMFI was significantly associated with the level of serum UA, and the higher SMFI may indicate a higher risk of HUA, independent of BMI.
A Simple Techno-Economic Assessment for Scaling-Up the Enzymatic Hydrolysis of MSW Pulp
Authors: Climent Barba Fernando , Grasham Olivier , Puri Dhivya J. , Blacker A. John
Published: June 2022

A techno-economic assessment (TEA) of enzymatic hydrolyses of a municipal solid waste (MSW)-derived pulp was performed to compare various bioprocessing configurations for the production of platform sugars at both pilot and demonstration scales (two-stage continuous, batch, and two-stage fed-batch). The configurations modeled used either rotary drum and/or continuous stirred tank reactors. By using reaction kinetics and public vendor’s quotes, economic analyses were calculated for each of the proposed systems: capital expenditure (CapEx); operation expenditure (OpEx); revenue and profit; return on investment (ROI); and payback period (PP). The TEA showed that a two-stage continuous configuration with a total residence time of 54 h (6 and 48 h for primary and secondary stages) was the best option for obtaining sugars, showing sevenfold higher enzyme productivity and better profit than the reference systems. Although pilot-scale enzymatic hydrolysis demonstrated an unprofitable process, this was mainly due to the high associated enzyme cost. Increasing the scale diminished this problem, leading to higher profit per processed unit (£/kg lignocellulosic sugars). From an investment perspective, the two-stage 6/48 configuration gave a more attractive ROI and PP than the other designs.
Electrolysis Assisted Biomass Gasification for Liquid Fuels Production
Authors: Mesfun Sennai , Engvall Klas , Toffolo Andrea
Published: June 2022

Gasification is a promising pathway for converting biomass residues into renewable transportation fuels and chemicals needed to comply with the ambitious Swedish environmental targets. The paper investigates the integration of a molten carbonate electrolysis cell (MCEC) in biofuel production pathway from sawmill byproducts, to improve the performance of gas cleaning and conditioning steps prior to the final conversion of syngas into liquid biofuels. The energy, material, and economic performance of process configurations with different gasification technologies are simulated and compared. The results provide relevant information to develop the engineering of gas-to-liquid transportation fuels utilizing renewable electricity. The MCEC replaces the water-gas shift step of a conventional syngas conditioning process and enables increased product throughput by as much as 15%–31%. Depending on the process configuration and steam-methane reforming technology, biofuels can be produced to the cost range 140–155 €/MWh in the short-term.
Conductivity and Transference Number Determination Protocols for Solid Oxide Cell Materials
Authors: Hardy John S. , Kulkarni Aniruddha P. , Stevenson Jeffry W. , Marina Olga A.
Published: June 2022

To standardize materials and component characterization for next generation hydrogen production and energy generation solid oxide cell (SOC) technologies, test protocols are being established to facilitate comparison across the numerous laboratories and research institutions where SOC development for application in solid oxide fuel cells (SOFCs) and solid oxide electrolyzes cells (SOEC) is conducted. This paper proposes guiding protocols for fundamental electrical properties characterization of SOC materials, including temperature- and oxygen partial pressure (pO2)-dependent conductivity measurements, and use of the electromotive force for determining the transference numbers, or contributions of each charge carrier (i.e., ions and electrons), to the total conductivity. The protocol for Archimedes density measurements is also provided as an integral technique to both of these methods.
An Inverted U-shaped Relationship? The Impact of Government Subsidies on the R&D Investment of New Energy Companies: Economic Policy Uncertainty and Enterprise Heterogeneity Perspectives
Authors: Liu Manzhi , Wen Jixin , Liu Yingjie , Lv Xueqing , Liu Qiyao , Lu Jia , Qin Ying , Zhang Linlin
Published: June 2022

The government is actively pursuing a financial subsidy policy to assist new energy companies in strengthening their ability to innovate independently, but the impact of government subsidies has been contentious. Using 142 new energy listed companies in Shanghai and Shenzhen A-stocks from 2012 to 2018, a fixed-effect model was used to examine the impact of government subsidies on new energy companies’ R&D investment, as well as the changes in the relationship between the two under conditions of economic policy uncertainty and enterprise heterogeneity. The results indicate that government subsidies have an inverted U-shaped effect on enterprise R&D investment; that is, while appropriate subsidies promote enterprise R&D investment, excessive subsidies suffocate other funds invested by the company in R&D and exacerbate the company’s proclivity to invest in fixed assets. Furthermore, economic policy uncertainty has a more substantial negative adjustment effect on the relationship between government subsidies and corporate R&D investment than fixed-asset investment. Additionally, research indicates that in China’s eastern coastal regions, the impact of government subsidies on R&D investment is more remarkable for high-risk preference enterprises and non-state-owned enterprises than in the central and western regions, where the negative adjustment effect of economic policy uncertainty is more remarkable for low-risk-preference and non-state-owned enterprises. It is recommended that government departments ensure economic policy stability and continuity and that subsidy selection be more targeted and precise in determining subsidy funds.
Selection of Tropical Microalgae Species for Mass Production Based on Lipid and Fatty Acid Profiles
Authors: Andrew Audrey Rose , Yong Wilson Thau Lym , Misson Mailin , Anton Ann , Chin Grace Joy Wei Lie
Published: June 2022

Numerous recent studies have identified microalgae biofuel as one of the major renewable energy sources for sustainable development due to their high biomass productivity, high lipid content, and availability of locally adapted strains in various geographical locations. There have been minimal studies on the fatty acid composition of lipid production on local microalgae species in Sabah, Malaysia. Thus, screening for local microalgae species capable of producing biodiesel can aid in the selection of suitable species. This study aimed to isolate and identify promising local microalga as biodiesel feedstock for mass cultivation. Eight microalgae species,Acutodesmus obliquus,Chaetoceros muelleri,Isochrysis galbana,Ankistrodesmus falcatus,Chlamydomonas monadina,Chlorella emersonii,Nannochloropsis oculata, andTetraselmis chuii,were successfully isolated and identified from Kota Kinabalu, Sabah. The isolated microalgae were characterized based on the lipid/biomass productivity, lipid content and fatty acid profiles. These isolates had biomass productivity of 0.11–0.78 g/L/day, lipid content of 11.69–39.00% dry weight, and lipid productivity of 21.11–252.64 mg/L/day. According to GC-MS analyses, four isolates produced more than 80% of C14–C18fatty acids, which wereA. falcatus(95%),C. emersonii(93%),A. obliquus(91%), andC. muelleri(81%). Despite its low biomass productivity,C. muelleriwas chosen as the best biodiesel species candidate because of its moderately high lipid productivity (42.90 mg/L/day), highest lipid content (39% dry weight), high level of MUFAs and C14–C18FAs (81.47%), with the highest oleic acid proportion (28.38%), all of which are desirable characteristics for producing high-quality biodiesel.
Analysis of Surface Pressure Pulsation Characteristics of Centrifugal Pump Magnetic Liquid Sealing Film
Authors: Li Zhenggui , Wang Kun , Li Wangxu , Yan Shengnan , Chen Fang , Peng Shengyang
Published: June 2022

In order to discuss the surface pressure pulsation characteristics of the magnetic-fluid sealing membrane of centrifugal pump, this paper studies the surface pressure pulsation characteristics of the shaft end sealing membrane under different flow operating conditions of centrifugal pump based on the combination of numerical calculation and experimental verification. The results show that the pressure value on the surface of the magnetic-fluid sealing film decreases with the increase of the flow rate of the centrifugal pump, and the pressure on the surface of the magnetic-fluid sealing film has periodic pulsation, and the period is the time required for a single blade to sweep the volute separating tongue. In one rotation cycle of the runner, the number of reciprocating movements of the magnetic-hydraulic sealing film is the same as the number of blades of the runner. The main reason for the pressure pulsation is that the impeller periodically sweeps the fixed surface of the centrifugal pump.
Effect of China’s Land Resource Allocation Method on Enterprise Technological Innovation: Promoting or Inhibiting
Authors: Ma Jintao , Hu Qiuguang , Wei Xinyi
Published: June 2022

Whether the land resource allocation method with Chinese characteristics can continue to play a positive role must be explored in the context of high-quality development. This study is based on the panel data of A-share listed non-financial insurance enterprises from 2006 to 2018. The proportion of industrial land area in urban construction land area to characterize land resource allocation methods and analyzes the effect of China’s land resource allocation methods on enterprise technological innovation. Results show that 1) the land resource allocation methods of the large-scale transfer of industrial land and the restricted transfer of commercial and residential land inhibit enterprises from technological innovation. 2) The inhibition is heterogeneous given the nature of the enterprise and the degrees of technology intensity and regional differences. The effect is greater on state-owned enterprises and those in high-tech industries and eastern cities. 3) The increase in corporate R&D expenditure and government subsidies weakens the negative effect of China’s land resource allocation method to a certain extent. This study maintains that the reform of land resource allocation methods should be promoted following local conditions, the role of the market should be fully utilized, and the subjective initiative of local governments should also be mobilized to promote the overall transformation of the economy and society to innovation-driven development effectively.
Does Global Value Chain Embeddedness Matter for the Green Innovation Value Chain?
Authors: Hu Dianxi , Jiao Jianling , Chen Chuxi , Xiao Renqiao , Tang Yunshu
Published: June 2022

The global value chain (GVC) is a new model of international commodity manufacturing and trade that provides a unique channel to obtain innovative knowledge and technology spillover. However, the impact mechanism of GVC embeddedness on the internal processes of the green innovation value chain (GIVC) is not clear. This study opens the “black box” of green innovation processes, which is very important for connecting resource and industrial chains. The KPWW method and the super-efficiency network SBM-DEA model (NSBM-S) are used to measure the GVC embeddedness index and GIVC efficiency, respectively. A panel model is constructed to demonstrate the multidimensional impacts of the GVC position on GIVC. The result show that mean green technology R&D efficiency is less than mean green achievement transformation efficiency; the impact of the GVC embeddedness on the GIVC efficiency is mainly reflected in the rise of the GVC position rather than the deepening of GVC participation; and the impact of the rise of the GVC position on the green technology R&D efficiency is greater than that of green achievement transformation efficiency. Without considering the greenness characteristics of intermediate output, the impact of the GVC position on the general innovation value chain will be amplified. Our conclusions are conducive to identifying the weak links in green innovation processes and provide novel empirical evidence for formulating sustainable development countermeasures in an open economy.
Identification of Alternative Splicing-Related Genes CYB561 and FOLH1 in the Tumor-Immune Microenvironment for Endometrial Cancer Based on TCGA Data Analysis
Authors: Sun Dan , Zhang Aiqian , Gao Bingsi , Zou Lingxiao , Huang Huan , Zhao Xingping , Xu Dabao
Published: June 2022

Background: Advanced and recurrent endometrial cancer EC remains controversial. Immunotherapy will play a landmark role in cancer treatment, and alternative splicing (AS) of messenger RNA (mRNA) may offer the potential of a broadened target space.

Methods: We downloaded the clinical information and mRNA expression profiles from The Cancer Genome Atlas (TCGA) database. Hub genes were extracted from 11 AS-related genes to analyze the correlation between clinical parameters and the tumor-immune microenvironment. We also analyzed the correlations between the copy numbers, gene expressions of hub genes, and immune cells. The correlation between the risk score and the six most important checkpoint genes was also investigated. The ESTIMATE algorithm was finally performed on each EC sample based on the high- and low-risk groups.

Results: The risk score was a reliable and stable independent risk predictor in the Uterine Corpus Endometrial Carcinoma (UCEC) cohort. CYB561|42921|AP and FOLH1|15817|ES were extracted. The expression of CYB561 and FOLH1 decreased gradually with the increased grade and International Federation of Gynecology and Obstetrics (FIGO) stage (p < 0.05). Gene copy number changes in CYB561 and FOLH1 led to the deletion number of myeloid DC cells and T cell CD8+. Low expression of both CYB561 and FOLH1 was associated with poor prognosis (p < 0.001). The checkpoint genes, CTLA-4 and PDCD1, exhibited a negative correlation with the risk score of AS in UCEC.

Conclusion: AS-related gene signatures were related to the immune-tumor microenvironment and prognosis. These outcomes were significant for studying EC’s immune-related mechanisms and exploring novel prognostic predictors and precise therapy methods.
Time Course Analysis of Transcriptome in Human Myometrium Depending on Labor Duration and Correlating With Postpartum Blood Loss
Authors: Chen Lina , Luo Yihong , Chen Yunshan , Wang Lele , Wang Xiaodi , Zhang Guozheng , Ji Kaiyuan , Liu Huishu
Published: June 2022

The maintenance of coordinated powerful episodic contractions of the uterus is the crucial factor for normal labor. The uterine contractility is gradually enhanced with the progression of labor, which is related to the gene expression of the myometrium. Competing endogenous RNA (ceRNA) can also regulate the gene expression. To better understand the role of ceRNA network in labor, transcriptome sequencing was performed on the myometrium of 17 parturients at different labor durations (0–24 h). From this, expression levels of mRNA, long non-coding RNA (lncRNA), circular RNA (circRNA), and microRNA (miRNA) were correlated with labor duration. Then, targeting relationships between mRNAs, lncRNAs, circRNAs, and miRNAs were predicted, and the ceRNA regulatory network was established. The mRNA expression patterns associated with cervical dilation and postpartum bleeding were further investigated. This analysis identified 932 RNAs positively correlated with labor duration (859 mRNAs, 28 lncRNAs, and 45 circRNAs) and 153 RNAs negatively correlated with labor duration (122 mRNAs, 28 lncRNAs, and 3 miRNAs). These mRNAs were involved in protein metabolism, transport, and cytoskeleton functions. According to the targeting relationship among these ceRNAs and mRNAs, a ceRNA network consisting of 3 miRNAs, 72 mRNAs, 2 circRNAs, and 1 lncRNA was established. In addition, two mRNA expression patterns were established using time-series analysis of mRNA expression in different phases of cervical dilation. A ceRNA network analysis for blood loss was performed; postpartum bleeding was closely related to inflammatory response, angiogenesis, and hemostasis. This study identified human myometrial transcriptome and established the ceRNA regulatory network depending on labor duration and highlighted the dynamic changes that occur at ceRNAs during parturition, which need to be considered more in the future to better understand how changes in gene expression are relevant to functional changes in human myometrium at labor.
Association of Single-Nucleotide Polymorphisms of rs2383206, rs2383207, and rs10757278 With Stroke Risk in the Chinese Population: A Meta-analysis
Authors: Hu Xuemei , Wang Dongsen , Cui Chunying , Wu Qingjian
Published: June 2022

Several studies have reported that chromosome 9p21 is significantly associated with ischemic stroke (IS) risk, with the G allele associated with increased risk. However, controversial results have been reported in the literature. We systematically assessed the relationship between stroke and three 9p21 loci (rs2383206, rs2383207, and rs10757278) in this meta-analysis. First, we searched the PubMed and Embase databases for relevant studies. We then calculated odds ratios using the chi-squared test. The evaluation of experimental data was performed using bias tests and sensitivity analyses. We analyzed data from 16 studies involving 18,584 individuals of Chinese ancestry, including 14,033 cases and 14,656 controls. Our results indicated that chromosome 9p21 is significantly associated with IS (odds ratio: 1.15, 95% confidence interval: 1.1–1.20, p < 0.0001). Because the three single-nucleotide polymorphisms (rs2383206, rs2383207, and 10757278) have a linkage disequilibrium relationship, all three may increase the risk of IS.
m6A Methylation in Cardiovascular Diseases: From Mechanisms to Therapeutic Potential
Authors: Li Longbo , Xu Nannan , Liu Jia , Chen Zhenzhen , Liu Xu , Wang Junnan
Published: June 2022

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide. Recent studies have shown that n6-methyladenosine (m6A) plays a major role in cardiovascular homeostasis and pathophysiology. These studies have confirmed that m6A methylation affects the pathophysiology of cardiovascular diseases by regulating cellular processes such as differentiation, proliferation, inflammation, autophagy, and apoptosis. Moreover, plenty of research has confirmed that m6A modification can delay the progression of CVD via the post-transcriptional regulation of RNA. However, there are few available summaries of m6A modification regarding CVD. In this review, we highlight advances in CVD-specific research concerning m6A modification, summarize the mechanisms underlying the involvement of m6A modification during the development of CVD, and discuss the potential of m6A modification as a therapeutic target of CVD.
Prenatal Exposure to Ambient Air Pollution and Epigenetic Aging at Birth in Newborns
Authors: Song Ashley Y. , Feinberg Jason I. , Bakulski Kelly M. , Croen Lisa A. , Fallin M. Daniele , Newschaffer Craig J. , Hertz-Picciotto Irva , Schmidt Rebecca J. , Ladd-Acosta Christine , Volk Heather E.
Published: June 2022

In utero air pollution exposure has been associated with adverse birth outcomes, yet effects of air pollutants on regulatory mechanisms in fetal growth and critical windows of vulnerability during pregnancy are not well understood. There is evidence that epigenetic alterations may contribute to these effects. DNA methylation (DNAm) based age estimators have been developed and studied extensively with health outcomes in recent years. Growing literature suggests environmental factors, such as air pollution and smoking, can influence epigenetic aging. However, little is known about the effect of prenatal air pollution exposure on epigenetic aging. In this study, we leveraged existing data on prenatal air pollution exposure and cord blood DNAm from 332 mother-child pairs in the Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), two pregnancy cohorts enrolling women who had a previous child diagnosed with autism spectrum disorder, to assess the relationship of prenatal exposure to air pollution and epigenetic aging at birth. DNAm age was computed using existing epigenetic clock algorithms for cord blood tissue—Knight and Bohlin. Epigenetic age acceleration was defined as the residual of regressing chronological gestational age on DNAm age, accounting for cell type proportions. Multivariable linear regression models and distributed lag models (DLMs), adjusting for child sex, maternal race/ethnicity, study sites, year of birth, maternal education, were completed. In the single-pollutant analysis, we observed exposure to PM2.5, PM10, and O3 during preconception period and pregnancy period were associated with decelerated epigenetic aging at birth. For example, pregnancy average PM10 exposure (per 10 unit increase) was associated with epigenetic age deceleration at birth (weeks) for both Knight and Bohlin clocks (β = −0.62, 95% CI: −1.17, −0.06; β = −0.32, 95% CI: −0.63, −0.01, respectively). Weekly DLMs revealed that increasing PM2.5 during the first trimester and second trimester were associated with decelerated epigenetic aging and that increasing PM10 during the preconception period was associated with decelerated epigenetic aging, using the Bohlin clock estimate. Prenatal ambient air pollution exposure, particularly in early and mid-pregnancy, was associated with decelerated epigenetic aging at birth.
Clinical Characteristics of Anti-N-Methyl-d-Aspartate Receptor Encephalitis Overlapping with Demyelinating Diseases: A Review
Authors: Zhang Shujiang , Yang Yuan , Liu Wenyu , Li Zuoxiao , Li Jinmei , Zhou Dong
Published: June 2022

Anti-N-methyl-d-aspartate receptor encephalitis (NMDARe), a common autoimmune encephalitis, can be accompanied by demyelinating disorders, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). To compare the clinical characteristics of patients with different overlapping syndromes, we searched the PubMed database and performed a systematic review. Of the 79 patients with overlapping syndromes, 15 had MS, 18 had aquaporin-4-antibody-positive NMOSD (AQP4-Ab-positive NMOSD), and 46 had MOGAD. Compared with classical NMDARe, overlapping syndromes showed atypical symptoms, such as limb weakness, sensory disturbance, and visual impairments in addition to the main symptoms of NMDARe and a lower ratio of ovarian teratoma. Patients with MOGAD overlap were the youngest, while patients with MS and AQP4-Ab-positive NMOSD overlap tended to be older than patients with classical NMDARe. A majority of patients with NMDARe who overlapped with MS or AQP4-Ab-positive NMOSD were female, but this was not the case for patients overlapped with MOGAD. When NMDARe and demyelinating diseases occurred sequentially, the interval was the longest in patients with NMDARe overlapped with MS. A favorable outcome was observed in patients overlapping with MOGAD, but no robust comparison can be drawn with the patients overlapping with AQP4-Ab-positive NMOSD and MS regarding the small number of available data. The long-term prognosis of overlapping syndromes needs further investigation.
Itaconate Suppresses Formation of Neutrophil Extracellular Traps (NETs): Involvement of Hypoxia-Inducible Factor 1α (Hif-1α) and Heme Oxygenase (HO-1)
Authors: Burczyk Gabriela , Cichon Iwona , Kolaczkowska Elzbieta
Published: June 2022

Neutrophil extracellular traps (NETs) immobilize pathogens during early stages of systemic inflammation but as the reaction progresses they become detrimental to endothelial cells and the organ-specific cells. For this reason it would be of importance to control their formation by either physiological or pharmacological means. Endogenously, formation of NETs is under control of cellular and whole organism metabolism as shown previously in the course of bacterial systemic inflammation, obesity or the combination of the two. Numerous leukocytes are subjected to immunometabolic regulation and in macrophages exposure to lipopolysaccharide (LPS) leads to two breaks in the Krebs cycle that impact this cell functioning. As a consequence of the first break, anti-microbial itaconic acid (itaconate) is produced whereas the second break activates hypoxia-inducible factor-1α (Hif-1α). In turn, itaconate activates transcription of the anti-inflammatory nuclear factor erythroid 2-related factor 2 (Nrf2) which upregulates cyto-protective heme oxygenase (HO-1). Here we report that exogenously added derivative of the itaconic acid, 4-octyl itaconate (4-OI), diminishes formation of NETs by neutrophils of either normal (lean) or obese mice, and independently of the age of the animals or immunoaging. Elucidating the mechanism of this inhibition we unravel that although Nrf2/HO-1 expression itself is not altered by 4-OI, it is up-regulated when compared against the NET formation while Hif-1α is downregulated in 4-OI-pre-treated LPS-stimulated neutrophils in either way. We further show that blockage of Hif-1α by its specific inhibitor diminishes NET release as does inhibition by 4-OI. Also inhibition of HO-1 activity correlates with diminished LPS-induced NET release upon pre-treatment with 4-OI albeit LPS alone induced NETs are not HO-1-dependent. In summary, we unravel that 4-OI inhibits NET formation by murine neutrophils independently of their origin (health vs. metabolically challenged animals) and the age of individuals/immunosenescence via inhibition of Hif-1α and induction of HO-1.
Altered Circulating Immune Cell Distribution in Traumatic Spinal Cord Injury Patients in Relation to Clinical Parameters
Authors: Fraussen Judith , Beckers Lien , van Laake-Geelen Charlotte C. M. , Depreitere Bart , Deckers Jens , Cornips Erwin M. J. , Peuskens Dieter , Somers Veerle
Published: June 2022

Following a spinal cord injury (SCI), an inflammatory immune reaction is triggered which results in advanced secondary tissue damage. The systemic post-SCI immune response is poorly understood. This study aimed to extensively analyse the circulating immune cell composition in traumatic SCI patients in relation to clinical parameters. High-dimensional flow cytometry was performed on peripheral blood mononuclear cells of 18 traumatic SCI patients and 18 healthy controls to determine immune cell subsets. SCI blood samples were collected at multiple time points in the (sub)acute (0 days to 3 weeks post-SCI, (s)aSCI) and chronic (6 to >18 weeks post-SCI, cSCI) disease phase. Total and CD4+ T cell frequencies were increased in cSCI patients. Both CD4+ T cells and B cells were shifted towards memory phenotypes in (s)aSCI patients and cSCI patients, respectively. Most profound changes were observed in the B cell compartment. Decreased immunoglobulin (Ig)G+ and increased IgM+ B cell frequencies reflected disease severity, as these correlated with American Spinal Injury Association (ASIA) impairment scale (AIS) scores. Post-SCI B cell responses consisted of an increased frequency of CD74+ cells and CD74 expression level within total B cells and B cell subsets. Findings from this study suggest that post-SCI inflammation is driven by memory immune cell subsets. The increased CD74 expression on post-SCI B cells could suggest the involvement of CD74-related pathways in neuroinflammation following SCI. In addition, the clinical and prognostic value of monitoring circulating IgM+ and IgG+ B cell levels in SCI patients should be further evaluated.
Development of a Humanized VHH Based Recombinant Antibody Targeting Claudin 18.2 Positive Cancers
Authors: Zhong Weixiang , Lu Yimin , Ma Zhe , He Yinjun , Ding Yongfeng , Yao Gaofeng , Zhou Zhenxing , Dong Jiali , Fang Yongliang , Jiang Weiqin , Wang Weilin , Huang Yanshan
Published: June 2022

Claudin 18.2 (CLDN18.2), a tight junction (TJ) family protein controlling molecule exchange between cells, is frequently over-expressed in gastric cancer, pancreatic adenocarcinomas and in a fraction of non–small cell lung cancer cases. The tumor properties indicate that CLDN18.2 could be an attractive drug target for gastric and pancreatic cancers. In this study, we present effective strategies for developing anti-CLDN18.2 therapeutic candidates, based on variable domain of heavy chain of heavy chain antibodies (VHHs). CLDN18.2-specific VHHs were isolated by panning a phage display library from an alpaca immunized with a stable cell line highly expressing CLDN18.2. Humanized VHHs fused with human IgG1 Fc, as potential therapeutic candidates, exhibited desirable binding specificity and affinity to CLDN18.2. In vitro experiments showed that hu7v3-Fc was capable of eliciting both antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) on CLDN18.2 positive tumor cells. In the mouse xenograft model, the anti-tumor efficacy of hu7v3-Fc was significantly more potent than Zolbetuximab, the benchmark anti-CLDN18.2 monoclonal antibody. Moreover, in vivo biodistribution using zirconium-89 (89Zr) labeled antibodies demonstrated that hu7v3-Fc (89Zr-hu7v3-Fc) exhibited a better tumor penetration and a faster tumor uptake than Zolbetuximab (89Zr-Zolbetuximab), which might be attributed to its smaller size and higher affinity. Taken together, anti-CDLN18.2 hu7v3-Fc is a promising therapeutic agent for human CLDN18.2 positive cancers. Furthermore, hu7v3 has emerged as a potential module for novel CLDN18.2 related therapeutics.
Immunovirotherapy Based on Recombinant Vesicular Stomatitis Virus: Where Are We?
Authors: Zhang Yuguo , Nagalo Bolni Marius
Published: June 2022

Vesicular stomatitis virus (VSV), a negative-strand RNA virus of theVesiculovirusgenus, has demonstrated encouraging anti-neoplastic activity across multiple human cancer types. VSV is particularly attractive as an oncolytic agent because of its broad tropism, fast replication kinetics, and amenability to genetic manipulations. Furthermore, VSV-induced oncolysis can elicit a potent antitumor cytotoxic T-cell response to viral proteins and tumor-associated antigens, resulting in a long-lasting antitumor effect. Because of this multifaceted immunomodulatory property, VSV was investigated extensively as an immunovirotherapy alone or combined with other anticancer modalities, such as immune checkpoint blockade. Despite these recent opportunities to delineate synergistic and additive antitumor effects with existing anticancer therapies, FDA approval for the use of oncolytic VSV in humans has not yet been granted. This mini-review discusses factors that have prompted the use of VSV as an immunovirotherapy in human cancers and provides insights into future perspectives and research areas to improve VSV-based oncotherapy.
CMV-Responsive CD4 T Cells Have a Stable Cytotoxic Phenotype Over the First Year Post-Transplant in Patients Without Evidence of CMV Viremia
Authors: Higdon Lauren E. , Ahmad Ayah A. , Schaffert Steven , Margulies Kenneth B. , Maltzman Jonathan S.
Published: June 2022

Cytomegalovirus (CMV) infection is a known cause of morbidity and mortality in solid organ transplant recipients. While primary infection is controlled by a healthy immune system, CMV is never eradicated due to viral latency and periodic reactivation. Transplantation and associated therapies hinder immune surveillance of CMV. CD4 T cells are an important part of control of CMV reactivation. We therefore investigated how CMV impacts differentiation, functionality, and expansion of protective CD4 T cells from recipients of heart or kidney transplant in the first year post-transplant without evidence of CMV viremia. We analyzed longitudinal peripheral blood samples by flow cytometry and targeted single cell RNA sequencing coupled to T cell receptor (TCR) sequencing. At the time of transplant, CD4 T cells from CMV seropositive transplant recipients had a higher degree of immune aging than the seronegative recipients. The phenotype of CD4 T cells was stable over time. CMV-responsive CD4 T cells in our transplant cohort included a large proportion with cytotoxic potential. We used sequence analysis of TCRαβ to identify clonal expansion and found that clonally expanded CMV-responsive CD4 T cells were of a predominantly aged cytotoxic phenotype. Overall, our analyses suggest that the CD4 response to CMV is dominated by cytotoxicity and not impacted by transplantation in the first year. Our findings indicate that CMV-responsive CD4 T cells are homeostatically stable in the first year after transplantation and identify subpopulations relevant to study the role of this CD4 T cell population in post-transplant health.
Plasmablast Expansion Following the Tetravalent, Live-Attenuated Dengue Vaccine Butantan-DV in DENV-Naïve and DENV-Exposed Individuals in a Brazilian Cohort
Authors: Silveira Cássia G. T. , Magnani Diogo M. , Costa Priscilla R. , Avelino-Silva Vivian I. , Ricciardi Michael J. , Timenetsky Maria do Carmo S. T. , Goulart Raphaella , Correia Carolina A. , Marmorato Mariana P. , Ferrari Lilian , Nakagawa Zelinda B. , Tomiyama Claudia , Tomiyama Helena , Kalil Jorge , Palacios Ricardo , Precioso Alexander R. , Watkins David I. , Kallás Esper G.
Published: June 2022

An effective vaccine against the dengue virus (DENV) should induce a balanced, long-lasting antibody (Ab) response against all four viral serotypes. The burst of plasmablasts in the peripheral blood after vaccination may reflect enriched vaccine-specific Ab secreting cells. Here we characterize the acute plasmablast responses from naïve and DENV-exposed individuals following immunization with the live attenuated tetravalent (LAT) Butantan DENV vaccine (Butantan-DV). The frequency of circulating plasmablasts was determined by flow cytometric analysis of fresh whole blood specimens collected from 40 participants enrolled in the Phase II Butantan-DV clinical trial (NCT01696422) before and after (days 6, 12, 15 and 22) vaccination. We observed a peak in the number of circulating plasmablast at day 15 after vaccination in both the DENV naïve and the DENV-exposed vaccinees. DENV-exposed vaccinees experienced a significantly higher plasmablast expansion. In the DENV-naïve vaccinees, plasmablasts persisted for approximately three weeks longer than among DENV-exposed volunteers. Our findings indicate that the Butantan-DV can induce plasmablast responses in both DENV-naïve and DENV-exposed individuals and demonstrate the influence of pre-existing DENV immunity on Butantan DV-induced B-cell responses.