bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of the Ubiquitin System in Chronic Pain
Authors: Cheng Jiurong , Deng Yingdong , Zhou Jun
Published: May 2021

As a significant public health issue, chronic pain, mainly neuropathic pain (NP) and inflammatory pain, has a severe impact. The underlying mechanisms of chronic pain are enigmatic at present. The roles of ubiquitin have been demonstrated in various physiological and pathological conditions and underscore its potential as therapeutic targets. The dysfunction of the component of the ubiquitin system that occurs during chronic pain is rapidly being discovered. These results provide insight into potential molecular mechanisms of chronic pain. Chronic pain is regulated by ubiquitination, SUMOylation, ubiquitin ligase, and deubiquitinating enzyme (DUB), etc. Insight into the mechanism of the ubiquitin system regulating chronic pain might contribute to relevant therapeutic targets and the development of novel analgesics.
An Interpretable Machine Learning Method for the Detection of Schizophrenia Using EEG Signals
Authors: Vázquez Manuel A. , Maghsoudi Arash , Mariño Inés P.
Published: May 2021

In this work we propose a machine learning (ML) method to aid in the diagnosis of schizophrenia using electroencephalograms (EEGs) as input data. The computational algorithm not only yields a proposal of diagnostic but, even more importantly, it provides additional information that admits clinical interpretation. It is based on an ML model called random forest that operates on connectivity metrics extracted from the EEG signals. Specifically, we use measures of generalized partial directed coherence (GPDC) and direct directed transfer function (dDTF) to construct the input features to the ML model. The latter allows the identification of the most performance-wise relevant features which, in turn, provide some insights about EEG signals and frequency bands that are associated with schizophrenia. Our preliminary results on real data show that signals associated with the occipital region seem to play a significant role in the diagnosis of the disease. Moreover, although every frequency band might yield useful information for the diagnosis, the beta and theta (frequency) bands provide features that are ultimately more relevant for the ML classifier that we have implemented.
A High-Throughput Comparative Proteomics of Milk Fat Globule Membrane Reveals Breed and Lactation Stages Specific Variation in Protein Abundance and Functional Differences Between Milk of Saanen Dairy Goat and Holstein Bovine
Authors: Jia Wei , Zhang Rong , Zhu Zhenbao , Shi Lin
Published: May 2021

Large variations in the bioactivities and composition of milk fat globule membrane (MFGM) proteins were observed between Saanen dairy goat and Holstein bovine at various lactation periods. In the present study, 331, 250, 182, and 248 MFGM proteins were characterized in colostrum and mature milk for the two species by Q-Orbitrap HRMS-based proteomics techniques. KEGG pathway analyses displayed that differentially expressed proteins in colostrum involved in galactose metabolism and an adipogenesis pathway, and the differentially expressed proteins in mature milk associated with lipid metabolism and a PPAR signaling pathway. These results indicated that the types and functions of MFGM proteins in goat and bovine milk were different, and goat milk had a better function of fatty acid metabolism and glucose homeostasis, which can enhance our understanding of MFGM proteins in these two species across different lactation periods, and they provide significant information for the study of lipid metabolism and glycometabolism of goat milk.
Selenium Transport Mechanism via Selenoprotein P—Its Physiological Role and Related Diseases
Authors: Saito Yoshiro
Published: May 2021

Selenoprotein P (SELENOP) is selenium (Se)-containing protein in plasma, which is primarily produced in the liver. The “P” in SELENOP originated from the presence in plasma. SELENOP contains selenocysteine, a cysteine analog containing Se instead of sulfur. SELENOP is a multi-functional protein to reduce phospholipid hydroperoxides and to deliver Se from the liver to other tissues, such as those of the brain and testis, playing a pivotal role in Se metabolism and antioxidative defense. Decrease in SELENOP causes various dysfunctions related to Se deficiency and oxidative stress, while excessive SELENOP causes insulin resistance. This review focuses on the Se transport system of SELENOP, particularly its molecular mechanism and physiological role in Se metabolism. Furthermore, the chemical form of Se and its biological meaning is discussed.
Pembrolizumab in FIGO IVB Verrucous Carcinoma of the Vulva: A Case Report
Authors: Wang Yuhan , Lin Rongchun , Zhang Bingzhong , Zhou Hui , Lin Zhongqiu , Yao Tingting
Published: May 2021

Background

Vulvar cancer is the fourth most common gynecologic cancer, and prognosis is poor in advanced vulvar cancer patients. Treatment for advanced vulvar cancer has not been satisfactory. In this report, we firstly report a FIGO IVB vulva verrucous carcinoma patient who obtained good prognosis after systemic treatment.

Case Presentation

A patient was admitted to hospital due to her vulvar lesion persistent for past 14 years. The vulvar mass has widely invaded urethra, part of anus, the lower third of the vagina, bilateral superior and inferior branches of pubis, and bilateral internal and external muscles of obturator. Multiple metastatic lymph nodes were also found in the pelvic cavity. The histopathological studies confirmed vulvar verrucous carcinoma with a PD-L1 overexpression. After six courses of neoadjuvant chemotherapy and pembrolizumab, the patient underwent radical vulvectomy and achieved optimal cytoreduction. Postoperative pathology found no residual tumor. The patient then received one course of postoperative chemotherapy and pembrolizumab, underwent radiation therapy, and was disease free after 6 months follow-up.

Conclusion

Our individualized treatment strategy is successful. Pembrolizumab is safe and effective in the treatment of advanced vulvar verrucous carcinoma with PD-L1 overexpression.
Radiomic Analysis of Contrast-Enhanced Mammography With Different Image Types: Classification of Breast Lesions
Authors: Wang Simin , Mao Ning , Duan Shaofeng , Li Qin , Li Ruimin , Jiang Tingting , Wang Zhongyi , Xie Haizhu , Gu Yajia
Published: May 2021

Objective: A limited number of studies have focused on the radiomic analysis of contrast-enhanced mammography (CEM). We aimed to construct several radiomics-based models of CEM for classifying benign and malignant breast lesions.

Materials and Methods: The retrospective, double-center study included women who underwent CEM between November 2013 and February 2020. Radiomic analysis was performed using high-energy (HE), low-energy (LE), and dual-energy subtraction (DES) images from CEM. Datasets were randomly divided into the training and testing sets at a ratio of 7:3. The maximum relevance minimum redundancy (mRMR) method and least absolute shrinkage and selection operator (LASSO) logistic regression were used to select the radiomic features and construct the best classification models. The performances of the models were assessed by the area under the receiver operating characteristic curve (AUC) with a 95% confidence interval (CI). Leave-group-out cross-validation (LGOCV) for 100 rounds was performed to obtain the mean AUCs, which were compared by the Wilcoxon rank-sum test and the Kruskal–Wallis rank-sum test.

Results: A total of 192 women with 226 breast lesions (101 benign; 125 malignant) were enrolled. The median age was 48 years (range, 22–70 years). For the classification of breast lesions, the AUCs of the best models were 0.931 (95% CI: 0.873–0.989) for HE, 0.897 (95% CI: 0.807–0.981) for LE, 0.882 (95% CI: 0.825–0.987) for DES images and 0.960 (95% CI: 0.910–0.998) for all of the CEM images in the testing set. According to LGOCV, the models constructed with the HE images and all of the CEM images showed the highest mean AUCs for the training (0.931 and 0.938, respectively; P < 0.05 for both) and testing sets (0.892 and 0.889, respectively; P = 0.55 for both), which were significantly higher than those of the two models constructed with the LE and DES images in the training (0.912 and 0.899, respectively; all P < 0.05) and testing sets (0.866 and 0.862, respectively; all P < 0.05).

Conclusions: Radiomic analysis of CEM images was valuable for classifying benign and malignant breast lesions. The use of HE images or all three types of CEM images can achieve the best performance.
Comprehensive Analysis of GLUT1 Immune Infiltrates and ceRNA Network in Human Esophageal Carcinoma
Authors: Liu Xu-Sheng , Gao Yan , Wu Li-Bing , Wan Hua-Bing , Yan Peng , Jin Yang , Guo Shi-Bo , Wang Ya-Lan , Chen Xue-Qin , Zhou Lu-Meng , Yang Jian-Wei , Kui Xue-Yan , Liu Xiao-Yu , Pei Zhi-Jun
Published: May 2021

Background

Glucose transporter 1 (GLUT1) is encoded by the solute carrier family 2A1 (SLC2A1) gene and is one of the glucose transporters with the greatest affinity for glucose. Abnormal expression of GLUT1 is associated with a variety of cancers. However, the biological role of GLUT1 in esophageal carcinoma (ESCA) remains to be determined.

Methods

We analyzed the expression of GLUT1 in pan-cancer and ESCA as well as clinicopathological analysis through multiple databases. Use R and STRING to perform GO/KEGG function enrichment and PPI analysis for GLUT1 co-expression. TIMER and CIBERSORT were used to analyze the relationship between GLUT1 expression and immune infiltration in ESCA. The TCGA ESCA cohort was used to analyze the relationship between GLUT1 expression and m6A modification in ESCA, and to construct a regulatory network in line with the ceRNA hypothesis.

Results

GLUT1 is highly expressed in a variety of tumors including ESCA, and is closely related to histological types and histological grade. GO/KEGG functional enrichment analysis revealed that GLUT1 is closely related to structural constituent of cytoskeleton, intermediate filament binding, cell-cell adheres junction, epidermis development, and P53 signaling pathway. PPI shows that GLUT1 is closely related to TP53, GIPC1 and INS, and these three proteins all play an important role in tumor proliferation. CIBERSORT analysis showed that GLUT1 expression is related to the infiltration of multiple immune cells. When GLUT1 is highly expressed, the number of memory B cells decreases. ESCA cohort analysis found that GLUT1 expression was related to 7 m6A modifier genes. Six possible crRNA networks in ESCA were constructed by correlation analysis, and all these ceRNA networks contained GLUT1.

Conclusion

GLUT1 can be used as a biomarker for the diagnosis and treatment of ESCA, and is related to tumor immune infiltration, m6A modification and ceRNA network.
Study of an Online Plan Verification Method and the Sensitivity of Plan Delivery Accuracy to Different Beam Parameter Errors in Proton and Carbon Ion Radiotherapy
Authors: Zhao Jun , Chen Zhi , Wu Xianwei , Xing Ying , Li Yongqiang
Published: May 2021

For scanning beam particle therapy, the plan delivery accuracy is affected by spot size deviation, position deviation and particle number deviation. Until now, all plan verification systems available for particle therapy have been designed for pretreatment verification. The purpose of this study is to introduce a method for online plan delivery accuracy checks and to evaluate the sensitivity of plan delivery accuracy to different beam parameter errors. A program was developed using MATLAB to reconstruct doses from beam parameters recorded in log files and to compare them with the doses calculated by treatment planning system (TPS). Both carbon ion plans and proton plans were evaluated in this study. The dose reconstruction algorithm is verified by comparing the dose from the TPS with the reconstructed dose under the same beam parameters. The sensitivity of plan delivery accuracy to different beam parameter errors was analyzed by comparing the dose reconstructed from the pseudo plans that manually added errors with the original plan dose. For the validation of dose reconstruction algorithm, mean dose difference between the reconstructed dose and the plan dose were 0.70% ± 0.24% and 0.51% ± 0.25% for carbon ion beam and proton beam, respectively. According to our simulation, the delivery accuracy of the carbon ion plan is more sensitive to spot position deviation and particle number deviation, and the delivery accuracy of the proton plan is more sensitive to spot size deviation. To achieve a 90% gamma pass rate with 3 mm/3% criteria, the average spot size deviation, position deviation, particle number deviation should be within 23%, 1.9 mm, and 1.5% and 20%, 2.1 mm, and 1.6% for carbon ion beam and proton beam, respectively. In conclusion, the method that we introduced for online plan delivery verification is feasible and reliable. The sensitivity of plan delivery accuracy to different errors was clarified for our system. The methods used in this study can be easily repeated in other particle therapy centers.
Bioinformatics Profiling of Five Immune-Related lncRNAs for a Prognostic Model of Hepatocellular Carcinoma
Authors: Wu Fahong , Wei Hangzhi , Liu Guiyuan , Zhang Youcheng
Published: May 2021

Hepatocellular carcinoma (HCC), one of the most common tumors worldwide, has the fifth highest mortality rate, which is increasing every year. At present, many studies have revealed that immunotherapy has an important effect on many malignant tumors. The main purpose of our research was to verify and establish a new immune-related lncRNA model and to explore the potential immune mechanisms. We analysed the pathways and mechanisms of immune-related lncRNAs by bioinformatics analysis, screened key lncRNAs based on Cox regression analysis, and determined the characteristics of the immune-related lncRNAs. On this basis, a predictive model was established. Through a comparison of specificity and sensitivity, we found that the constructed model was superior to the known markers of HCC. Then, the cell types were identified by the relative subgroup (CIBERSORT) algorithm for RNA transcripts. A signature model was eventually constructed, and we proved that it was a survival factor for HCC. Moreover, five kinds of immune cells were significantly positively correlated with the signature. The results indicated that these five kinds of lncRNAs may be related to the immune infiltration of hepatocellular carcinoma. To verify these findings, we selected the top coexpressed lncRNA, AC099850.3, for further study. We found that AC099850.3 could promote the migration and proliferation of hepatocellular carcinoma cells in vitro. RT-PCR experiments found that AC099850.3 could promote the expression of the cell cycle molecules BUB1, CDK1, PLK1, and TTK, and western blotting to prove that the expression of the molecules CD155 and PD-L1 was inhibited in the interference group. In conclusion, we used five kinds of immune-related lncRNAs to construct prognostic signatures to explore the mechanism, which provides a new way to study therapies for HCC.
Impact of Total Epinephrine Dose on Long Term Neurological Outcome for Cardiac Arrest Patients: A Cohort Study
Authors: Shi Xiaowei , Yu Jiong , Pan Qiaoling , Lu Yuanqiang , Li Lanjuan , Cao Hongcui
Published: May 2021

Introduction: Although epinephrine is universally acknowledged to increase return of spontaneous circulation (ROSC) after cardiac arrest, its balanced effects on later outcomes remain uncertain, causing potential harm during post-resuscitation phase. Recent studies have questioned the efficacy and potential deleterious effects of epinephrine on long-term survival and neurological outcomes, despite that the adverse relationship between epinephrine dose and outcome can be partially biased by longer CPR duration and underlying comorbidities. This study explored the long-term effect of epinephrine when used in a cohort of patients that underwent cardiac arrest during cardiopulmonary resuscitation.

Methods: The data were originally collected from a retrospective institutional database from January 2007 to December 2015 and are now available on Dryad (via: https://doi.org/10.5061/dryad.qv6fp83). Use of epinephrine was coded by dose (<2 mg, 2 mg, 3–4 mg, ≥5 mg). A favorable neurological outcome was defined using a Cerebral Performance Category (CPC) 1 or 2. The association between epinephrine dosing and 3-months neurological outcome was analyzed by univariate analysis and multivariate logistic regression.

Results: Univariate and multivariate analysis demonstrated a negative association between total epinephrine dose and neurological outcome. Of the 373 eligible patients, 92 received less than 2 mg of epinephrine, 60 received 2 mg, 97 received 3–4 mg and 124 received more than 5 mg. Compared to patients who received less than 2 mg of epinephrine, the adjusted odds ratio (OR) of a favorable neurological outcome was 0.8 (95% confidence interval [CI]: 0.38–1.68) for 2 mg of epinephrine, 0.43 (95% confidence interval [CI]: 0.21–0.89) for 3–4 mg of epinephrine and 0.40 (95% confidence interval [CI]: 0.17–0.96) for more than 5 mg of epinephrine.

Conclusion: In this cohort of patients who achieved ROSC, total epinephrine dosing during resuscitation was associated with a worse neurological outcome three months after cardiac arrest, after adjusting other confounding factors. Further researches are needed to investigate the long-term effect of epinephrine on cardiac arrest patients.
Benefits and Harms of Low-Dose Rivaroxaban in Asian Patients With Atrial Fibrillation: A Systematic Review and Meta-analysis of Real-World Studies
Authors: Qian Jun , Yan Yi-Dan , Yang Sheng-Yan , Zhang Chi , Li Wen-Yan , Gu Zhi-Chun
Published: May 2021

Background: Low-dose prescription of rivaroxaban was common among patients with atrial fibrillation (AF) in Asia. However, the benefits and harms of rivaroxaban at a low dosage in Asian patients with AF remains unclear. Accordingly, we aimed to collect and summarize all available evidence to fill this important knowledge gap.

Methods: In this systematic review and meta-analysis, we systematically searched databases of MEDLINE, EMBASE, and Cochrane Library for relevant studies from inception until February 23, 2021. Eligible retrospective nationwide or health insurance database studies or prospective registration studies that reported efficacy (stroke/systemic embolism), safety (major bleeding, intracranial hemorrhage, gastrointestinal bleeding), or other outcomes (myocardial infarction, death) of low-dose rivaroxaban in comparison with warfarin in AF patients were enrolled. Data extraction and study quality assessment were conducted by two authors independently. Low dosing of rivaroxaban (15/10 mg) was defined as the received dose lower than the recommended dose (20 mg) approved in most districts. Hazard ratio (HR) with 95% confidence intervals (95% CIs) was pooled using a random-effect model. Subgroup analyses were conducted according to different dose regimens. Sensitivity analyses were conducted by sequential elimination of each study from the pool. Since potential effect modifiers (patient demographics, differences of each study, and others) may lead to bias in primacy outcomes, we performed a meta-regression analysis to explore the influence of these factors on the primary efficacy and safety outcomes.

Results: Totally, 12 studies involving 292,815 Asian patients with AF were included. All studies were detected as low to moderate risk bias. Low-dose rivaroxaban treatment in Asian AF patients was associated with a reduced risk of stroke/systemic embolism (HR: 0.76, 95% CI: 0.70–0.84, I2: 57.8%), major bleeding (HR: 0.72, 95% CI: 0.62–0.84, I2: 81.5%), and all-cause death (HR: 0.65, 95% CI: 0.58–0.73, I2: 81.7%) when compared with warfarin. Furthermore, consistent results were observed among different dose regimens (10/15/20 mg) in all the clinical outcomes (Pinteraction > 0.05 for each outcome). Meta-regression analysis failed to detect any potential confounding to impact the primacy outcomes.

Conclusion: Insights from the present meta-analysis, we found that low-dose rivaroxaban, even at a dosage of 10 mg daily, was associated with a reduced risk of stroke/SE and bleeding than warfarin in Asian AF patients. However, owing to considerable heterogeneity among included studies, further prospective studies are required to confirm these findings.
MicroRNAs Regulating Mitochondrial Function in Cardiac Diseases
Authors: Zhang Guang-Qiong , Wang Sheng-Quan , Chen Yan , Fu Ling-Yun , Xu Yi-Ni , Li Ling , Tao Ling , Shen Xiang-Chun
Published: May 2021

Mitochondria are the key organelles that supply cellular energy. As the most active organ in the body, the energy required to maintain the mechanical function of the heart requires a high quantity of high-quality mitochondria in cardiomyocytes. MicroRNAs (miRNAs) are single-stranded noncoding RNAs, approximately 22 nt in length, which play key roles in mediating post-transcriptional gene silencing. Numerous studies have confirmed that miRNAs can participate in the occurrence and development of cardiac diseases by regulating mitochondrial function-related genes and signaling pathways. Therefore, elucidating the crosstalk that occurs between miRNAs and mitochondria is important for the prevention and treatment of cardiac diseases. In this review, we discuss the biogenesis of miRNAs, the miRNA-mediated regulation of major genes involved in the maintenance of mitochondrial function, and the effects of miRNAs on mitochondrial function in cardiac diseases in order to provide a theoretical basis for the clinical prevention and treatment of cardiac disease and the development of new drugs.
Pharmacokinetic Study of Oral 14C-Radiolabeled Hyzetimibe, A New Cholesterol Absorption Inhibitor
Authors: Liao Jianwei , Wang Xin , Li Zhenyu , Ouyang Dongsheng
Published: May 2021

Background and objectives: Hyzetimibe is a candidate drug being investigated as the second-in-class cholesterol absorption inhibitor; it lowers plasma levels of low-density lipoprotein cholesterol (LDL-C) by blocking the Niemann-Pick C1-like 1 protein, a transporter mainly expressed in the intestine that allows dietary cholesterol to enter the body from the intestinal lumen. Previous studies on the metabolism of hyzetimibe in healthy volunteers were not enough to show the biotransformation and excretion pathway; in particular, whether hyzetimibe maintains pharmacological action for duration sufficient to pass through the hepatic-intestinal circulation remains unknown. Furthermore, it remains unclear whether the differences between the chemical structures of ezetimibe and hyzetimibe would result in different pharmacokinetic characteristics. Given that the molecular target is in the intestine and the substantial hepatic-intestinal circulation is a metabolic characteristic of the drug, a study of hyzetimibe as an oral 14C-radiolabeled drug, compared with routinely metabolized drugs, would play an important role in uncovering pharmacokinetic details.

Methods: After an overnight fast and before taking medication, six healthy male volunteers swallowed an investigational product suspension containing 20 mg/∼100 μCi of 14C-labeled hyzetimibe as a single dose. Whole-blood, plasma, urine, and fecal samples were collected, and hyzetimibe and its metabolites were measured. Pharmacokinetic variables of hyzetimibe and its metabolites were calculated and statistically analyzed according to obtained concentration data. Safety data were collected throughout the study.

Results: The major metabolite detected in plasma was hyzetimibe-glucuronide, which accounted for 97.2% of the total plasma radioactivity. The mean cumulative excretion of total radioactivity of the dose was 16.39% in urine and 76.90% in feces. Unchanged drug and hyzetimibe-glucuronide were identified as the major components in the feces and the urine, respectively. The main metabolic conversions of hyzetimibe were glucuronidation (M1), mono-oxidation (M4), and mono-oxidation with additional sulfonation (M7). Hyzetimibe was considered generally safe and well tolerated.

Conclusion: This study of 14C-radiolabeled hyzetimibe provides a full profile of the biotransformation and excretion routes of hyzetimibe to improve the understanding of the pharmacokinetic characteristics of hyzetimibe. The changed hydroxyl group in the hyzetimibe structure made it easier for that drug, compared with ezetimibe, to combine with glucuronic acid and subsequently increased the urinary excretion of hyzetimibe vs. ezetimibe. These differences highlight the need to investigate in more detail the different pharmacokinetic impacts on the efficacy and safety of hyzetimibe and ezetimibe.
ShenLian Extract Enhances TGF-β Functions in the Macrophage-SMC Unit and Stabilizes Atherosclerotic Plaques
Authors: Liu Li , Li Qi , Yin Jie , Zhao Zheng , Sun Lidong , Ran Qingsen , Du Xinke , Wang Yajie , Li Yujie , Yang Qing , Chen Ying , Weng Xiaogang , Cai Weiyan , Zhu Xiaoxin
Published: May 2021

Background/Aim: Macrophage polarization and phenotypic switching of smooth muscle cells (SMCs) are multi-faceted events dominating atherosclerosis (AS) progression. TGF-β was proved to been one of the bridge on the crosstalk between macrophage and SMC. ShenLian (SL) was extracted from a potent anti-atherosclerotic formula. However, its exact mechanism rebalancing inflammatory microenvironment of AS remain largely unknown. Within the entirety of macrophage and SMC, this study investigated the pharmacological effects of SL on stabilizing atherosclerotic plaques.

Methods: The main components of SL were examined by high performance liquid chromatography. Co-culture and conditioned medium models of macrophage/SMC interactions were designed to identify the relationship between macrophage polarization and switching of SMC phenotypes. Flow cytometry, immunofluorescent staining, RT-PCR, western blotting, and ELISA were used to determine the expression of molecules relating to AS progression. An atherosclerosis animal model, established by placing a perivascular collar on the right common carotid artery in ApoE−/− mice, was used to investigate whether TGF-β is the key molecular mediator of SL in crosstalk between macrophage and SMC. Plaque size was defined by nuclear magnetic resonance imaging. Key markers related to phenotypic transformation of macrophage and SMC were determined by immunohistochemical staining.

Results: Results revealed that, accompanied by rebalanced M2 macrophage polarization, SL supported SMC phenotypic transformation and functionally reconstruct the ECM of plaques specifically in macrophage-SMC co-cultural model. Molecularly, such activity of SL closely related to the activation of STAT3/SOCS3 pathway. Furthermore, in co-culture system, up-regulation of α-SMA induced by SL could neutralized by 1D11, a TGF-β neutralizing antibody, indicating that SL mediated Macrophage-SMC communication by enhancing TGF-β. In the AS model constructed by ApoE−/− mice, effects of SL on phenotypic transformation of macrophage and SMC has been well verified. Specific blocking of TGF-β largely attenuated the aforementioned effects of SL.

Conclusion: Our findings highlighted that TGF-β might be the responsive factor of SL within macrophage and SMC communication. This study revealed that crosstalk between macrophage and SMC forms a holistic entirety promoting atherosclerotic plaque stability.
Development of Store-Operated Calcium Entry-Targeted Compounds in Cancer
Authors: Liang Xiaojing , Zhang Ningxia , Pan Hongming , Xie Jiansheng , Han Weidong
Published: May 2021

Store-operated Ca2+ entry (SOCE) is the major pathway of Ca2+ entry in mammalian cells, and regulates a variety of cellular functions including proliferation, motility, apoptosis, and death. Accumulating evidence has indicated that augmented SOCE is related to the generation and development of cancer, including tumor formation, proliferation, angiogenesis, metastasis, and antitumor immunity. Therefore, the development of compounds targeting SOCE has been proposed as a potential and effective strategy for use in cancer therapy. In this review, we summarize the current research on SOCE inhibitors and blockers, discuss their effects and possible mechanisms of action in cancer therapy, and induce a new perspective on the treatment of cancer.
ZhiJingSan Inhibits Osteoclastogenesis via Regulating RANKL/NF-κB Signaling Pathway and Ameliorates Bone Erosion in Collagen-Induced Mouse Arthritis
Authors: Ling Yuanyuan , Yang Jie , Hua Di , Wang Dawei , Zhao Chenglei , Weng Ling , Yue Dandan , Cai Xueting , Meng Qinghai , Chen Jiao , Sun Xiaoyan , Kong Weikang , Zhu Lizhong , Cao Peng , Hu Chunping
Published: May 2021

Bone erosion is the most evident pathological condition of rheumatoid arthritis (RA), which is the main cause of joint deformities and disability in RA patients. At present, the conventional RA drugs have not achieved satisfactory effect in improving bone erosion. ZhiJingSan (ZJS), which is a traditional Chinese prescription composed of scolopendra (dried body ofScolopendra subspinipes mutilans L. Koch,scolopendridae) and scorpion (dried body ofButhus martensii Karsch, Buthus), exhibits anti-rheumatism, analgesic and joint deformities improvement effects. This study aimed to assess the therapeutic effect of ZJS on RA bone erosion and to elucidate the underlying mechanism. The effect of ZJS on RA bone erosion was investigated in a murine model of bovine collagen-induced arthritis (CIA), and the underlying mechanism was investigatedin vitroin an osteoclast differentiation cell model. Administration of ZJS delayed the onset of arthritis, alleviated joint inflammation, and attenuated bone erosion in the CIA mice. Meanwhile, ZJS decreased the serum levels of TNF-α, IL-6, and anti-bovine collagen II-specific antibodies. Furthermore, ZJS treatment reduced the number of osteoclasts and the expression of cathepsin K in the ankle joints of CIA mice. ZJS also inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation and the expression of MMP9 and cathepsin Kin vitro. Mechanistically, ZJS blocked RANKL-induced p65 phosphorylation, nucleation, and inhibited the expression of downstream NFATc1 and c-Fos in bone marrow-derived macrophages (BMMs). Taken together, ZJS exerts a therapeutic effect on bone erosion in CIA mice by inhibiting RANKL/NF-κB-mediated osteoclast differentiation, which suggested that ZJS is a promising prescription for treating RA bone erosion.
Photon-Assisted Seebeck Effect in a Quantum Dot Coupled to Majorana Zero Modes
Authors: He Tian-Yu , Sun Hailing , Zhou Guofu
Published: May 2021

The Seebeck effect is investigated within the framework of a non-equilibrium Green's function technique in a quantum dot (QD) sandwiched between the left and right leads held at different temperatures. We consider that the QD is shelled by a photon field and is side-coupled to a topological superconductor nanowire hosting Majorana zero modes (MZMs). It is found that the thermopower (Seebeck coefficient) can be obviously enhanced by weak QD-MZMs coupling at low temperatures, in addition to its sign reversion that may be used for detecting the existence of MZMs. In the presence of a photon field, the thermopower can be further enhanced due to decreased electrical conductance when electrons' transport probability through each channel is reduced by photon-assisted tunneling (PAT). The hybridization between the MZMs will also induce sign reversion of the thermopower in the absence of a photon field, whereas it has less impact on the thermopower when the QD is shelled by the photon field.
Transit Time Measurement in Indicator Dilution Curves: Overcoming the Missing Ground Truth and Quantifying the Error
Authors: Naber Ady , Reiß Michael , Nahm Werner
Published: May 2021

The vascular function of a vessel can be qualitatively and intraoperatively checked by recording the blood dynamics inside the vessel via fluorescence angiography (FA). Although FA is the state of the art in proving the existence of blood flow during interventions such as bypass surgery, it still lacks a quantitative blood flow measurement that could decrease the recurrence rate and postsurgical mortality. Previous approaches show that the measured flow has a significant deviation compared to the gold standard reference (ultrasonic flow meter). In order to systematically address the possible sources of error, we investigated the error in transit time measurement of an indicator. Obtainingin vivoindicator dilution curves with a known ground truth is complex and often not possible. Further, the error in transit time measurement should be quantified and reduced. To tackle both issues, we first computed many diverse indicator dilution curves using anin silicosimulation of the indicator's flow. Second, we post-processed these curves to mimic measured signals. Finally, we fitted mathematical models (parabola, gamma variate, local density random walk, and mono-exponential model) to re-continualize the obtained discrete indicator dilution curves and calculate the time delay of two analytical functions. This re-continualization showed an increase in the temporal accuracy up to a sub-sample accuracy. Thereby, the Local Density Random Walk (LDRW) model performed best using the cross-correlation of the first derivative of both indicator curves with a cutting of the data at 40% of the peak intensity. The error in frames depends on the noise level and is for a signal-to-noise ratio (SNR) of 20dBand a sampling rate offs= 60Hzatfs-1·0.25(±0.18), so this error is smaller than the distance between two consecutive samples. The accurate determination of the transit time and the quantification of the error allow the calculation of the error propagation onto the flow measurement. Both can assist surgeons as an intraoperative quality check and thereby reduce the recurrence rate and post-surgical mortality.
Persistently Increased Systemic ACE2 Activity Is Associated With an Increased Inflammatory Response in Smokers With COVID-19
Authors: Kaur Gagandeep , Yogeswaran Shaiesh , Muthumalage Thivanka , Rahman Irfan
Published: May 2021

Background: Tobacco smoking is known to be involved in the pathogenesis of several cardiopulmonary diseases. Additionally, smokers are highly susceptible to infectious agents due to weakened immunity. However, the progression of lung injury based on SARS-CoV-2-mediated COVID-19 pathogenesis amongst smokers and those with pre-existing pulmonary diseases is not known. We determined the systemic levels and activity of COVID-19 associated proteins, cytokine/chemokines, and lipid mediators (lipidomics) amongst COVID-19 patients with and without a history of smoking to understand the underlying susceptible factor in the pathogenesis of COVID-19.

Methods: We obtained serum from healthy (CoV−), COVID-19 positive (CoV+), and COVID-19 recovered (CoV Rec) subjects with and without a history of smoking. We conducted a Luminex multiplex assay (cytokine levels), LC/MS (eicosanoids or oxylipin panel), and ACE2 enzymatic activity assays on the serum samples to determine the systemic changes in COVID-19 patients.

Results: On comparing the levels of serum ACE2 amongst COVID-19 (positive and recovered) patients and healthy controls, we found a pronounced increase in serum ACE2 levels in patients with COVID-19 infection. Furthermore, ACE2 enzyme activity was significantly increased amongst COVID-19 patients with a smoking history. Also, we analyzed the levels of Angiotensin 1–7 (Ang1–7) peptide, the product of enzymatic action of ACE2, in the serum samples. We found significantly high levels of Ang1–7 in the serum of both CoV+ and CoV Rec patients. Our data further demonstrated a smoking-induced increase in serum furin and inflammatory cytokine [IFNγ(p = 0.0836), Eotaxin (p < 0.05), MCP-1 (p < 0.05), and IL-9 (p = 0.0991)] levels in COVID-19 patients as compared to non-smoking controls. Overall, our results show that smoking adversely affects the levels of systemic inflammatory markers and COVID-19 associated proteins, thus suggesting that COVID-19 infection may have severe outcomes amongst smokers.
In vivo Dominant-Negative Effect of an SCN5A Brugada Syndrome Variant
Authors: Doisne Nicolas , Grauso Marta , Mougenot Nathalie , Clergue Michel , Souil Charlotte , Coulombe Alain , Guicheney Pascale , Neyroud Nathalie
Published: May 2021

Loss-of-function mutations in the cardiac Na+ channel α-subunit Nav1.5, encoded by SCN5A, cause Brugada syndrome (BrS), a hereditary disease characterized by sudden cardiac death due to ventricular fibrillation. We previously evidenced in vitro the dominant-negative effect of the BrS Nav1.5-R104W variant, inducing retention of wild-type (WT) channels and leading to a drastic reduction of the resulting Na+ current (INa). To explore this dominant-negative effect in vivo, we created a murine model using adeno-associated viruses (AAVs).

Methods

Due to the large size of SCN5A, a dual AAV vector strategy was used combining viral DNA recombination and trans-splicing. Mice were injected with two AAV serotypes capsid 9: one packaging the cardiac specific troponin-T promoter, the 5′ half of hSCN5A cDNA, a splicing donor site and a recombinogenic sequence; and another packaging the complementary recombinogenic sequence, a splicing acceptor site, the 3′ half of hSCN5A cDNA fused to the gfp gene sequence, and the SV40 polyA signal. Eight weeks after AAV systemic injection in wild-type (WT) mice, echocardiography and ECG were recorded and mice were sacrificed. The full-length hSCN5A-gfp expression was assessed by western blot and immunohistochemistry in transduced heart tissues and the Na+ current was recorded by the patch-clamp technique in isolated adult GFP-expressing heart cells.

Results

Almost 75% of the cardiomyocytes were transduced in hearts of mice injected with hNav1.5 and ∼30% in hNav1.5-R104W overexpressing tissues. In ventricular mice cardiomyocytes expressing R104W mutant channels, the endogenous INa was significantly decreased. Moreover, overexpression of R104W channels in normal hearts led to a decrease of total Nav1.5 expression. The R104W mutant also induced a slight dilatation of mice left ventricles and a prolongation of RR interval and P-wave duration in transduced mice. Altogether, our results demonstrated an in vivo dominant-negative effect of defective R104W channels on endogenous ones.

Conclusion

Using a trans-splicing and viral DNA recombination strategy to overexpress the Na+ channel in mouse hearts allowed us to demonstrate in vivo the dominant-negative effect of a BrS variant identified in the N-terminus of Nav1.5.
Using a Stacked Autoencoder for Mobility and Fall Risk Assessment via Time–Frequency Representations of the Timed Up and Go Test
Authors: Chen Shih-Hai , Lee Chia-Hsuan , Jiang Bernard C. , Sun Tien-Lung
Published: May 2021

Fall risk assessment is very important for the graying societies of developed countries. A major contributor to the fall risk of the elderly is mobility impairment. Timely detection of the fall risk can facilitate early intervention to avoid preventable falls. However, continuous fall risk monitoring requires extensive healthcare and clinical resources. Our objective is to develop a method suitable for remote and long-term health monitoring of the elderly for mobility impairment and fall risk without the need for an expert. We employed time–frequency analysis (TFA) and a stacked autoencoder (SAE), which is a deep neural network (DNN)-based learning algorithm, to assess the mobility and fall risk of the elderly according to the criteria of the timed up and go test (TUG). The time series signal of the triaxial accelerometer can be transformed by TFA to obtain richer image information. On the basis of the TUG criteria, the semi-supervised SAE model was able to achieve high predictive accuracies of 89.1, 93.4, and 94.1% for the vertical, mediolateral and anteroposterior axes, respectively. We believe that deep learning can be used to analyze triaxial acceleration data, and our work demonstrates its applicability to assessing the mobility and fall risk of the elderly.
Regulation of Coronary Blood Flow by the Carotid Body Chemoreceptors in Ovine Heart Failure
Authors: Pachen Mridula , Abukar Yonis , Shanks Julia , Lever Nigel , Ramchandra Rohit
Published: May 2021

Carotid bodies (CBs) are peripheral chemoreceptors, which are primary sensors of systemic hypoxia and their activation produces respiratory, autonomic, and cardiovascular adjustments critical for body homeostasis. We have previously shown that carotid chemoreceptor stimulation increases directly recorded cardiac sympathetic nerve activity (cardiac SNA) which increases coronary blood flow (CoBF) in conscious normal sheep. Previous studies have shown that chemoreflex sensitivity is augmented in heart failure (HF). We hypothesized that carotid chemoreceptor stimulation would increase CoBF to a greater extent in HF than control sheep. Experiments were conducted in conscious HF sheep and control sheep (n = 6/group) implanted with electrodes to record diaphragmatic electromyography (dEMG), flow probes to record CoBF as well as arterial pressure. There was a significant increase in mean arterial pressure (MAP), CoBF and coronary vascular conductance (CVC) in response to potassium cyanide (KCN) in both groups of sheep. To eliminate the effects of metabolic vasodilation, the KCN was repeated while the heart was paced at a constant level. In this paradigm, the increase in CoBF and CVC was augmented in the HF group compared to the control group. Pre-treatment with propranolol did not alter the CoBF or the CVC increase in the HF group indicating this was not mediated by an increase in cardiac sympathetic drive. The pressor response to CB activation was abolished by pre-treatment with intravenous atropine in both groups, but there was no change in the CoBF and vascular conductance responses. Our data suggest that in an ovine model of HF, carotid body (CB) mediated increases in CoBF and CVC are augmented compared to control animals. This increase in CoBF is mediated by an increase in cardiac SNA in the control group but not the HF group.
Similarities and Differences in the GFP Movement in the Zygotic and Somatic Embryos of Arabidopsis
Authors: Godel-Jędrychowska Kamila , Kulińska-Łukaszek Katarzyna , Kurczyńska Ewa
Published: May 2021

Intercellular signaling during embryo patterning is not well understood and the role of symplasmic communication has been poorly considered. The correlation between the symplasmic domains and the development of the embryo organs/tissues during zygotic embryogenesis has only been described for a few examples, including Arabidopsis. How this process occurs during the development of somatic embryos (SEs) is still unknown. The aim of these studies was to answer the question: do SEs have a restriction in symplasmic transport depending on the developmental stage that is similar to their zygotic counterparts? The studies included an analysis of the GFP distribution pattern as expressed under diverse promoters in zygotic embryos (ZEs) and SEs. The results of the GFP distribution in the ZEs and SEs showed that 1/the symplasmic domains between the embryo organs and tissues in the SEs was similar to those in the ZEs and 2/the restriction in symplasmic transport in the SEs was correlated with the developmental stage and was similar to the one in their zygotic counterparts, however, with the spatio-temporal differences and different PDs SEL value between these two types of embryos.
A Computer-Based Method for the Investigation of Human Behavior in the Iterative Chicken Game
Authors: Kim Sung-Phil , Kim Minju , Lee Jongmin , Cho Yang Seok , Kwon Oh-Sang
Published: May 2021

The present study develops an artificial agent that plays the iterative chicken game based on a computational model that describes human behavior in competitive social interactions in terms of fairness. The computational model we adopted in this study, named as the self-concept fairness model, decides the agent’s action according to the evaluation of fairness of both opponent and self. We implemented the artificial agent in a computer program with a set of parameters adjustable by researchers. These parameters allow researchers to determine the extent to which the agent behaves aggressively or cooperatively. To demonstrate the use of the proposed method for the investigation of human behavior, we performed an experiment in which human participants played the iterative chicken game against the artificial agent. Participants were divided into two groups, each being informed to play with either a person or the computer. The behavioral analysis results showed that the proposed method can induce changes in the behavioral pattern of human players by changing the agent’s behavioral pattern. Also, we found that participants tended to be more sensitive to fairness when they played with a human opponent than with a computer opponent. These results support that the artificial agent developed in this study will be useful to investigate human behavior in competitive social interactions.
Do Experiences Studying Abroad Promote Dialectical Thinking? Empirical Evidence From Chinese International Students
Authors: Hu Xiaomeng , Wang Yang , Liao Shanhui , Peng Kaiping
Published: May 2021

Our current work seeks to provide direct empirical evidence on whether Chinese international students’ experiences studying abroad promote dialectical thinking. We collected behavioral data from 258 Chinese international students studying in multiple regions. We found that there was a main effect among the four conditions (i.e., studying abroad, exposure to foreign culture, hometown, and typical day). More specifically, when primed with studying abroad or typical day (relative to hometown culture), participants were more likely to show tolerance for contradiction by deeming both sides of contradictory scientific statements as convincing and rating them more favorably. Therefore, it is plausible that Chinese international students’ experiences studying abroad promote their dialectical thinking. More work is needed to further this line of research by (1) extending these effects with other measures of dialectical thinking such as perception of interconnectedness and prediction of change, (2) adopting differing paradigms to provide more robust findings, and (3) probing the underlying processes as to why experiences studying abroad promote dialectical thinking.
Epidemiology of Sleep Disturbances and Their Effect on Psychological Distress During the COVID-19 Outbreak: A Large National Study in China
Authors: Cui Xilong , He Yuqiong , Gong Jingbo , Luo Xuerong , Liu Jianbo
Published: May 2021

Background: The purpose of the current study was to assess the prevalence of sleep disturbances among Chinese people during the COVID-19 pandemic in a large national survey, analyze the relationship between sleep disturbances and mental health status, and explore the influencing factors of the relationship between sleep disturbances and mental health status.

Methods: An online survey was accessed by 19,740 people throughout China from February 14 to 21, 2020. The survey included the Depression Anxiety Stress Scale-21 (DASS-21) to measure psychological distress and two questions about sleep disturbances. Logistic regression analyses and moderation analysis were performed.

Results: (1) Among the 14,505 respondents included in analyses, 3,783 (26.08%) reported sleep disturbances at least 3 days during the past week. (2) Sleep disturbances increased the risk of depression, anxiety, and stress (p < 0.05). (3) Gender, age, education, occupation, frequency of attending to epidemic information, nervousness about supplies, receiving provisions of living necessities from the service department during the outbreak, number of correct responses to questions about the epidemic, and isolation/quarantine affected the risk of mental health problems among participants experiencing sleep disturbances (p < 0.05). (4) A moderation analysis found that sleep problems were more likely to affect depression, anxiety, and stress scores in men than women during the COVID-19 outbreak.

Conclusion: During the COVID-19 outbreak, 26.08% people surveyed experienced sleep disturbances, and the presence of sleep disturbances was positively related to depression, anxiety, and stress, especially among front-line anti-epidemic workers, younger people, people living in isolation/quarantine, people with a college or greater education, and males.