bluuebunny/crossref_metadata_2025 huggingface dataset:
In-Hospital Outcomes of Acute Kidney Injury After Pediatric Cardiac Surgery: A Meta-Analysis
Authors: Van den Eynde Jef , Rotbi Hajar , Gewillig Marc , Kutty Shelby , Allegaert Karel , Mekahli Djalila
Published: September 2021

Background: Cardiac surgery-associated acute kidney injury (CS-AKI) is associated with increased morbidity and mortality in both adults and children. This study aimed to investigate the in-hospital outcomes of CS-AKI in the pediatric population.

Methods: PubMed/MEDLINE, Embase, Scopus, and reference lists of relevant articles were searched for studies published by August 2020. Random-effects meta-analysis was performed, comparing in-hospital outcomes between patients who developed CS-AKI and those who did not.

Results: Fifty-eight publications between 2008 and 2020 consisting of 18,334 participants (AKI: 5,780; no AKI: 12,554) were included. Higher rates of in-hospital mortality (odds ratio [OR] 7.22, 95% confidence interval [CI] 5.27–9.88), need for renal replacement therapy (RRT) (OR 18.8, 95% CI 11.7–30.5), and cardiac arrhythmias (OR 2.67, 95% 1.86–4.80) were observed in patients with CS-AKI. Furthermore, patients with AKI had longer ventilation times (mean difference [MD] 1.76 days, 95% CI 1.05–2.47), pediatric intensive care unit (PICU) length of stay (MD 3.31, 95% CI 2.52–4.10), and hospital length of stay (MD 5.00, 95% CI 3.34–6.67).

Conclusions: CS-AKI in the pediatric population is associated with a higher risk of mortality, cardiac arrhythmias and need for RRT, as well as greater mechanical ventilation time, PICU and hospital length of stay. These results might help improve the clinical care protocols prior to cardiac surgery to minimize the disease burden of CS-AKI in children. Furthermore, etiology-specific approaches to AKI are warranted, as outcomes are likely impacted by the underlying cause.
Clinical Progress on Management of Pneumonia Due to COVID-19 With Chinese Traditional Patent Medicines
Authors: Wu Ying , Zhong Ping
Published: September 2021

Background: The outbreak of new coronavirus has tremendously threatened the public health system worldwide, including China. Chinese patent medicines (CPMs) have greatly contributed to the prevention and treatment of this viral infection, as well as the recovery of patients with COVID-19 infection. Therefore, numerous experts and guidelines recommend to take CPMs to treat pneumonia due to COVID-19.

Aim of the Study: The present study reviewed CPMs recommended by the < Guidelines for diagnosis and management of COVID-19 (8th edition)> regarding evidence of their efficacy from clinical studies and the underlying mechanisms, which will lay the foundation for clinical use of these CPMs for COVID-19.

Methods: The composition, efficacy, indications, history of use, and relevant clinical research on 14 recommended CPMs, including Huoxiangzhengqi capsules (pills, liquid, oral solution), Jinhuaqinggan granules, Lianhuaqingwen capsules (granules), Shufengjiedu capsules, Xiyanping injections, Xuebijing injections, Reduning injections, Tanreqing injections, Xingnaojing injections, Shenfu injections, Shengmai injections, Angongniuhuang pills, Suhexiang pills, were searched in both Chinese and English databases based on differences in stages of the disease and manifestations of such patients. Advantages of these CPMs over conventional treatments and their underlying mechanisms were explored by analyzing results from published articles and undergoing clinical trials.

Results: Findings from clinical studies and Chinese experience in using these CPMs showed that CPMs, when used in combination with conventional treatments, were effective in managing COVID-19 with few side effects.

Conclusion: CPMs have excellent efficacy in managing COVID-19 with a great potential for clinical use.
Advances in Chemical Constituents, Clinical Applications, Pharmacology, Pharmacokinetics and Toxicology of Erigeron breviscapus
Authors: Wu Ruixia , Liang Yan , Xu Min , Fu Ke , Zhang Yangliu , Wu Lei , Wang Zhang
Published: September 2021

Dengzhanxixin (DZXX), the dried whole plant of Erigeron breviscapus (Vaniot) Hand.-Mazz., belonging to Compositae and first published in Materia Medica of South Yunnan by Lan Mao in the Ming Dynasty (1368 AD–1644 AD), is included in Medicinal Materials and Decoction Pieces of the 2020 edition of the Pharmacopeia of the People’s Republic of China. Its main chemical components are flavonoids that mainly include flavonoid, flavonols, dihydroflavones, flavonol glycosides, flavonoid glycosides, coffee acyl compounds, and other substances, such as volatile oil compounds, coumarins, aromatic acids, pentacyclic terpenoids, phytosterols, and xanthones. Among them, scutellarin and 1,5-dicoffeoylquininic acid are the main active components of DZXX. DZXX has pharmacological effects, such as improving cerebral and cerebrovascular ischemia, increasing blood flow, inhibiting platelet aggregation, promoting antithrombotic formation, improving microcirculation, reducing blood viscosity, protecting optic nerves, exhibiting anti-inflammatory properties, scavenging free radicals, and eliciting antioxidant activities. It is widely used in the treatment of cardiovascular and cerebrovascular ischemic diseases, kidney diseases, liver diseases, diabetic complications, and glaucoma. Pharmacokinetic studies have shown that the active components of DZXX have a low bioavailability and a high elimination rate in vivo. Nevertheless, its utilization can be improved through liposome preparation and combination with other drugs. Acute and subacute toxicity studies have shown that DZXX is a safe medicinal material widely used in clinical settings. However, its target and drug action mechanism are unclear because of the complexity of its composition. In this paper, the clinical application and pharmacological toxicology of DZXX are reviewed to provide a reference for further studying its active components and action mechanism.
Favipiravir Versus Arbidol for Clinical Recovery Rate in Moderate and Severe Adult COVID-19 Patients: A Prospective, Multicenter, Open-Label, Randomized Controlled Clinical Trial
Authors: Chen Chang , Zhang Yi , Huang Jianying , Yin Ping , Cheng Zhenshun , Wu Jianyuan , Chen Song , Zhang Yongxi , Chen Bo , Lu Mengxin , Luo Yongwen , Ju Lingao , Zhang Jingyi , Wang Xinghuan
Published: September 2021

Background: In addition to supportive therapy, antiviral therapy is an effective treatment for coronavirus disease 2019 (COVID-19).

Objective: To compare the efficacy and safety of favipiravir and umifenovir (Arbidol) to treat COVID-19 patients.

Methods: We conducted a prospective, randomized, controlled, open-label multicenter trial involving adult patients with COVID-19. Enrolled patients with initial symptoms within 12 days were randomly assigned in a 1:1 ratio to receive conventional therapy plus Arbidol (200 mg*3/day) or favipiravir (1600 mg*2/first day followed by 600 mg*2/day) for 7 days. The primary outcome was the clinical recovery rate at day 7 of drug administration (relief for pyrexia and cough, respiratory frequency ≤24 times/min; oxygen saturation ≥98%). Latency to relief for pyrexia and cough and the rate of auxiliary oxygen therapy (AOT) or noninvasive mechanical ventilation (NMV)/mechanical ventilation (MV) were the secondary outcomes. Safety data were collected for 17 days.

Results: A total of 240 enrolled COVID-19 patients underwent randomization; 120 patients were assigned to receive favipiravir (116 assessed), and 120 patients were assigned to receive Arbidol (120 assessed). The clinical recovery rate at day 7 of drug administration did not significantly differ between the favipiravir group (71/116) and Arbidol group (62/120) (p = 0.1396, difference in recovery rate: 0.0954; 95% CI: −0.0305∼0.2213). Favipiravir contributed to relief for both pyrexia (difference: 1.70 days, p < 0.0001) and cough (difference: 1.75 days, p < 0.0001). No difference was observed in the AOT or NMV/MV rate (both p > 0.05). The most frequently observed favipiravir-associated adverse event was increased serum uric acid (16/116, OR: 5.52, p = 0.0014).

Conclusion: Among patients with COVID-19, favipiravir, compared to Arbidol, did not significantly improve the clinical recovery rate at day 7. Favipiravir significantly improved the latency to relieve pyrexia and cough. Adverse effects caused by favipiravir are mild and manageable.
Development, Testing, Parameterisation and Calibration of a Human PBPK Model for the Plasticiser, Di-(2-propylheptyl) Phthalate (DPHP) Using in Silico, in vitro and Human Biomonitoring Data
Authors: McNally Kevin , Sams Craig , Hogg Alex , Lumen Annie , Loizou George
Published: September 2021

A physiologically based pharmacokinetic model for Di-(2-propylheptyl) phthalate (DPHP) was developed to interpret the biokinetics in humans after single oral doses. The model was parameterized with in vitro and in silico derived parameters and uncertainty and sensitivity analysis was used during the model development process to assess structure, biological plausibility and behaviour prior to simulation and analysis of human biological monitoring data. To provide possible explanations for some of the counter-intuitive behaviour of the biological monitoring data the model included a simple lymphatic uptake process for DPHP and enterohepatic recirculation (EHR) for DPHP and the mono ester metabolite mono-(2-propylheptyl) phthalate (MPHP). The model was used to simultaneously simulate the concentration-time profiles of blood DPHP, MPHP and the urinary excretion of two metabolites, mono-(2-propyl-6-hydroxyheptyl) phthalate (OH-MPHP) and mono-(2-propyl-6-carboxyhexyl) phthalate (cx-MPHP). The availability of blood and urine measurements permitted a more robust qualitative and quantitative investigation of the importance of EHR and lymphatic uptake. Satisfactory prediction of blood DPHP and urinary metabolites was obtained whereas blood MPHP was less satisfactory. However, the delayed peak of DPHP concentration relative to MPHP in blood and second order metabolites in urine could be explained as a result of three processes: 1) DPHP entering the systemic circulation from the lymph, 2) rapid and very high protein binding and 3) the efficiency of the liver in removing DPHP absorbed via the hepatic route. The use of sensitivity analysis is considered important in the evaluation of uncertainty around in vitro and in silico derived parameters. By quantifying their impact on model output sufficient confidence in the use of a model should be afforded. This approach could expand the use of PBPK models since parameterization with in silico techniques allows for rapid model development. This in turn could assist in reducing the use of animals in toxicological evaluations by enhancing the utility of “read across” techniques.
Efficacy of Zhuyu Pill Intervention in a Cholestasis Rat Model: Mutual Effects on Fecal Metabolism and Microbial Diversity
Authors: Yu Han , Liu Chao , Zhang Fenghua , Wang Jianfei , Han Jun , Zhou Xin , Wen Yueqiang , Shen Tao
Published: September 2021

Cholestasis is a clinical condition resulting from impaired bile flow. Currently, patients with cholestasis face several barriers in seeking diagnosis and treatment. Zhuyu Pill (ZYP) is an ancient classic formula of the Coptis-Evodia herb couples (CEHC), and has been used for cholestasis treatment in the clinic, however, its underlying biological activity in cholestasis remain to be clarified. In this study, an α-naphthyl-isothiocyanate (ANIT, 50 mg/kg)-induced rat model of cholestasis was treated with ZYP. Serum biochemical indices and histopathological evaluation was performed, together with the metabolomics analyses of feces and 16S rDNA sequencing of the fecal microbiota. We evaluated the anti-cholestatic activity of ZYP and investigated the mechanisms underlying its correlation with fecal microbiota and fecal metabolite regulation. The relationships between biochemical indices and changes in gene expression associated with liver injury, levels fecal metabolites, and composition of fecal microbiota were analyzed. The results showed that both high (1.2 g/kg) and low (0.6 g/kg) doses of ZYP could effectively improve biochemical parameters in the blood of cholestasis-induced rat models; the intervention effect of high dose ZYP was superior to that that of lower dose ZYP. Based on a metabolomics test of fecal samples, significantly altered metabolites in the ANIT and ZYP treatment group were identified. In total, 734 metabolites were differentially expressed, and whose biological functions were mainly associated with amino acid metabolism, steroid hormone biosynthesis, and bile secretion. In addition, sequencing of the 16S rDNA unit in fecal samples revealed that the ZYP could improve the fecal microbiota dysbiosis that ANIT had induced. Therefore, we conclude that ANIT altering of blood biochemical and metabolic profiles and of fecal microbiota could effectively be alleviated with ZYP treatment. This study contributes to the “TCM wisdom” applied in clinical diagnosis and treatment of cholestasis.
A Systematic Review and a Meta-Analysis Comparing Prophylactic and Therapeutic Low Molecular Weight Heparins for Mortality Reduction in 32,688 COVID-19 Patients
Authors: Giossi Riccardo , Menichelli Danilo , Pani Arianna , Tratta Elena , Romandini Alessandra , Roncato Rossana , Nani Alessandro , Schenardi Paolo , Diani Erika , Fittipaldo Veronica Andrea , Farcomeni Alessio , Scaglione Francesco , Pastori Daniele
Published: September 2021

Background: Antithrombotic treatment, including low molecular weight heparin (LMWH) or unfractionated heparin (UFH), has been proposed as a potential therapy for coronavirus disease 2019 (COVID-19) to lower diffuse intravascular clotting activation. However, it is unclear whether prophylactic or therapeutic doses have similar efficacy in reducing mortality.

Methods: We performed a systematic review (PROSPERO registration CRD42020179955) and meta-analysis including observational cohort studies and randomized controlled trials (RCT) evaluating the effectiveness of heparins (either LMWH, UFH, or fondaparinux) in COVID-19 patients. Heparin treatment was compared to no anticoagulation. A subgroup analysis on prophylactic or therapeutic doses compared to no anticoagulation was performed. Prophylactic dose was also compared to full dose anticoagulation. Primary endpoint was all-cause mortality. Secondary endpoints were major bleeding and length of hospital stay (LOS).

Results: 33 studies (31 observational, 2 RCT) were included for a total overall population of 32,688 patients. Of these, 21,723 (66.5%) were on heparins. 31 studies reported data on all-cause mortality, showing that both prophylactic and full dose reduced mortality (pooled Hazard Ratio [HR] 0.63, 95% confidence interval [CI] 0.57-0.69 and HR 0.56, 95% CI 0.47-0.66, respectively). However, the full dose was associated with a higher risk of major bleeding (Odds Ratio [OR] 2.01, 95% CI 1.14–3.53) compared to prophylactic dose. Finally, LOS was evaluated in 3 studies; no difference was observed between patients with and without heparins (0.98, −3.87, 5.83 days).

Conclusion: Heparin at both full and prophylactic dose is effective in reducing mortality in hospitalized COVID-19 patients, compared to no treatment. However, full dose was associated with an increased risk of bleeding.

Systematic Review Registration: https://clinicaltrials.gov/, identifier CRD42020179955
Therapeutic Effects of Stem Cells From Different Source on Renal Ischemia- Reperfusion Injury: A Systematic Review and Network Meta-analysis of Animal Studies
Authors: Shang Zhizhong , Jiang Yanbiao , Guan Xin , Wang Anan , Ma Bin
Published: September 2021

Objective: Although stem cell therapy for renal ischemia-reperfusion injury (RIRI) has made immense progress in animal studies, conflicting results have been reported by the investigators. Therefore, we aimed to systematically evaluate the effects of different stem cells on renal function of animals with ischemia-reperfusion injury and to compare the efficacies of stem cells from various sources.

Methods: PubMed, Web of Science, Embase, Cochrane, CNKI, VIP, CBM, and WanFang Data were searched for records until April 2021. Two researchers independently conducted literature screening, data extraction, and literature quality evaluation.

Results and conclusion: Seventy-two animal studies were included for data analysis. Different stem cells significantly reduced serum creatinine and blood urea nitrogen levels in the early and middle stages (1 and 7 days) compared to the negative control group, however there was no significant difference in the late stage among all groups (14 days); In the early stage (1 day), the renal histopathological score in the stem cell group was significantly lower than that in the negative control group, and there was no significant difference among these stem cells. In addition, there was no significant difference between stem cell and negative control in proliferation of resident cells, however, significantly less apoptosis of resident cells than negative control. In conclusion, the results showed that stem cells from diverse sources could improve the renal function of RIRI animals. ADMSCs and MDMSCs were the most-researched stem cells, and they possibly hold the highest therapeutic potential. However, the quality of evidence included in this study is low, and there are many risks of bias. The exact efficacy of the stem cells and the requirement for further clinical studies remain unclear.
Guhong Injection Alleviates Cerebral Ischemia–Reperfusion Injury via the PKC/HIF-1α Pathway in Rats
Authors: Yu Li , Zhang Yangyang , Zhao Xixi , Wan Haitong , He Yu , Jin Weifeng
Published: September 2021

Guhong injection (GHI) is a drug for ischemic stroke created by combining safflower, a traditional Chinese medicine, and aceglutamide, a Western medicine. In this study, we investigated the curative effect of GHI on cerebral ischemia–reperfusion (I/R) injury via the PKC/HIF-1α pathway in rats. Adult male Sprague Dawley rats were randomly divided into seven groups: sham-operated, middle cerebral artery occlusion (MCAO), GHI, nimodipine injection (NMDP), MCAO + LY317615 (PKC inhibitor), GHI + LY317615, and NMDP + LY317615. After establishing an MCAO rat model, we performed neurological deficit testing, 2,3,5-triphenyltetrazolium chloride staining, hematoxylin and eosin (HE) staining, enzyme-linked immunosorbent assay, Western blotting, and q-PCR to detect the brain damage in rats. Compared with the MCAO group, the GHI and GHI + LY317615 group showed neurological damage amelioration as well as decreases in serum hypoxia-inducible factor-1α (HIF-1α), protein kinase C (PKC), and erythropoietin levels; brain HIF-1α and inducible nitric oxide synthase protein expression; and brain HIF-1α and NOX-4 mRNA expression. These effects were similar to those in the positive control groups NMDP and NMDP + LY317615. Thus, our results confirmed GHI can ameliorate cerebral I/R injury in MCAO rats possibly via the PKC/HIF-1α pathway.
Pharmacological Effects of Polyphenol Phytochemicals on the JAK-STAT Signaling Pathway
Authors: Yin Qianqian , Wang Longyun , Yu Haiyang , Chen Daquan , Zhu Wenwei , Sun Changgang
Published: September 2021

The JAK-STAT signaling pathway is a common pathway of many cytokine signal transductions, closely related to cell proliferation, apoptosis, differentiation, and inflammatory response. It is essential for inhibiting the inflammatory response, initiating innate immunity, and coordinating adaptive immune mechanisms. Owing to the nature of this pathway and its potential cross-epitopes with multiple alternative pathways, the long-term efficacy of monotherapy-based adaptive targeting therapy is limited, and the majority of drugs targeting STATs are still in the preclinical phase. Meanwhile, curcumin, quercetin, and several kinds of plant polyphenol chemicals play roles in multiple sites of the JAK-STAT pathway to suppress abnormal activation. Polyphenol compounds have shown remarkable effects by acting on the JAK-STAT pathway in anti-inflammatory, antitumor, and cardiovascular disease control. This review summarizes the pharmacological effects of more than 20 kinds of phytochemicals on JAK-STAT signaling pathway according to the chemical structure of polyphenolic phytochemicals.
The Pathological Mechanism and Potential Application of IL-38 in Autoimmune Diseases
Authors: Han Miao-miao , Yuan Xin-rong , Shi Xiang , Zhu Xing-Yu , Su Yue , Xiong De-Kai , Zhang Xing-Min , Zhou Huan , Wang Ji-Nian
Published: September 2021

Interleukin-38 (IL-38), a new cytokine of interleukin-1 family (IL-1F), is expressed in the human heart, kidney, skin, etc. Recently, new evidence indicated that IL-38 is involved in the process of different autoimmune diseases. Autoimmune diseases are a cluster of diseases accompanied with tissue damage caused by autoimmune reactions, including rheumatoid arthritis (RA), psoriasis, etc. This review summarized the links between IL-38 and autoimmune diseases, as well as the latest knowledge about the function and regulatory mechanism of IL-38 in autoimmune diseases. Especially, this review focused on the differentiation of immune cells and explore future prospects, such as the application of IL-38 in new technologies. Understanding the function of IL-38 is helpful to shed light on the progress of autoimmune diseases.
Interventional Efects of the Topical of “Sanse Powder” Essential Oils Nanoemulsion on Knee Osteoarthritis in Rats by Targeting the ERS/TXNIP/NLRP3 Signaling Axis
Authors: Liu Zixiu , Liao Taiyang , Yang Nan , Ding Liang , Li Xiaochen , Wu Peng , Wang Peimin
Published: September 2021

Purpose: Our recent research is dedicated to finding effective drugs for the treatment of knee osteoarthritis (KOA) from traditional Chinese medicine and trying to make full use of modern science and technology to uncover the mechanisms and targets behind them. Synovial inflammation is one of the key pathological features of KOA, and a growing number of researchers realize that early intervention of synovial inflammation may be able to reverse disease progression. The close association of traditional natural products with modern nanotechnology may be important for improving the anti-synovitis efficacy. The purpose of our research was to explore the anti-synovitis mechanism of NEs-SP-EO that might be associated with the ERS/TXNIP/NLRP3 signalling axis.

Methods: Chemical composition of “Sanse Powder” essential oil (SP-EO) and NEs-SP-EO were analyzed by GC-MS. NEs-SP-EO were prepared and characterized by nanoparticle tracking analysis, polydispersity index (PDI), zeta potential (ZP), ultraviolet-visible spectroscopy, and transmission electronic microscopy. The CCK8 assay for cell viability of NEs-SP-EO was performed on fibroblast-like synovial cells (FLSs) and the inflammatory environment was stimulated by LPS to explore the therapeutic mechanisms in vitro. Experiments of NEs-SP-EO in vivo were performed in male SD rats.

Results: The GC-MS results showed that 30 compounds were present in SP-EO and 11 components of NEs-SP-EO were identified. The results also showed that the formulation of NEs-SP-EO exhibited suitable particle size, negative charge, and stable system. In vitro and vivo testing, NEs-SP-EO produced anti-synovitis efficacy by reduced the induction of the ERS/TXNIP/NLRP3 signaling axis as well as regulating the overproduction of IL-1β, IL-18.

Conclusion: We have developed a new type of essential oil nanoemulsion from “Sanse Powder” and demonstrated that it can managing synovitis of KOA. Besides, we have initially explored the anti-inflammatory mechanism that may be related to the ERS/TXNIP/NLRP3 signaling axis.
α-Mangostin Induces Apoptosis and Inhibits Metastasis of Breast Cancer Cells via Regulating RXRα-AKT Signaling Pathway
Authors: Zhu Xiuzhi , Li Jialin , Ning Huiting , Yuan Zhidong , Zhong Yue , Wu Suzhen , Zeng Jin-Zhang
Published: September 2021

Mangostin, which has the function of anti-inflammatory, antioxidant, and anticancer, etc, is one of the main active ingredients of the hull of the mangosteen. The main objective of the study was to elucidate its anti-cancer function and possible mechanism. α-Mangostin was separated and structurally confirmed. MTT method was used to check the effect of mangostin on breast cancer cell proliferation. Then the effect of α-Mangostin on the transcriptional activity of RXRα was tested by dual-luciferase reporter gene assay. And Western blot (WB) was used to detect the expression of apoptosis-related proteins or cell cycle-associated proteins after treatment. Also, this study was to observe the effects of α-Mangostin on the invasion of breast cancer cell line MDA-MB-231. α-Mangostin regulates the downstream effectors of the PI3K/AKT signaling pathway by degrading RXRα/tRXRα. α-Mangostin can trigger PARP cleavage and induce apoptosis, which may be related to the induction of upregulated BAX expression and downregulation of BAD and cleaved caspase-3 expression in MDA-MB-231 cells through blockade of AKT signaling. The experiments verify that α-Mangostin have evident inhibition effects of invasion and metastasis of MDA-MB-231 cells. Cyclin D1 was involved in the anticancer effects of α-Mangostin on the cell cycle in MDA-MB-231 cells. α-Mangostin induces apoptosis, suppresses the migration and invasion of breast cancer cells through the PI3K/AKT signaling pathway by targeting RXRα, and cyclin D1 has involved in this process.
Spermine-Related DNA Hypermethylation and Elevated Expression of Genes for Collagen Formation are Susceptible Factors for Chemotherapy-Induced Hand-Foot Syndrome in Chinese Colorectal Cancer Patients
Authors: Li Mingming , Chen Jiani , Liu Shaoqun , Sun Xiaomeng , Xu Huilin , Gao Qianmin , Chen Xintao , Xi Chaowen , Huang Doudou , Deng Yi , Zhang Feng , Gao Shouhong , Qiu Shi , Tao Xia , Zhai Jingwen , Wei Hua , Yao Houshan , Chen Wansheng
Published: September 2021

Hand-foot syndrome (HFS) is a common capecitabine-based chemotherapy-related adverse event (CRAE) in patients with colorectal cancer (CRC). It is of great significance to comprehensively identify susceptible factors for HFS, and further to elucidate the biomolecular mechanism of HFS susceptibility. We performed an untargeted multi-omics analysis integrating DNA methylation, transcriptome, and metabolome data of 63 Chinese CRC patients who had complete CRAE records during capecitabine-based chemotherapy. We found that the metabolome changes for each of matched plasma, urine, and normal colorectal tissue (CRT) in relation to HFS were characterized by chronic tissue damage, which was indicated by reduced nucleotide salvage, elevated spermine level, and increased production of endogenous cytotoxic metabolites. HFS-related transcriptome changes of CRT showed an overall suppressed inflammation profile but increased M2 macrophage polarization. HFS-related DNA methylation of CRT presented gene-specific hypermethylation on genes mainly for collagen formation. The hypermethylation was accumulated in the opensea and shore regions, which elicited a positive effect on gene expression. Additionally, we developed and validated models combining relevant biomarkers showing reasonably good discrimination performance with the area under the receiver operating characteristic curve values from 0.833 to 0.955. Our results demonstrated that the multi-omics variations associated with a profibrotic phenotype were closely related to HFS susceptibility. HFS-related biomolecular variations in CRT contributed more to the relevant biomolecular mechanism of HFS than in plasma and urine. Spermine-related DNA hypermethylation and elevated expression of genes for collagen formation were closely associated with HFS susceptibility. These findings provided new insights into the susceptible factors for chemotherapy-induced HFS, which can promote the implementation of individualized treatment against HFS.
Mechanical Deconvolution of Elastic Moduli by Indentation of Mechanically Heterogeneous Materials
Authors: Boots J. N. M. , Kooi R. , Kodger T. E. , van der Gucht J.
Published: September 2021

Most materials are mechanically heterogeneous on a certain length scale. In many applications, this heterogeneity is crucial for the material’s function, and exploiting mechanical heterogeneity could lead to new materials with interesting features, which require accurate understanding of the local mechanical properties. Generally used techniques to probe local mechanics in mechanically heterogeneous materials include indentation and atomic force microscopy. However, these techniques probe stresses at a region of finite size, so that experiments on a mechanically heterogeneous material lead to blurring or convolution of the measured stress signal. In this study, finite element method simulations are performed to find the length scale over which this mechanical blurring occurs. This length is shown to be a function of the probe size and indentation depth, and independent of the elastic modulus variations in the heterogeneous material, for both 1D and 2D modulus profiles. Making use of these findings, we then propose two deconvolution methods to approximate the actual modulus profile from the apparent, blurred measurements, paving the way for an accurate determination of the local mechanical properties of heterogeneous materials.
The Optimal Control Strategy of Virus Transmission Based on Caputo-Fabrizio Order
Authors: Yang Liangli , Su Yongmei , Yang Xue , Wang Zhen
Published: September 2021

Hepatitis B virus (HBV) is a serious threat to human health as it can cause the chronic hepatitis B, and eventually liver cancer. It also has become one of the major threats to public health in the world. In this paper, considering the rationality of using standard incidence in Caputo-Fabrizio fractional order HBV infection model, we propose a model with standard incidence. The analysis of local stability about the equilibrium and the simulation of global stability are given. We also use the real data to estimate the parameters of this model. The simulation results can fit the data well. Moreover, we propose an optimal control model and give the optimal therapy strategy, which show that optimal therapy can reduce the cost and side effects while ensuring the therapeutic effect.
Performance Investigation of a High Data Rate Mode Division Multiplexed-Free Space Optics Link Under Harsh Weather Conditions
Authors: Singh Mehtab , Pottoo Sahil Nazir , Suvidhi  , Dewra Sanjeev , Rishabh  , Grover Amit , Manikandan A. , Sheetal Anu
Published: September 2021

The requirement of high data rate information transmission is rising exponentially for supporting different services including social networking, web streaming, and biomedical sensor data transmission. Such services required high channel bandwidth with secure information transmission and immunity to electromagnetic interference. Radio over free space optics (RoFSO) is witnessed as a promising technological solution to provide high data rate transmission over free space channel. We report on the design of a 2×10 Gb/s-10 GHz RoFSO transmission system using the mode division multiplexing technique and evaluate its transmission performance over varying levels of dust weather conditions. The comparison of non-return to zero (NRZ) and return to zero (RZ) binary digital optical modulation techniques is carried out in the proposed system. It is found that the proposed system using NRZ modulation serves 14.5 km transmission range; however, in the case of RZ modulation, it was restricted to 10 km for a target bit error rate (BER) of 10−6, thus resulting in a noticeable link enhancement of 4.5 km. Also, we demonstrate NRZ-based MDM-RoFSO link performance and availability in dust weather conditions using the BER, maximum reachable link range, and eye diagram as key performance parameters. We obtain a reliable transmission of 20 Gb/s-20 GHz data through HG00 and HG01 channels over a link range of 2500–108 m depending on the external dust weather condition. Furthermore, since this investigation shows the feasibility of RoFSO for small size cells, which is an essential feature of 5G mobile network, the proposed system can thus be implemented as a backhaul/fronthaul link for high-band (above 6 GHz) 5G services and for providing secure transmission of biomedical sensor data.
Multiscale Three-Dimensional Morphological Characterization of Calcareous Sand Particles Using Spherical Harmonic Analysis
Authors: Liang Hui , Shen Yang , Xu Junhong , Shen Xue
Published: September 2021

Particle morphology is a fundamental inherent property that substantially affects the macroscopic behavior of granular materials. The division and separation of particle morphology at different scale levels contributes to the further multiscale morphology related orthogonal researches. In this context, the high-resolution X-ray micro-computed tomographic (X-CT) scanning and spherical harmonic (SH) analysis were combined to complete the precise and digitized reconstruction of sand particles. The 3D sphericity, roundness and roughness were introduced to define the particle morphology at three scale levels (the general shape, local angularity and surface textures). Two typical sand particles, Calcareous sand (CS) and Fujian sand (FS), were tested in this study. The results showed that the irregularity, angularity and roughness of CS is higher than that of FS, and the multiscale morphological features of the two types of natural sand were given and compared digitally.
Huang-Lian-Jie-Du Decoction Attenuates Atherosclerosis and Increases Plaque Stability in High-Fat Diet-Induced ApoE-/- Mice by Inhibiting M1 Macrophage Polarization and Promoting M2 Macrophage Polarization
Authors: Cai Yinhe , Wen Junmao , Ma Siwen , Mai Zhexing , Zhan Qunzhang , Wang Yijun , Zhang Yueyao , Chen He , Li Haiyi , Wu Wei , Li Rong , Luo Chuanjin
Published: September 2021

Macrophage polarization plays a vital impact in triggering atherosclerosis (AS) progression and regression. Huang-Lian-Jie-Du Decoction (HLJDD), a famous traditional Chinese decoction, displays notable anti-inflammatory and lipid-lowering effects in different animal models. However, its effects and mechanisms on AS have not been clearly defined. We determined whether HLJDD attenuated atherosclerosis and plaques vulnerability by regulating macrophage polarization in ApoE−/− mice induced by high-fat diet (HFD). Furthermore, we investigated the effects of HLJDD on macrophage polarization in oxidized low-density lipoprotein (ox-LDL) induced RAW264.7 cells. For in vivo assay, compared with the model group, HLJDD ameliorated lipid metabolism, with significantly decreased levels of serum triglyceride, total cholesterol (CHOL), and lipid density lipoprotein. HLJDD suppressed serum tumor necrosis factor α (TNF-α) and IL-1β levels with increased serum IL-10 level, and inhibited mRNA level of NLRP3 inflammasome in carotid tissues. HLJDD enhanced carotid lesion stability by decreasing macrophage infiltration together with increased expression of collagen fibers and α-SMA. Moreover, HLJDD inhibited M1 macrophage polarization, which decreased the expression and mRNA levels of M1 markers [inducible nitric oxide synthase (iNOS) and CD86]. HLJDD enhanced alternatively activated macrophage (M2) activation, which increased the expression and mRNA levels of M2 markers (Arg-1 and CD163). For in vitro assay, HLJDD inhibited foam cell formation in RAW264.7 macrophages disturbed by ox-LDL. Besides, groups with ox-LDL plus HLJDD drug had a lower expression of CD86 and mRNA levels of iNOS, CD86, and IL-1β, but higher expression of CD163 and mRNA levels of Arg-1, CD163, and IL-10 than ox-LDL group. Collectively, our results revealed that HLJDD alleviated atherosclerosis and promoted plaque stability by suppressing M1 polarization and enhancing M2 polarization.
Characterisation of the Myocardial Mitochondria Structural and Functional Phenotype in a Murine Model of Diabetic Cardiomyopathy
Authors: Parker Alex M. , Tate Mitchel , Prakoso Darnel , Deo Minh , Willis Andrew M. , Nash David M. , Donner Daniel G. , Crawford Simon , Kiriazis Helen , Granata Cesare , Coughlan Melinda T. , De Blasio Miles J. , Ritchie Rebecca H.
Published: September 2021

People affected by diabetes are at an increased risk of developing heart failure than their non-diabetic counterparts, attributed in part to a distinct cardiac pathology termed diabetic cardiomyopathy. Mitochondrial dysfunction and excess reactive oxygen species (ROS) have been implicated in a range of diabetic complications and are a common feature of the diabetic heart. In this study, we sought to characterise impairments in mitochondrial structure and function in a recently described experimental mouse model of diabetic cardiomyopathy. Diabetes was induced in 6-week-old male FVB/N mice by the combination of three consecutive-daily injections of low-dose streptozotocin (STZ, each 55 mg/kg i.p.) and high-fat diet (42% fat from lipids) for 26 weeks. At study end, diabetic mice exhibited elevated blood glucose levels and impaired glucose tolerance, together with increases in both body weight gain and fat mass, replicating several aspects of human type 2 diabetes. The myocardial phenotype of diabetic mice included increased myocardial fibrosis and left ventricular (LV) diastolic dysfunction. Elevated LV superoxide levels were also evident. Diabetic mice exhibited a spectrum of LV mitochondrial changes, including decreased mitochondria area, increased levels of mitochondrial complex-III and complex-V protein abundance, and reduced complex-II oxygen consumption. In conclusion, these data suggest that the low-dose STZ-high fat experimental model replicates some of the mitochondrial changes seen in diabetes, and as such, this model may be useful to study treatments that target the mitochondria in diabetes.
Effects of Lipid Deposition on Viscoelastic Response in Human Hepatic Cell Line HepG2
Authors: Li Rui , Bu Yang , Yang Chendong , Wang Jizeng
Published: September 2021

Hepatic steatosis is associated with various liver diseases. The main pathological feature of steatosis is the excessive lipid accumulation. Ultrasound has been extensively used for the diagnosis of hepatic steatosis. However, most ultrasound-based non-invasive methods are still not accurate enough for cases with light lipid infiltration. One important reason is that the extent to which lipid infiltration may affect mechanical properties of hepatocytes remains unknown. In this work, we used atomic force microscope and in vitro dose-dependent lipid deposition model to detect the quantitative changes of mechanical properties under different degrees of steatosis in a single-cell level. The results show that hepatic cells with lipid deposition can be treated as linear viscoelastic materials with the power law creep compliance and relaxation modulus. Further analysis showed that even slight accumulation of lipid can lead to measurable decrease of stiffness and increased fluidity in liver cells. The accurate detection of viscoelastic properties of hepatocytes and the analysis methods may provide novel insights into hepatic steatosis grading, especially in the very early stage with reversible liver lesion. The application of viscoelasticity index for grading fat deposition might be a new detection indicator in future clinical diagnosis.
Fast Optical Investigation of Cardiac Electrophysiology by Parallel Detection in Multiwell Plates
Authors: Credi Caterina , Balducci Valentina , Munagala U. , Cianca C. , Bigiarini S. , de Vries Antoine A. F. , Loew Leslie M. , Pavone Francesco S. , Cerbai Elisabetta , Sartiani Laura , Sacconi Leonardo
Published: September 2021

Current techniques for fast characterization of cardiac electrophysiology employ optical technologies to control and monitor action potential features of single cells or cellular monolayers placed in multiwell plates. High-speed investigation capacities are commonly achieved by serially analyzing well after well employing fully automated fluorescence microscopes. Here, we describe an alternative cost-effective optical approach (MULTIPLE) that exploits high-power LED arrays to globally illuminate a culture plate and an sCMOS sensor for parallel detection of the fluorescence coming from multiple wells. MULTIPLE combines optical detection of action potentials using a red-shifted voltage-sensitive fluorescent dye (di-4-ANBDQPQ) with optical stimulation, employing optogenetic actuators, to ensure excitation of cardiomyocytes at constant rates. MULTIPLE was first characterized in terms of interwell uniformity of the illumination intensity and optical detection performance. Then, it was applied for probing action potential features in HL-1 cells (i.e., mouse atrial myocyte-like cells) stably expressing the blue light-activatable cation channel CheRiff. Under proper stimulation conditions, we were able to accurately measure action potential dynamics across a 24-well plate with variability across the whole plate of the order of 10%. The capability of MULTIPLE to detect action potential changes across a 24-well plate was demonstrated employing the selective Kv11.1 channel blocker (E-4031), in a dose titration experiment. Finally, action potential recordings were performed in spontaneous beating human induced pluripotent stem cell derived cardiomyocytes following pharmacological manipulation of their beating frequency. We believe that the simplicity of the presented optical scheme represents a valid complement to sophisticated and expensive state-of-the-art optical systems for high-throughput cardiac electrophysiological investigations.
Regulation of the Muscarinic M3 Receptor by Myocardin-Related Transcription Factors
Authors: Liu Li , Rippe Catarina , Hansson Ola , Kryvokhyzha Dmytro , Fisher Steven , Ekman Mari , Swärd Karl
Published: September 2021

Myocardin-related transcription factors (MRTFs: myocardin/MYOCD, MRTF-A/MRTFA, and MRTF-B/MRTFB) are co-factors of serum response factor (SRF) that activate the smooth muscle cell (SMC) gene program and that play roles in cardiovascular development and mechanobiology. Gain and loss of function experiments have defined the SMC gene program under control of MRTFs, yet full understanding of their impact is lacking. In the present study, we tested the hypothesis that the muscarinic M3 receptor (CHRM3) is regulated by MRTFs together with SRF. Forced expression of MYOCD (8d) in human coronary artery (SMC) followed by RNA-sequencing showed increased levels of M2, M3, and M5 receptors (CHRM2: 2-fold, CHRM3: 16-fold, and CHRM5: 2-fold). The effect of MYOCD on M3 was confirmed by RT-qPCR using both coronary artery and urinary bladder SMCs, and correlation analyses using human transcriptomic datasets suggested that M3 may also be regulated by MRTF-B. Head-to-head comparisons of MYOCD, MRTF-A and MRTF-B, argued that while all MRTFs are effective, MRTF-B is the most powerful transactivator of CHRM3, causing a 600-fold increase at 120h. Accordingly, MRTF-B conferred responsiveness to the muscarinic agonist carbachol in Ca2+ imaging experiments. M3 was suppressed on treatment with the MRTF-SRF inhibitor CCG-1423 using SMCs transduced with either MRTF-A or MRTF-B and using intact mouse esophagus in culture (by 92±2%). Moreover, silencing of SRF with a short hairpin reduced CHRM3 (by >60%) in parallel with α-actin (ACTA2). Tamoxifen inducible knockout of Srf in smooth muscle reduced Srf (by 54±4%) and Chrm3 (by 41±6%) in the urinary bladder at 10days, but Srf was much less reduced or unchanged in aorta, ileum, colon, trachea, and esophagus. Longer induction (21d) further accentuated the reduction of Chrm3 in the bladder and ileum, but no change was seen in the aorta. Single cell RNA-sequencing revealed that Mrtfb dominates in ECs, while Myocd dominates in SMCs, raising the possibility that Chrm3 may be driven by Mrtfb-Srf in the endothelium and by Myocd-Srf in SMCs. These findings define a novel transcriptional control mechanism for muscarinic M3 receptors in human cells, and in mice, that could be targeted for therapy.
Decompression Illness in Repetitive Breath-Hold Diving: Why Ischemic Lesions Involve the Brain?
Authors: Kohshi Kiyotaka , Denoble Petar J. , Tamaki Hideki , Morimatsu Yoshitaka , Ishitake Tatsuya , Lemaître Frédéric
Published: September 2021

Nitrogen (N2) accumulation in the blood and tissues can occur due to breath-hold (BH) diving. Post-dive venous gas emboli have been documented in commercial BH divers (Ama) after repetitive dives with short surface intervals. Hence, BH diving can theoretically cause decompression illness (DCI). “Taravana,” the diving syndrome described in Polynesian pearl divers by Cross in the 1960s, is likely DCI. It manifests mainly with cerebral involvements, especially stroke-like brain attacks with the spinal cord spared. Neuroradiological studies on Ama divers showed symptomatic and asymptomatic ischemic lesions in the cerebral cortex, subcortex, basal ganglia, brainstem, and cerebellum. These lesions localized in the external watershed areas and deep perforating arteries are compatible with cerebral arterial gas embolism. The underlying mechanisms remain to be elucidated. We consider that the most plausible mechanisms are arterialized venous gas bubbles passing through the lungs, bubbles mixed with thrombi occlude cerebral arteries and then expand from N2 influx from the occluded arteries and the brain. The first aid normobaric oxygen appears beneficial. DCI prevention strategy includes avoiding long-lasting repetitive dives for more than several hours, prolonging the surface intervals. This article provides an overview of clinical manifestations of DCI following repetitive BH dives and discusses possible mechanisms based on clinical and neuroimaging studies.
Underwater and Surface Swimming Parameters Reflect Performance Level in Elite Swimmers
Authors: Pla Robin , Poszalczyk Gauthier , Souaissia Cyrine , Joulia Fabrice , Guimard Alexandre
Published: September 2021

Although the role of underwater phases is well-known, no study has taken an interest in describing and quantifying the distance and time spent in apnea as a condition for optimal performance. This study aimed to investigate the impact of time and distance spent underwater and surface parameters on the swimming performance of elite swimmers. The performances of 79 swimmers in 100-m freestyle were analyzed (short-course). The underwater and spatiotemporal parameters of three groups have been recorded: finalists of the 2018 World Swimming Championships (WORLD), French swimmers who reached a 100 m performance time under 50 s at the 2018 French National Championships (UND50), and those who reached a 100 m performance time above 50 s (UP50). The WORLD group spent more distance underwater (37.50 ± 4.92 m) in comparison with UND50 (31.90 ± 4.88 m, p < 0.05) and UP50 (31.94 ± 4.93 m, p < 0.01) groups. The total percentage of non-swimming time was higher for WORLD (39.11 ± 4.73%) vs. UND50 (34.21 ± 4.55%, p < 0.05) and UP50 (33.94 ± 5.00%, p < 0.01). In addition, underwater speed was higher for WORLD (2.54 ± 0.05 m/s) compared with UND50 (2.46 ± 0.09 m/s, p < 0.05) and UP50 (2.38 ± 0.11 m/s, p < 0.01). Three parameters among the underwater phases (i.e. distance underwater, speed underwater, and total percentage of non-swimming time) determine the 100-m freestyle short course performance. These data suggest an appropriate focus on specific apnea training to improve underwater skills during short-course swimming performances.