bluuebunny/crossref_metadata_2025 huggingface dataset:
The Causes of Death and Their Influence in Life Expectancy of Children Aged 5–14 Years in Low- and Middle-Income Countries From 1990 to 2019
Authors: Liang Juanjuan , Du Yuanze , Qu Xiang , Ke Changrong , Yi Guipeng , Liu Mi , Lyu Juncheng , Ren Yanfeng , Xing Jie , Wang Chunping , Liu Shiwei
Published: May 2022

Introduction

Although child and adolescent health is the core of the global health agenda, the cause of death and its expected contribution to life expectancy (LE) among those aged 5–14 are under-researched across countries, especially in low- and middle-income countries (LMICs).

Methods

Death rates per 10 years age group including a 5–14-year-old group were calculated by the formula, which used the population and the number of deaths segmented by the cause of death and gender from the 2019 Global Burden of Disease (GBD) study. LE and cause-eliminated LE in 10-year intervals were calculated by using life tables.

Results

In 2019, the global mortality rate for children and adolescents aged 5–14 years was 0.522 (0.476–0.575) per 1,000, and its LF was 71.377 years. In different-income regions, considerable heterogeneity remains in the ranking of cause of death aged 5–14 years. The top three causes of death in low-income countries (LICs) are enteric infections [0.141 (0.098–0.201) per 1,000], other infectious diseases [0.103 (0.073–0.148) per 1,000], and neglected tropical diseases and malaria [0.102 (0.054–0.172) per 1,000]. Eliminating these mortality rates can increase the life expectancy of the 5–14 age group by 0.085, 0.062, and 0.061 years, respectively. The top three causes of death in upper-middle income countries (upper MICs) are unintentional injuries [0.066 (0.061–0.072) per 1,000], neoplasm [0.046 (0.041–0.050) per 1,000], and transport injuries [0.045 (0.041–0.049) per 1,000]. Eliminating these mortality rates can increase the life expectancy of the 5–14 age group by 0.045, 0.031, and 0.030 years, respectively.

Conclusion

The mortality rate for children and adolescents aged 5–14 years among LMICs remains high. Considerable heterogeneity was observed in the main causes of death among regions. According to the main causes of death at 5–14 years old in different regions and countries at different economic levels, governments should put their priority in tailoring their own strategies to decrease preventable mortality.
The Role of CXC Chemokines in Cardiovascular Diseases
Authors: Lu Xiyi , Wang Zhen , Ye Di , Feng Yongqi , Liu Menglin , Xu Yao , Wang Menglong , Zhang Jishou , Liu Jianfang , Zhao Mengmeng , Xu Shuwan , Ye Jing , Wan Jun
Published: May 2022

Cardiovascular disease (CVD) is a class of diseases with high disability and mortality rates. In the elderly population, the incidence of cardiovascular disease is increasing annually. Between 1990 and 2016, the age-standardised prevalence of CVD in China significantly increased by 14.7%, and the number of cardiovascular disease deaths increased from 2.51 million to 3.97 million. Much research has indicated that cardiovascular disease is closely related to inflammation, immunity, injury and repair. Chemokines, which induce directed chemotaxis of reactive cells, are divided into four subfamilies: CXC, CC, CX3C, and XC. As cytokines, CXC chemokines are similarly involved in inflammation, immunity, injury, and repair and play a role in many cardiovascular diseases, such as atherosclerosis, myocardial infarction, cardiac ischaemia-reperfusion injury, hypertension, aortic aneurysm, cardiac fibrosis, postcardiac rejection, and atrial fibrillation. Here, we explored the relationship between the chemokine CXC subset and cardiovascular disease and its mechanism of action with the goal of further understanding the onset of cardiovascular disease.
Naoluo Xintong Decoction in the Treatment of Ischemic Stroke: A Network Analysis of the Mechanism of Action
Authors: Wang Ni , Chu Furui , Fei Changyi , Pan Lingyu , Wang Yongzhong , Chen Weidong , Peng Daiyin , Duan Xianchun , He Ling
Published: May 2022

The mechanism of action of Naoluo Xintong decoction (NLXTD) for the treatment of ischemic stroke (IS) is unknown. We used network analysis and molecular docking techniques to verify the potential mechanism of action of NLXTD in treating IS. The main active components of NLXTD were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, and IS targets were collected from the Online Mendelian Inheritance in Man (OMIM), GeneCards, and Drugbank databases; their intersection was taken. In addition, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed and used to build protein-protein interaction networks. AutoDock Vina software was used for molecular docking, and animal experiments were conducted to verify the results. Hematoxylin and eosin staining was used to observe the brain morphology of rats in each group, and real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression level of relative mRNA in the brain tissue of rats. Western blot was used to detect the expression level of relative protein in the brain tissue of rats. Network analysis and molecular docking results showed that CASP3, NOS3, VEGFA, TNF, PTGS2, and TP53 are important potential targets for NLXTD in the treatment of IS. RT-qPCR and western blot results showed that NLXTD inhibited the expression of CASP3, TNF, PTGS2, and TP53 and promoted the expression of VEGFA and NOS3. NLXTD treats IS by modulating pathways and targets associated with inflammation and apoptosis in a multicomponent, multitarget manner.
Design, Synthesis, and Antileukemic Evaluation of a Novel Mikanolide Derivative Through the Ras/Raf/MEK/ERK Pathway
Authors: Rao Qing , Xie Kaiqiang , Varier Krishnapriya M. , Huang Lei , Song Jingrui , Yang Jue , Qiu Jianfei , Huang Yubing , Li Yan , Gajendran Babu , Li Yanmei , Liu Sheng
Published: May 2022

Chronic myeloid leukemia (CML) accounts for a major cause of death in adult leukemia patients due to mutations or other reasons for dysfunction in the ABL proto-oncogene. The ubiquitous BCR–ABL expression stimulates CML by activating CDK1 and cyclin B1, promoting pro-apoptotic, and inhibiting antiapoptotic marker expression along with regulations in RAS pathway activation. Thus, inhibitors of cyclins and the RAS pathway by ERK are of great interest in antileukemic treatments. Mikanolide is a sesquiterpene dilactone isolated from several Asteraceae family Mikania sp. plants. Sesquiterpene dilactone is a traditional medicine for treating ailments, such as flu, cardiovascular diseases, bacterial infections, and other blood disorders. It is used as a cytotoxic agent as well. The need of the hour is potent chemotherapeutic agents with cytotoxic effects inhibition of proliferation and activation of apoptotic machinery. Recently, ERK inhibitors are used in clinics as anticancer agents. Thus, in this study, we synthesized 22-mikanolide derivatives that elucidated to be potent antileukemic agents in vitro. However, a bioactive mikanolide derivative, 3g, was found with potent antileukemic activity, through the Ras/Raf/MEK/ERK pathway. It can arrest the cell cycle by inhibiting phosphorylation of CDC25C, triggering apoptosis, and promoting DNA and mitochondrial damage, thus suggesting it as a potential chemotherapeutic agent for leukemia patients.
Miya Improves Osteoarthritis Characteristics via the Gut-Muscle-Joint Axis According to Multi-Omics Analyses
Authors: Xu Tianyang , Yang Dong , Liu Kaiyuan , Gao Qiuming , Liu Zhongchen , Li Guodong
Published: May 2022

Background: The gut microbiota is associated with osteoarthritis (OA) progression. Miya (MY) is a product made from Clostridium butyricum, a member of gut microbiota. This study was conducted to investigate the effects of MY on OA and its underlying mechanisms.

Methods: An OA rat model was established, and MY was used to treat the rats for 4 weeks. Knee joint samples from the rats were stained with hematoxylin-eosin, and fecal samples from the OA and OA+MY groups were subjected to 16S rDNA sequencing and metabolomic analysis. The contents of succinate dehydrogenase and muscle glycogen in the tibia muscle were determined, and related genes and proteins were detected using quantitative reverse transcription polymerase chain reaction and western blotting.

Results: Hematoxylin and eosin staining showed that treatment with MY alleviated the symptoms of OA. According to the sequencing results, MY significantly increased the Chao1, Shannon, and Pielou evenness values compared to those in the untreated group. At the genus level, the abundances of Prevotella, Ruminococcus, Desulfovibrio, Shigella, Helicobacter, and Streptococcus were higher in the OA group, whereas Lactobacillus, Oscillospira, Clostridium, and Coprococcus were enriched after MY treatment. Metabolomic analysis revealed 395 differentially expressed metabolites. Additionally, MY treatment significantly increased the succinate dehydrogenase and muscle glycogen contents in the muscle caused by OA (p > 0.05). Finally, AMPK, Tfam, Myod, Ldh, Chrna1, Chrnd, Rapsyn, and Agrin were significantly downregulated in the muscles of OA mice, whereas Lcad, Mcad, and IL-1β were upregulated; MY significantly reversed these trends induced by OA.

Conclusions: MY may promote the repair of joint damage and protect against OA via the gut-muscle-joint axis.
Treatment Effect of Long-Term Antipsychotics on Default-Mode Network Dysfunction in Drug-Naïve Patients With First-Episode Schizophrenia: A Longitudinal Study
Authors: Deng Mengjie , Liu Zhening , Shen Yanyu , Cao Hengyi , Zhang Manqi , Xi Chang , Zhang Wen , Tan Wenjian , Zhang Jinqiang , Chen Eric , Lee Edwin , Pu Weidan
Published: May 2022

Background: The maintenance of antipsychotic treatment is an efficient way to prevent the relapse of schizophrenia (SCZ). Previous studies have identified beneficial effects of antipsychotics on brain structural and functional abnormalities during mostly the acute phase in SCZ, but seldom is known about the effects of long-term antipsychotics on the brain. The present study focused on the long-term antipsychotic effect on the default mode network (DMN) dysfunction in SCZ.

Methods: A longitudinal study of the functional connectivity (FC) of 11 DMN subdivisions was conducted in 86 drug-naive first-episode patients with SCZ at the baseline and after a long-term atypical antipsychotic treatment (more than 6 months) based on the resting-state functional magnetic resonance image. In total, 52 patients completed the follow-up of clinical and neuroimaging investigations.

Results: At the baseline, relative to healthy controls, altered connectivities within the DMN and between the DMN and the external attention system (EAS) were observed in patients. After treatment, along with significant relief of symptoms, most FC alterations between the DMN and the EAS at the baseline were improved after treatment, although the rehabilitation of FC within the DMN was only observed at the link between the posterior cingulate cortex and precuneus. Greater reductions in negative and positive symptoms were both related to the changes of DMN-EAS FC in patients.

Conclusion: Our findings provide evidence that maintenance antipsychotics on SCZ is beneficial for the improvement of DMN-EAS competitive imbalance, which may partly contribute to the efficient relapse prevention of this severe mental disorder.
Pharmacokinetic Assessment of Staphylococcal Phage K Following Parenteral and Intra-articular Administration in Rabbits
Authors: Totten Katherine M.C. , Cunningham Scott A. , Gades Naomi M. , Etzioni Athema , Patel Robin
Published: May 2022

The therapeutic value of phage as an alternative to antibiotics for the treatment of bacterial infections is being considered in the wake of mounting antibiotic resistance. In this study, the pharmacokinetic properties ofStaphylococcus aureusphage K following intravenous and intra-articular administration were investigated in a rabbit model. Using a traditional plaque assay and a novel quantitative PCR assay to measure phage levels in specimens over time, it was found that intra-articularly administered phage enters the systemic circulation; that phage may be detected in synovial fluid up to 24 h following the intra-articular, but not intravenous, administration; and that qPCR-based enumeration is generally more sensitive than plaque enumeration, with fair to moderate correlation between the two methods. Findings presented should inform the design of phage therapy experiments and therapeutic drug monitoring in preclinical and human phage studies.
Chemo-Immunotherapy Regimes for Recurrent or Metastatic Nasopharyngeal Carcinoma: A Network Meta-Analysis and Cost-Effectiveness Analysis
Authors: Zhu Youwen , Liu Kun , Ding Dong , Wang Kailing , Liu Xiaoting , Tan Xiao
Published: May 2022

Introduction: In 2021, two phase III clinical trials confirmed that toripalimab or camrelizumab combined with gemcitabine and cisplatin (TGP or CGP) provide more benefits in the first-line treatment of R/M NPC than GP. Fortunately, TGP and CGP were recently approved as first-line treatments for cases experiencing R/M NPC by the China National Medical Products Administration in 2021. However, due to the high cost and variety of treatment options, the promotion of chemo-immunotherapeutics in the treatment of R/M NPC remains controversial. Therefore, we performed a cost-effectiveness assessment of the two newly approved treatment strategies to assess which treatments provide the greatest clinical benefits at a reasonable cost.

Methods: A cost-effectiveness analysis and network meta-analysis network meta-analysis was conducted based on the JUPITER-02 and CAPTAIN-first Phase 3 randomized clinical trials. A Markov model was expanded for the evaluation of the effectiveness and cost of TGP, CGP, and GP chemotherapy with a 10-years horizon and measured the health achievements in quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), and life-years (LYs). We constructed a treatment strategy and other parameters based on two clinical trials and performed one-way and probabilistic sensitivity experiments for the evaluation of the uncertainty in the model.

Results: For the model of patients with treatment-R/M NPC, TGP was associated with a total cost of $48,525 and 2.778 QALYs (4.991 LYs), leading to an ICER of $15,103 per QALY ($10,321 per LY) compared to CGP. On comparing the GP chemotherapy, we found TGP and CGP incurred substantial health costs, resulting in ICERs of $19,726 per QALY and $20,438 per QALY, respectively. The risk of adverse events (AEs) and the price of the drugs had significant impacts on the ICER. At the assumed willingness-to-pay (WTP) threshold of $35,673 per QALY, there were approximately 75.8 and 68.5% simulations in which cost-effectiveness was achieved for TGP and CGP, respectively.

Conclusion: From the Chinese payer’s perspective, TGP is more possible to be a cost-effective regimen compared with CGP and GP for first-line treatment of patients with R/M NPC at a WTP threshold of $35,673 per QALY.
The Alleviation of LPS-Induced Murine Acute Lung Injury by GSH-Mediated PEGylated Artesunate Prodrugs
Authors: Hao Dan-Li , Wang Ya-Jie , Yang Jia-Ying , Xie Ran , Jia Ling-Yu , Cheng Jin-Tang , Ma Hai , Tian Ji-Xiang , Guo Shan-Shan , Liu Ting , Sui Feng , Zhao Yu , Chen Yan-Jun , Zhao Qing-He
Published: May 2022

Acute lung injury (ALI) or its aggravated stage acute respiratory distress syndrome (ARDS) is a common severe clinical syndrome in intensive care unit, may lead to a life-threatening form of respiratory failure, resulting in high mortality up to 30–40% in most studies. Nanotechnology-mediated anti-inflammatory therapy is an emerging novel strategy for the treatment of ALI, has been demonstrated with unique advantages in solving the dilemma of ALI drug therapy. Artesunate (ART), a derivative of artemisinin, has been reported to have anti-inflammatory effects. Therefore, in the present study, we designed and synthesized PEGylated ART prodrugs and assessed whether ART prodrugs could attenuate lipopolysaccharide (LPS) induced ALI in vitro and in vivo. All treatment groups were conditioned with ART prodrugs 1 h before challenge with LPS. Significant increased inflammatory cytokines production and decreased GSH levels were observed in the LPS stimulated mouse macrophage cell line RAW264.7. Lung histopathological changes, lung W/D ratio, MPO activity and total neutrophil counts were increased in the LPS-induced murine model of ALI via nasal administration. However, these results can be reversed to some extent by treatment of ART prodrugs. The effectiveness of mPEG2k-SS-ART in inhibition of ALI induced by LPS was confirmed. In conclusion, our results demonstrated that the ART prodrugs could attenuate LPS-induced ALI effectively, and mPEG2k-SS-ART may serve as a novel strategy for treatment of inflammation induced lung injury.
Safety, Pharmacokinetics/Pharmacodynamics, and Absolute Bioavailability of Dexmedetomidine Hydrochloride Nasal Spray in Healthy Subjects: A Randomized, Parallel, Escalating Dose Study
Authors: Kuang Yun , Wang Sai-Ying , Wang Meng-Na , Yang Guo-Ping , Guo Can , Yang Shuang , Zhang Xing-Fei , Yang Xiao-Yan , Pei Qi , Zou Chan , He Yan-Hong , Zhou Ying-Yong , Duan Kai-Ming , Huang Jie
Published: May 2022

Background: The present study evaluated the safety, pharmacokinetics/pharmacodynamics (PK/PD), and absolute bioavailability (Fabs) of Dex nasal spray in healthy adult subjects, which serves as a bridge for the subsequent study in children.

Methods: Part 1: a double-blind, placebo-controlled, single ascending dose study was performed on 48 subjects. For 20-/40-μg groups, every 6/2 subjects received either Dex/placebo nasal spray or Dex/placebo injection in two periods. In total, 12/4 subjects each received 100 μg Dex/placebo nasal spray. Part 2: a randomized, double-blind, placebo-controlled study; 12/4 subjects received 150 μg Dex/placebo nasal spray. Part 3: a randomized, open, self-crossover study; 12 subjects received 20 μg and 100 μg Dex nasal spray in two periods alternately. The method of administration was optimized in Part 2 and Part 3.

Results: In part 1, Dex nasal spray was well tolerated up to the maximum dose of 100 μg, whereas the Fabs was tolerated to only 28.9%–32.3%. In Part 2 and Part 3, the optimized nasal spray method was adopted to promote the Fabs of Dex nasal spray to 74.1%–89.0%. A severe adverse event was found in Part 2. In Part 3 (100 μg), the Ramsay score increased the most and lasted the longest, whereas the BIS score decreased most significantly.

Conclusion: Using the optimized nasal spray method, a single dose of 20/100 μg of the test drug was safe and tolerable, and 100 μg may have approached or reached the plateau of sedation. In addition, it is found that the optimized method can greatly improve the bioavailability of the test drug, leading to its higher reference value.
Ferroptosis and Tumor Drug Resistance: Current Status and Major Challenges
Authors: Nie Zhenyu , Chen Mei , Gao Yuanhui , Huang Denggao , Cao Hui , Peng Yanling , Guo Na , Wang Fei , Zhang Shufang
Published: May 2022

Ferroptosis is a novel type of regulated cell death, whose unique metabolic characteristics are commonly used to evaluate the conditions of various diseases especially in tumors. Accumulating evidence supports that ferroptosis can regulate tumor development, metastasis, and therapeutic responses. Considering to the important role of chemotherapy in tumor treatment, drug resistance has become the most serious challenge. Revealing the molecular mechanism of ferroptosis is expected to solve tumor drug resistance and find new therapies to treat cancers. In this review, we discuss the relationship between ferroptosis and tumor drug resistance, summarize the abnormal ferroptosis in tissues of different cancer types and current research progress and challenges in overcoming treatment resistance, and explore the concept of targeting ferroptosis to improve tumor treatment outcomes.
Croton urucurana Baill. Ameliorates Metabolic Associated Fatty Liver Disease in Rats
Authors: Auth Pablo Alvarez , da Silva Gustavo Ratti , Amaral Eduarda Carolina , Bortoli Victor Fajardo , Manzano Mariana Inocencio , de Souza Lauro Mera , Lovato Evellyn Claudia Wietzikoski , Ribeiro-Paes João Tadeu , Gasparotto Junior Arquimedes , Lívero Francislaine Aparecida dos Reis
Published: May 2022

Background: Metabolic associated fatty liver disease (MAFLD) affects a quarter of the worldwide population, but no drug therapies have yet been developed. Croton urucurana Baill. (Euphorbiaceae) is a medicinal species, that is, widely distributed in Brazil. It is used in popular medicine to treat gastrointestinal, cardiovascular, and endocrine system diseases. However, its hepatoprotective and lipid-lowering effects have not yet been scientifically investigated.

Aim of the study: The present study investigated the effects of an extract of C. urucurana in a rat model of MAFLD that was associated with multiple risk factors, including hypertension, smoking, and dyslipidemia.

Material and Methods: The phytochemical composition of C. urucurana was evaluated by liquid chromatography-mass spectrometry. Spontaneously hypertensive rats received a 0.5% cholesterol-enriched diet and were exposed to cigarette smoke (9 cigarettes/day for 10 weeks). During the last 5 weeks, the animals were orally treated with vehicle (negative control [C-] group), C. urucurana extract (30, 100, and 300 mg/kg), or simvastatin + enalapril (two standard reference drugs that are commonly used to treat dyslipidemia and hypertension, respectively). One group of rats that were not exposed to these risk factors was also evaluated (basal group). Blood was collected for the analysis of cholesterol, triglyceride, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels. The liver and feces were collected for lipid quantification. The liver was also processed for antioxidant and histopathological analysis.

Results: The main constituents of the C. urucurana extract were flavonoids, glycosides, and alkaloids. The model successfully induced MAFLD, reflected by increases in AST and ALT levels, and induced oxidative stress in the C- group. Treatment with the C. urucurana extract (300 mg/kg) and simvastatin + enalapril decreased plasma and hepatic lipid levels. In contrast to simvastatin + enalapril treatment, C. urucurana reduced AST and ALT levels. Massive lesions were observed in the liver in the C- group, which were reversed by treatment with the C. urucurana extract (300 mg/kg).

Conclusion:C. urucurana extract exerted promising hepatoprotective and lipid-lowering effects in a preclinical rat model of MAFLD.
Dandelion Seed Extract Affects Tumor Progression and Enhances the Sensitivity of Cisplatin in Esophageal Squamous Cell Carcinoma
Authors: Li Yuxi , Deng Yuying , Zhang Xiuli , Fu Han , Han Xue , Guo Wenqing , Zhao Wei , Zhao Xuening , Yu Chunxue , Li Hui , Lei Kaijian , Wang Tianxiao
Published: May 2022

Like dandelion, dandelion seed also have anti-inflammatory activity. Therefore, in this article, we intend to explore the anti-cancer availability of aqueous dandelion seed extract (DSE) in esophageal squamous cell carcinoma (ESCC). Firstly, the effects of DSE on cell proliferation, apoptosis, migration, invasion and angiogenesis were investigated. Then to explore the mechanism of DSE against ESCC, the levels of proliferation-associated proteins (PI3K, Akt and pAkt), apoptosis-associated proteins (survivin, Bcl-2, Bax, caspase3 and caspase9), metastasis-associated proteins (MMP2, MMP9, VEGF) and EMT progression-associated proteins (Snail, E-cadherin and Vimentin) were analyzed. Next, we further explored the effect of DSE on the sensitivity of cisplatin (DDP) in ESCC cells and investigated the effect of DSE combined with DDP on DNA damage repair-associated proteins (MSH2, MLH1 and ERCC1) and drug resistant target protein STAT3. The results indicated that DSE selectively inhibited cell growth, proliferation, migration, invasion, angiogenesis and induced cell apoptosis in ESCC cells. It was observed the decreased PI3K, Akt and pAkt proteins levels in KYSE450 and Eca109 cells administrated with DSE. The data also showed that the application of DSE decreased the level of survivin and the ratio of Bcl-2/Bax, while increased the levels of caspase3 and caspase9. We also observed that DSE significantly decreased the levels of MMP2, MMP9 and VEGF proteins and inhibited the EMT progression in KYSE450 and Eca109 cells. In addition, survivin plays a critical role in DSE against ESCC followed with the application of survivin inhibitor YM155 impairing the inhibitory abilities of DSE in ESCC cells. Meanwhile, it was observed that DSE enhances the sensitivity of DDP to human ESCC cells via promoting DNA damage and inhibiting phosphorylation of STAT3. Therefore, DSE may affect ESCC progression and enhance the sensitivity of cisplatin, and consequently become an effective anti-cancer option for human ESCC treatment.
Activation of Wnt/Beta-Catenin Signaling Pathway as a Promising Therapeutic Candidate for Cerebral Ischemia/Reperfusion Injury
Authors: Mo Zhizhun , Zeng Zhongyi , Liu Yuxiang , Zeng Linsheng , Fang Jiansong , Ma Yinzhong
Published: May 2022

Stroke is one of the leading causes of mortality, and survivors experience serious neurological and motor behavioral deficiencies. Following a cerebral ischemic event, substantial alterations in both cellular and molecular activities occur because of ischemia/reperfusion injury. Wnt signaling is an evolutionarily conserved signaling pathway that has been manifested to play a key role in embryo development and function maintenance in adults. Overactivation of Wnt signaling has previously been investigated in cancer-based research studies. Recently, abnormal Wnt signaling activity has been observed in ischemic stroke, which is accompanied by massive blood–brain barrier (BBB) disruption, neuronal apoptosis, and neuroinflammation within the central nervous system (CNS). Significant therapeutic effects were observed after reactivating the adynamic signaling activity of canonical Wnt signaling in different cell types. To better understand the therapeutic potential of Wnt as a novel target for stroke, we reviewed the role of Wnt signaling in the pathogenesis of stroke in different cell types, including endothelial cells, neurons, oligodendrocytes, and microglia. A comprehensive understanding of Wnt signaling among different cells may help to evaluate its potential value for the development of novel therapeutic strategies based on Wnt activation that can ameliorate complications and improve functional rehabilitation after ischemic stroke.
Wavelength-Tunable Kerr-Lens Mode-Locked Femtosecond Cr:ZnS Laser With a ∼300-nm Tuning Range From 2.2 to 2.5 μm
Authors: Wang Qing , Wang Runyu , Yang Fan , Li Yan
Published: May 2022

Tunable 2∼3-μm femtosecond lasers are of high interest in various applications, such as medical diagnostics and molecular spectroscopy. Cr:ZnSe/ZnS is extremely suited for broadband tunable femtosecond lasers due to its excellent emission bands. In this article, we demonstrate a wavelength-tunable Kerr-lens mode-locked Cr:ZnS laser by utilizing a birefringent filter. The group delay dispersion of the operation and the thickness of the birefringent are finely optimized. With the rotation of the birefringent filter, the scheme offers a tuning bandwidth of over 300 nm from 2,220 nm to 2,520 nm. To the best of our knowledge, it is the broadest tuning range among the reported femtosecond Cr:ZnS lasers.
Extracellular Inflammasome Particles Are Released After Marathon Running and Induce Proinflammatory Effects in Endothelial Cells
Authors: Kogel Alexander , Fikenzer Sven , Uhlmann Luisa , Opitz Lena , Kneuer Jasmin M. , Haeusler Karl Georg , Endres Matthias , Kratzsch Jürgen , Schwarz Viktoria , Werner Christian , Kalwa Hermann , Gaul Susanne , Laufs Ulrich
Published: May 2022

Objectives: The intracellular NLRP3 inflammasome is an important regulator of sterile inflammation. Recent data suggest that inflammasome particles can be released into circulation. The effects of exercise on circulating extracellular apoptosis-associated speck-like protein (ASC) particles and their effects on endothelial cells are not known.

Methods: We established a flow cytometric method to quantitate extracellular ASC specks in human serum. ASC specks were quantitated in 52 marathon runners 24–72 h before, immediately after, and again 24–58 h after the run. For mechanistic characterization, NLRP3 inflammasome particles were isolated from a stable mutant NLRP3 (p.D303N)-YFP HEK cell line and used to treat primary human coronary artery endothelial cells.

Results: Athletes showed a significant increase in serum concentration of circulating ASC specks immediately after the marathon (+52% compared with the baseline, p < 0.05) and a decrease during the follow-up after 24–58 h (12% reduction compared with immediately after the run, p < 0.01). Confocal microscopy revealed that human endothelial cells can internalize extracellular NLRP3 inflammasome particles. After internalization, endothelial cells showed an inflammatory response with a higher expression of the cell adhesion molecule ICAM1 (6.9-fold, p < 0.05) and increased adhesion of monocytes (1.5-fold, p < 0.05).

Conclusion: These findings identify extracellular inflammasome particles as novel systemic mediators of cell–cell communication that are transiently increased after acute extensive exercise with a high mechanical muscular load.
Association of Hemoglobin Glycation Index With Contrast-Induced Acute Kidney Injury in Patients Undergoing Coronary Angiography: A Retrospective Study
Authors: Chen Zhezhe , Li Duanbin , Lin Maoning , Jiang Hangpan , Xu Tian , Shan Yu , Fu Guosheng , Wang Min , Zhang Wenbin
Published: May 2022

Background: The hemoglobin glycation index (HGI) quantifies interindividual variation in glycation and is positively associated with cardiovascular diseases. However, the association between HGI and contrast-induced acute kidney injury (CI-AKI) remains unclear. Therefore, this study aimed to assess the association of HGI with CI-AKI.

Methods: In this observational study, a total of 3,142 patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) were included. The HGI was calculated as the difference between the measured glycated hemoglobin (HbA1c) and predicted HbA1c. CI-AKI was defined as an increase of either 25% or 0.5 mg/dl (44.2 μmol/L) in the serum creatinine (SCr) level within 72 h following the exposure to contrast medium. Piecewise linear regression analysis was conducted to testify the association of HGI with the proportion of SCr elevation. Modified Poisson’s regression analysis was performed to determine the association between HGI and CI-AKI. Exploratory analysis was also performed according to the stratification of HbA1c levels.

Results: Among 3,142 patients, the average age was 66.9 years and 483 of them (15.4%) suffered CI-AKI. Piecewise linear regression analysis demonstrated the linear association of HGI with the proportion of SCr elevation on both positive and negative sides of HGI [HGI <0: β = −9.537, 95% CI (−12.057 to −7.017), p < 0.001; HGI ≥0: β = 1.655, 95% CI (0.125 to 3.186), p = 0.034]. Modified Poisson’s regression analysis showed that the higher absolute value of HGI was strongly associated with higher incidence of CI-AKI [(<−1.0 vs. −0.2 to 0.2): aRR = 1.897, 95% CI [1.467 to 2.452], p < 0.001 (≥1.0 vs. −0.2 to 0.2): aRR = 1.545, 95% CI (1.171 to 2.037), p = 0.002]. Furthermore, the results in exploratory analysis showed that such association still remained irrespective of HbA1c levels.

Conclusion: The higher absolute value of HGI was strongly associated with higher incidence of CI-AKI in patients undergoing CAG and PCI.
S-Thyroid Computer-Aided Diagnosis Ultrasound System of Thyroid Nodules: Correlation Between Transverse and Longitudinal Planes
Authors: Yang Keen , Chen Jing , Wu Huaiyu , Tian Hongtian , Ye Xiuqin , Xu Jinfeng , Luo Xunpeng , Dong Fajin
Published: May 2022

Introduction: We compare the differences in the diagnostic results of S-thyroid, a computer-aided diagnosis (CAD) software, based on two mutually perpendicular planes.

Methods: Initially, 149 thyroid nodules confirmed by surgical pathology were enrolled in our study. CAD in our study was based on the ACR TI-RADS lexicon. t test, rank-sum test, and Chi-square test were used. The interclass correlation coefficient and Cohen’s kappa were used to explore the correlation between CAD features. Receiver operating characteristic was plotted for different combinations of CAD features.

Results: The patient’s age, transverse diameter, longitudinal diameter, shape, margin, echogenicity, echogenic foci, composition, TI-RADS classification, and risk probability of nodules in the transverse and longitudinal planes were related to thyroid cancer (p < 0.05). The AUC (95%CI) of TI-RADS classification in the transverse plane of CAD is better than that of the longitudinal plane [0.90 (0.84–0.95) vs. 0.83 (0.77–0.90), p = 0.04]. The AUC (95%CI) of risk probability of nodules in the transverse planes shows no difference from that in the longitudinal plane statistically [0.90 (0.85–0.95) vs. 0.88 (0.82–0.94), p = 0.52]. The AUC (95% CI), specificity, sensitivity, and accuracy [TI-RADS classification (transverse plane) + TI-RADS classification (longitudinal plane) + risk (transverse plane) + risk (longitudinal plane)] are 0.93 (0.89–0.97), 86.15%, 90.48%, and 88.59%, respectively.

Conclusion: The diagnosis of thyroid cancer in the CAD transverse plane was superior to that in the CAD longitudinal plane when using the TI-RADS classification, but there was no difference in the diagnosis between the two planes when using risk. However, the combination of CAD transverse and longitudinal planes had the best diagnostic ability.
Identification and Classification of Downy Mildew Severity Stages in Watermelon Utilizing Aerial and Ground Remote Sensing and Machine Learning
Authors: Abdulridha Jaafar , Ampatzidis Yiannis , Qureshi Jawwad , Roberts Pamela
Published: May 2022

Remote sensing and machine learning (ML) could assist and support growers, stakeholders, and plant pathologists determine plant diseases resulting from viral, bacterial, and fungal infections. Spectral vegetation indices (VIs) have shown to be helpful for the indirect detection of plant diseases. The purpose of this study was to utilize ML models and identify VIs for the detection of downy mildew (DM) disease in watermelon in several disease severity (DS) stages, including low, medium (levels 1 and 2), high, and very high. Hyperspectral images of leaves were collected in the laboratory by a benchtop system (380–1,000 nm) and in the field by a UAV-based imaging system (380–1,000 nm). Two classification methods, multilayer perceptron (MLP) and decision tree (DT), were implemented to distinguish between healthy and DM-affected plants. The best classification rates were recorded by the MLP method; however, only 62.3% accuracy was observed at low disease severity. The classification accuracy increased when the disease severity increased (e.g., 86–90% for the laboratory analysis and 69–91% for the field analysis). The best wavelengths to differentiate between the DS stages were selected in the band of 531 nm, and 700–900 nm. The most significant VIs for DS detection were the chlorophyll green (Cl green), photochemical reflectance index (PRI), normalized phaeophytinization index (NPQI) for laboratory analysis, and the ratio analysis of reflectance spectral chlorophyll-a, b, and c (RARSa, RASRb, and RARSc) and the Cl green in the field analysis. Spectral VIs and ML could enhance disease detection and monitoring for precision agriculture applications.
Phylogeography and Population Genetics of Rosa chinensis var. spontanea and R. lucidissima Complex, the Important Ancestor of Modern Roses
Authors: Jian Hongying , Zhao Ling , Zhang Hao , Ma Changle , Wang Qigang , Yan Huijun , Qiu Xianqin , Zhou Ningning , Zhang Ting
Published: May 2022

Rosa chinensis var. spontanea and R. lucidissima complex are the morphologically very similar key ancestors of modern roses with high importance in rose research and breeding. Although widely distributed in subtropical central and southwestern China, these two taxa are highly endangered. We sampled a total of 221 specimens and 330 DNA samples from 25 populations across the two taxa's whole range. Leaf morphological traits were compared. Two chloroplast DNA intergenic spacers (trnG-trnS, petL-psbE) and ITS were used for population genetics and phylogenetic study to delimit the boundary between the two taxa, assess the genetic variation, uncover the possible evolutionary mechanism responsible for the differentiation within the complex, and make the conservation recommendations. The complex exhibited high levels of genetic variation (hTcpDNA = 0.768, hTITS = 0.726) and high population differentiation even over small geographic distance. We suggest R. chinensis var. spontanea and R. lucidissma be treated as independent taxa, and the northern populations around and within the Sichuan Basin being R. chinensis var. spontanea, having broader leaflets and paler full-blooming flowers, while those in the middle and southern Yunnan-Guizhou Plateau and the adjacent regions being R. lucidissma, having narrower leaflets and darker full-blooming flowers. Transitional areas between the southeastern Sichuan Basin and northeastern Guizhou are the contact or the hybridization zone of the two taxa. Ancestral haplotypes of the complex (R. lucidissma) evolved at about 1.21–0.86 Mya in southeastern Yunnan-Guizhou Plateau and its adjacent regions and survived there during the Quaternary Oscillation. Ancestral haplotypes of R. chinensis var. spontanea deviated from R. lucidissma at about 0.022–0.031 Mya at the transitional areas (Daloushan and Wulingshan Mountains) between the northeastern edge of Yunnan-Guizhou Plaeteau and the southeastern border of Sichuan Basin, where they survived the LGM. The evolution of the complex included spatial isolation and inter-species hybridization. The complex's endangered status might be the result of over-exploitation for its ornamental and medical value, or due to reforestation of some originally open habitats. We provide specific recommendations for the two taxa's in situ and ex situ conservation.
Deep Insights Into the Plastome Evolution and Phylogenetic Relationships of the Tribe Urticeae (Family Urticaceae)
Authors: Ogoma Catherine A. , Liu Jie , Stull Gregory W. , Wambulwa Moses C. , Oyebanji Oyetola , Milne Richard I. , Monro Alexandre K. , Zhao Ying , Li De-Zhu , Wu Zeng-Yuan
Published: May 2022

Urticeae s.l., a tribe of Urticaceae well-known for their stinging trichomes, consists of more than 10 genera and approximately 220 species. Relationships within this tribe remain poorly known due to the limited molecular and taxonomic sampling in previous studies, and chloroplast genome (CP genome/plastome) evolution is still largely unaddressed. To address these concerns, we used genome skimming data—CP genome and nuclear ribosomal DNA (18S-ITS1-5.8S-ITS2-26S); 106 accessions—for the very first time to attempt resolving the recalcitrant relationships and to explore chloroplast structural evolution across the group. Furthermore, we assembled a taxon rich two-locus dataset of trnL-F spacer and ITS sequences across 291 accessions to complement our genome skimming dataset. We found that Urticeae plastomes exhibit the tetrad structure typical of angiosperms, with sizes ranging from 145 to 161 kb and encoding a set of 110–112 unique genes. The studied plastomes have also undergone several structural variations, including inverted repeat (IR) expansions and contractions, inversion of the trnN-GUU gene, losses of the rps19 gene, and the rpl2 intron, and the proliferation of multiple repeat types; 11 hypervariable regions were also identified. Our phylogenomic analyses largely resolved major relationships across tribe Urticeae, supporting the monophyly of the tribe and most of its genera except for Laportea, Urera, and Urtica, which were recovered as polyphyletic with strong support. Our analyses also resolved with strong support several previously contentious branches: (1) Girardinia as a sister to the Dendrocnide-Discocnide-Laportea-Nanocnide-Zhengyia-Urtica-Hesperocnide clade and (2) Poikilospermum as sister to the recently transcribed Urera sensu stricto. Analyses of the taxon-rich, two-locus dataset showed lower support but was largely congruent with results from the CP genome and nuclear ribosomal DNA dataset. Collectively, our study highlights the power of genome skimming data to ameliorate phylogenetic resolution and provides new insights into phylogenetic relationships and chloroplast structural evolution in Urticeae.
Geographical and Temporal Diversity of ‘Candidatus Phytoplasma solani' in Wine-Growing Regions in Slovenia and Austria
Authors: Mehle Nataša , Kavčič Sanda , Mermal Sara , Vidmar Sara , Pompe Novak Maruša , Riedle-Bauer Monika , Brader Günter , Kladnik Aleš , Dermastia Marina
Published: May 2022

As the causal agent of the grapevine yellows disease Bois noir, ‘Candidatus Phytoplasma solani' has a major economic impact on grapevines. To improve the control of Bois noir, it is critical to understand the very complex epidemiological cycles that involve the multiple “Ca. P. solani” host plants and insect vectors, of which Hyalesthes obsoletus is the most important. In the present study, multiple genotyping of the tuf, secY, stamp, and vmp1 genes was performed. This involved archived grapevine samples that were collected during an official survey of grapevine yellows throughout the wine-growing regions of Slovenia (from 2003 to 2016), plus samples from Austrian grapevines, stinging nettle, field bindweed, and insect samples (collected from 2012 to 2019). The data show that the tuf-b2 type of the tuf gene has been present in eastern Slovenia since at least 2003. The hypotheses that the occurrence of the haplotypes varies due to the geographical position of Slovenia on the Italian–Slovenian Karst divide and that the haplotypes are similar between Slovenian and Austrian Styria were confirmed. The data also show haplotype changes for host plants and H. obsoletus associated with ‘Ca. P. solani,' which might be linked to new epidemiological cycles of this phytoplasma that involve not just new plant sources and new insect vectors, but also climate and land-use changes.
Arabinogalactan Protein-Like Proteins From Ulva lactuca Activate Immune Responses and Plant Resistance in an Oilseed Crop
Authors: Přerovská Tereza , Jindřichová Barbora , Henke Svatopluk , Yvin Jean-Claude , Ferrieres Vincent , Burketová Lenka , Lipovová Petra , Nguema-Ona Eric
Published: May 2022

Natural compounds isolated from macroalgae are promising, ecofriendly, and multifunctional bioinoculants, which have been tested and used in agriculture. Ulvans, for instance, one of the major polysaccharides present in Ulva spp. cell walls, have been tested for their plant growth-promoting properties as well as their ability to activate plant immune defense, on a large variety of crops. Recently, we have characterized for the first time an arabinogalactan protein-like (AGP-like) from Ulva lactuca, which exhibits several features associated to land plant AGPs. In land plant, AGPs were shown to play a role in several plant biological functions, including cell morphogenesis, reproduction, and plant-microbe interactions. Thus, isolated AGP-like proteins may be good candidates for either the plant growth-promoting properties or the activation of plant immune defense. Here, we have isolated an AGP-like enriched fraction from Ulva lactuca and we have evaluated its ability to (i) protect oilseed rape (Brassica napus) cotyledons against Leptosphaeria maculans, and (ii) its ability to activate immune responses. Preventive application of the Ulva AGP-like enriched fraction on oilseed rape, followed by cotyledon inoculation with the fungal hemibiotroph L. maculans, resulted in a major reduction of infection propagation. The noticed reduction correlated with an accumulation of H2O2 in treated cotyledons and with the activation of SA and ET signaling pathways in oilseed rape cotyledons. In parallel, an ulvan was also isolated from Ulva lactuca. Preventive application of ulvan also enhanced plant resistance against L. maculans. Surprisingly, reduction of infection severity was only observed at high concentration of ulvan. Here, no such significant changes in gene expression and H2O2 production were observed. Together, this study indicates that U. lactuca AGP-like glycoproteins exhibit promising elicitor activity and that plant eliciting properties of Ulva extract, might result not only from an ulvan-originated eliciting activities, but also AGP-like originated.
Integrative Metabolome and Transcriptome Analysis of Flavonoid Biosynthesis Genes in Broussonetia papyrifera Leaves From the Perspective of Sex Differentiation
Authors: Jiao Peng , Chaoyang Li , Wenhan Zhai , Jingyi Dai , Yunlin Zhao , Zhenggang Xu
Published: May 2022

Flavonoids are important secondary metabolites involved in plant development and environmental responses. Sex differences in flavonoids are common in plants. Broussonetia papyrifera is a dioecious plant that is rich in flavonoids. However, few studies have been done on its molecular mechanism, especially sex differences. In the present study, we performed an integrated transcriptomics and metabolomics analysis of the sex differences in the accumulation of flavonoids in B. papyrifera leaves at different developmental stages. In general, flavonoids accumulated gradually with developmental time, and the content in female plants was higher than that in male plants. The composition of flavonoids in female and male plants was similar, and 16 kinds of flavonoids accumulated after flowering. Correspondingly, a significant enrichment of differentially expressed genes and metabolites was observed in the flavonoid biosynthesis pathway. WGCNA and qRT-PCR analyses identified several key genes regulating the accumulation of flavonoids, such as those encoding CHS, CHI and DFR. In addition, 8 TFs were found to regulate flavonoid biosynthesis by promoting the expression of multiple structural genes. These findings provide insight into flavonoid biosynthesis in B. papyrifera associated molecular regulation.
Contribution of Academic Satisfaction Judgments to Subjective Well-Being
Authors: Zalazar-Jaime Mauricio F. , Moretti Luciana S. , Medrano Leonardo A.
Published: May 2022

The role of academic satisfaction (AS) on persistence and successful academic behavior has been the focus of research for decades. Nevertheless, driven by positive educational psychology, subjective well-being has been highlighted as another central feature in the academic path of students. Studies aimed at identifying the variables that contribute to explain different aspects of academic performance have been widely investigated, although studies aimed at identifying the determinants of subjective well-being are still limited. The present paper examined the contribution of AS judgments on subjective well-being (SWB). To this end, it was hypothesized that SWB levels depend on the balance between positive/negative emotions and life satisfaction judgments. Furthermore, it was stipulated that AS has an indirect contribution on SWB, through life satisfaction, whereas the balance of emotions influences both AS judgments and life satisfaction. Using an analysis strategy based on structural equation modeling, the results indicated that the model fitted satisfactorily, explaining 32% of the variance of SWB. Particularly, it was observed that AS judgments contributed to life satisfaction judgments (β = 0.34). Although no direct contribution of AS on SWB was reported, a total contribution partially mediated by life satisfaction judgments was revealed (total β = 0.19). These findings support the importance of academic satisfaction judgments, not only because of their importance in academic terms, but also because of their impact on university students’ subjective well-being and health.