bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Genetic Understanding of Photoperiodic Regulation of Flowering Time in Arabidopsis and Soybean
Authors: Luo Xiao , Yin Mengnan , He Yuehui
Published: January 2022

The developmental switch from a vegetative phase to reproduction (flowering) is essential for reproduction success in flowering plants, and the timing of the floral transition is regulated by various environmental factors, among which seasonal day-length changes play a critical role to induce flowering at a season favorable for seed production. The photoperiod pathways are well known to regulate flowering time in diverse plants. Here, we summarize recent progresses on molecular mechanisms underlying the photoperiod control of flowering in the long-day plant Arabidopsis as well as the short-day plant soybean; furthermore, the conservation and diversification of photoperiodic regulation of flowering in these two species are discussed.
Membrane Melatonin Receptors Activated Cell Signaling in Physiology and Disease
Authors: Nikolaev Georgi , Robeva Ralitsa , Konakchieva Rossitza
Published: January 2022

The pineal hormone melatonin has attracted great scientific interest since its discovery in 1958. Despite the enormous number of basic and clinical studies the exact role of melatonin in respect to human physiology remains elusive. In humans, two high-affinity receptors for melatonin, MT1 and MT2, belonging to the family of G protein-coupled receptors (GPCRs) have been cloned and identified. The two receptor types activate Gi proteins and MT2 couples additionally to Gq proteins to modulate intracellular events. The individual effects of MT1 and MT2 receptor activation in a variety of cells are complemented by their ability to form homo- and heterodimers, the functional relevance of which is yet to be confirmed. Recently, several melatonin receptor genetic polymorphisms were discovered and implicated in pathology—for instance in type 2 diabetes, autoimmune disease, and cancer. The circadian patterns of melatonin secretion, its pleiotropic effects depending on cell type and condition, and the already demonstrated cross-talks of melatonin receptors with other signal transduction pathways further contribute to the perplexity of research on the role of the pineal hormone in humans. In this review we try to summarize the current knowledge on the membrane melatonin receptor activated cell signaling in physiology and pathology and their relevance to certain disease conditions including cancer.
Overexpression of the Aldehyde Dehydrogenase Gene ZmALDH Confers Aluminum Tolerance in Arabidopsis thaliana
Authors: Du Han-Mei , Liu Chan , Jin Xin-Wu , Du Cheng-Feng , Yu Yan , Luo Shuai , He Wen-Zhu , Zhang Su-Zhi
Published: January 2022

Aluminum (Al) toxicity is the main factor limiting plant growth and the yield of cereal crops in acidic soils. Al-induced oxidative stress could lead to the excessive accumulation of reactive oxygen species (ROS) and aldehydes in plants. Aldehyde dehydrogenase (ALDH) genes, which play an important role in detoxification of aldehydes when exposed to abiotic stress, have been identified in most species. However, little is known about the function of this gene family in the response to Al stress. Here, we identified an ALDH gene in maize, ZmALDH, involved in protection against Al-induced oxidative stress. Al stress up-regulated ZmALDH expression in both the roots and leaves. The expression of ZmALDH only responded to Al toxicity but not to other stresses including low pH and other metals. The heterologous overexpression of ZmALDH in Arabidopsis increased Al tolerance by promoting the ascorbate-glutathione cycle, increasing the transcript levels of antioxidant enzyme genes as well as the activities of their products, reducing MDA, and increasing free proline synthesis. The overexpression of ZmALDH also reduced Al accumulation in roots. Taken together, these findings suggest that ZmALDH participates in Al-induced oxidative stress and Al accumulation in roots, conferring Al tolerance in transgenic Arabidopsis.
Downregulation of Methionine Cycle Genes MAT1A and GNMT Enriches Protein-Associated Translation Process and Worsens Hepatocellular Carcinoma Prognosis
Authors: Chen Po-Ming , Tsai Cheng-Hsueh , Huang Chieh-Cheng , Hwang Hau-Hsuan , Li Jian-Rong , Liu Chun-Chi , Ko Hsin-An , Chiang En-Pei Isabel
Published: January 2022

The major biological methyl donor, S-adenosylmethionine (adoMet) synthesis occurs mainly in the liver. Methionine adenosyltransferase 1A (MAT1A) and glycine N-methyltransferase (GNMT) are two key enzymes involved in the functional implications of that variation. We collected 42 RNA-seq data from paired hepatocellular carcinoma (HCC) and its adjacent normal liver tissue from the Cancer Genome Atlas (TCGA). There was no mutation found in MAT1A or GNMT RNA in the 42 HCC patients. The 11,799 genes were annotated in the RNA-Seq data, and their expression levels were used to investigate the phenotypes of low MAT1A and low GNMT by Gene Set Enrichment Analysis (GSEA). The REACTOME_TRANSLATION gene set was enriched and visualized in a heatmap along with corresponding differences in gene expression between low MAT1A versus high MAT1A and low GNMT versus high GNMT. We identified 43 genes of the REACTOME_TRANSLATION gene set that are powerful prognosis factors in HCC. The significantly predicted genes were referred into eukaryotic translation initiation (EIF3B, EIF3K), eukaryotic translation elongation (EEF1D), and ribosomal proteins (RPs). Cell models expressing various MAT1A and GNMT proved that simultaneous restoring the expression of MAT1A and GNMT decreased cell proliferation, invasion, as well as the REACTOME_TRANSLATION gene EEF1D, consistent with a better prognosis in human HCC. We demonstrated new findings that downregulation or defect in MAT1A and GNMT genes can enrich the protein-associated translation process that may account for poor HCC prognosis. This is the first study demonstrated that MAT1A and GNMT, the 2 key enzymes involved in methionine cycle, could attenuate the function of ribosome translation. We propose a potential novel mechanism by which the diminished GNMT and MAT1A expression may confer poor prognosis for HCC.
The Impact of the Microbiome on Resistance to Cancer Treatment with Chemotherapeutic Agents and Immunotherapy
Authors: Sevcikova Aneta , Izoldova Nikola , Stevurkova Viola , Kasperova Barbora , Chovanec Michal , Ciernikova Sona , Mego Michal
Published: January 2022

Understanding the mechanisms of resistance to therapy in human cancer cells has become a multifaceted limiting factor to achieving optimal cures in cancer patients. Besides genetic and epigenetic alterations, enhanced DNA damage repair activity, deregulation of cell death, overexpression of transmembrane transporters, and complex interactions within the tumor microenvironment, other mechanisms of cancer treatment resistance have been recently proposed. In this review, we will summarize the preclinical and clinical studies highlighting the critical role of the microbiome in the efficacy of cancer treatment, concerning mainly chemotherapy and immunotherapy with immune checkpoint inhibitors. In addition to involvement in drug metabolism and immune surveillance, the production of microbiota-derived metabolites might represent the link between gut/intratumoral bacteria and response to anticancer therapies. Importantly, an emerging trend of using microbiota modulation by probiotics and fecal microbiota transplantation (FMT) to overcome cancer treatment resistance will be also discussed.
Genome-Wide Characterization and Abiotic Stresses Expression Analysis of Annexin Family Genes in Poplar
Authors: Wei Hui , Movahedi Ali , Liu Guoyuan , Li Yixin , Liu Shiwei , Yu Chunmei , Chen Yanhong , Zhong Fei , Zhang Jian
Published: January 2022

Poplar is an illustrious industrial woody plant with rapid growth, providing a range of materials, and having simple post-treatment. Various kinds of environmental stresses limit its output. Plant annexin (ANN) is a calcium-dependent phospholipid-binding protein involved in plant metabolism, growth and development, and cooperatively regulating drought resistance, salt tolerance, and various stress responses. However, the features of the PtANN gene family and different stress responses remain unknown in poplar. This study identified 12 PtANN genes in the P. trichocarpa whole-genome and PtANNs divided into three subfamilies based on the phylogenetic tree. The PtANNs clustered into the same clade shared similar gene structures and conserved motifs. The 12 PtANN genes were located in ten chromosomes, and segmental duplication events were illustrated as the main duplication method. Additionally, the PtANN4 homogenous with AtANN1 was detected localized in the cytoplasm and plasma membrane. In addition, expression levels of PtANNs were induced by multiple abiotic stresses, which indicated that PtANNs could widely participate in response to abiotic stress. These results revealed the molecular evolution of PtANNs and their profiles in response to abiotic stress.
Synthesis of Nucleoside-like Molecules from a Pyrolysis Product of Cellulose and Their Computational Prediction as Potential SARS-CoV-2 RNA-Dependent RNA Polymerase Inhibitors
Authors: Defant Andrea , Dosi Federico , Innocenti Nicole , Mancini Ines
Published: January 2022

(1R,5S)-1-Hydroxy-3,6-dioxa-bicyclo[3.2.1]octan-2-one, available by an efficient catalytic pyrolysis of cellulose, has been applied as a chiral building block in the synthesis of seven new nucleoside analogues, with structural modifications on the nucleobase moiety and on the carboxyl- derived unit. The inverted configuration by Mitsunobu reaction used in their synthesis was verified by 2D-NOESY correlations, supported by the optimized structure employing the DFT methods. An in silico screening of these compounds as inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase has been carried out in comparison with both remdesivir, a mono-phosphoramidate prodrug recently approved for COVID-19 treatment, and its ribonucleoside metabolite GS-441524. Drug-likeness prediction and data by docking calculation indicated compound 6 [=(3S,5S)-methyl 5-(hydroxymethyl)-3-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)tetrahydrofuran-3-carboxylate] as the best candidate. Furthermore, molecular dynamics simulation showed a stable interaction of structure 6 in RNA-dependent RNA polymerase (RdRp) complex and a lower average atomic fluctuation than GS-441524, suggesting a well accommodation in the RdRp binding pocket.
The Evolution and Functional Roles of miR408 and Its Targets in Plants
Authors: Gao Yu , Feng Baohua , Gao Caixia , Zhang Huiquan , Wen Fengting , Tao Longxing , Fu Guanfu , Xiong Jie
Published: January 2022

MicroRNA408 (miR408) is an ancient and highly conserved miRNA, which is involved in the regulation of plant growth, development and stress response. However, previous research results on the evolution and functional roles of miR408 and its targets are relatively scattered, and there is a lack of a systematic comparison and comprehensive summary of the detailed evolutionary pathways and regulatory mechanisms of miR408 and its targets in plants. Here, we analyzed the evolutionary pathway of miR408 in plants, and summarized the functions of miR408 and its targets in regulating plant growth and development and plant responses to various abiotic and biotic stresses. The evolutionary analysis shows that miR408 is an ancient and highly conserved microRNA, which is widely distributed in different plants. miR408 regulates the growth and development of different plants by down-regulating its targets, encoding blue copper (Cu) proteins, and by transporting Cu to plastocyanin (PC), which affects photosynthesis and ultimately promotes grain yield. In addition, miR408 improves tolerance to stress by down-regulating target genes and enhancing cellular antioxidants, thereby increasing the antioxidant capacity of plants. This review expands and promotes an in-depth understanding of the evolutionary and regulatory roles of miR408 and its targets in plants.
Divergent Effect of Central Incretin Receptors Inhibition in a Rat Model of Sporadic Alzheimer’s Disease
Authors: Osmanovic Barilar Jelena , Knezovic Ana , Homolak Jan , Babic Perhoc Ana , Salkovic-Petrisic Melita
Published: January 2022

The incretin system is an emerging new field that might provide valuable contributions to the research of both the pathophysiology and therapeutic strategies in the treatment of diabetes, obesity, and neurodegenerative disorders. This study aimed to explore the roles of central glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) on cell metabolism and energy in the brain, as well as on the levels of these incretins, insulin, and glucose via inhibition of the central incretin receptors following intracerebroventricular administration of the respective antagonists in healthy rats and a streptozotocin-induced rat model of sporadic Alzheimer’s disease (sAD). Chemical ablation of the central GIP receptor (GIPR) or GLP-1 receptor (GLP-1R) in healthy and diseased animals indicated a region-dependent role of incretins in brain cell energy and metabolism and central incretin-dependent modulation of peripheral hormone secretion, markedly after GIPR inhibition, as well as a dysregulation of the GLP-1 system in experimental sAD.
Thymosin β4 Is an Endogenous Iron Chelator and Molecular Switcher of Ferroptosis
Authors: Lachowicz Joanna I. , Pichiri Giusi , Piludu Marco , Fais Sara , Orrù Germano , Congiu Terenzio , Piras Monica , Faa Gavino , Fanni Daniela , Dalla Torre Gabriele , Lopez Xabier , Chandra Kousik , Szczepski Kacper , Jaremko Lukasz , Ghosh Mitra , Emwas Abdul-Hamid , Castagnola Massimo , Jaremko Mariusz , Hannappel Ewald , Coni Pierpaolo
Published: January 2022

Thymosin β4 (Tβ4) was extracted forty years agofrom calf thymus. Since then, it has been identified as a G-actin binding protein involved in blood clotting, tissue regeneration, angiogenesis, and anti-inflammatory processes. Tβ4 has also been implicated in tumor metastasis and neurodegeneration. However, the precise roles and mechanism(s) of action of Tβ4 in these processes remain largely unknown, with the binding of the G-actin protein being insufficient to explain these multi-actions. Here we identify for the first time the important role of Tβ4 mechanism in ferroptosis, an iron-dependent form of cell death, which leads to neurodegeneration and somehow protects cancer cells against cell death. Specifically, we demonstrate four iron2+ and iron3+ binding regions along the peptide and show that the presence of Tβ4 in cell growing medium inhibits erastin and glutamate-induced ferroptosis in the macrophage cell line. Moreover, Tβ4 increases the expression of oxidative stress-related genes, namely BAX, hem oxygenase-1, heat shock protein 70 and thioredoxin reductase 1, which are downregulated during ferroptosis. We state the hypothesis that Tβ4 is an endogenous iron chelator and take part in iron homeostasis in the ferroptosis process. We discuss the literature data of parallel involvement of Tβ4 and ferroptosis in different human pathologies, mainly cancer and neurodegeneration. Our findings confronted with literature data show that controlled Tβ4 release could command on/off switching of ferroptosis and may provide novel therapeutic opportunities in cancer and tissue degeneration pathologies.
Glycosylation of Receptor Binding Domain of SARS-CoV-2 S-Protein Influences on Binding to Immobilized DNA Aptamers
Authors: Grabovenko Fedor , Nikiforova Liudmila , Yanenko Bogdan , Ulitin Andrey , Loktyushov Eugene , Zatsepin Timofei , Zavyalova Elena , Zvereva Maria
Published: January 2022

Nucleic acid aptamers specific to S-protein and its receptor binding domain (RBD) of SARS-CoV-2 (severe acute respiratory syndrome-related coronavirus 2) virions are of high interest as potential inhibitors of viral infection and recognizing elements in biosensors. Development of specific therapy and biosensors is complicated by an emergence of new viral strains bearing amino acid substitutions and probable differences in glycosylation sites. Here, we studied affinity of a set of aptamers to two Wuhan-type RBD of S-protein expressed in Chinese hamster ovary cell line and Pichia pastoris that differ in glycosylation patterns. The expression system for the RBD protein has significant effects, both on values of dissociation constants and relative efficacy of the aptamer binding. We propose glycosylation of the RBD as the main force for observed differences. Moreover, affinity of a several aptamers was affected by a site of biotinylation. Thus, the robustness of modified aptamers toward new virus variants should be carefully tested.
A Glutathione Peroxidase Gene from Litopenaeus vannamei Is Involved in Oxidative Stress Responses and Pathogen Infection Resistance
Authors: Fan Jinquan , Li Binbin , Hong Qianming , Yan Zeyu , Yang Xinjun , Lu Kecheng , Chen Guoliang , Wang Lei , Chen Yihong
Published: January 2022

In shrimp, several glutathione peroxidase (GPX) genes have been cloned and functionally studied. Increasing evidence suggests the genes’ involvement in white spot syndrome virus (WSSV)- or Vibrio alginolyticus-infection resistance. In the present study, a novel GXP gene (LvGPX3) was cloned in Litopenaeus vannamei. Promoter of LvGPX3 was activated by NF-E2-related factor 2. Further study showed that LvGPX3 expression was evidently accelerated by oxidative stress or WSSV or V. alginolyticus infection. Consistently, downregulated expression of LvGPX3 increased the cumulative mortality of WSSV- or V. alginolyticus-infected shrimp. Similar results occurred in shrimp suffering from oxidative stress. Moreover, LvGPX3 was important for enhancing Antimicrobial peptide (AMP) gene expression in S2 cells with lipopolysaccharide treatment. Further, knockdown of LvGPX3 expression significantly suppressed expression of AMPs, such as Penaeidins 2a, Penaeidins 3a and anti-lipopolysaccharide factor 1 in shrimp. AMPs have been proven to be engaged in shrimp WSSV- or V. alginolyticus-infection resistance; it was inferred that LvGPX3 might enhance shrimp immune response under immune challenges, such as increasing expression of AMPs. The regulation mechanism remains to be further studied.
Heat Shock Protein 60 Restricts Release of Mitochondrial dsRNA to Suppress Hepatic Inflammation and Ameliorate Non-Alcoholic Fatty Liver Disease in Mice
Authors: Huang Ying-Hsien , Wang Feng-Sheng , Wang Pei-Wen , Lin Hung-Yu , Luo Sheng-Dean , Yang Ya-Ling
Published: January 2022

Non-alcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, consists of fat deposited (steatosis) in the liver due to causes besides excessive alcohol use. The folding activity of heat shock protein 60 (HSP60) has been shown to protect mitochondria from proteotoxicity under various types of stress. In this study, we investigated whether HSP60 could ameliorate experimental high-fat diet (HFD)-induced obesity and hepatitis and explored the potential mechanism in mice. The results uncovered that HSP60 gain not only alleviated HFD-induced body weight gain, fat accumulation, and hepatocellular steatosis, but also glucose tolerance and insulin resistance according to intraperitoneal glucose tolerance testing and insulin tolerance testing in HSP60 transgenic (HSP60Tg) compared to wild-type (WT) mice by HFD. Furthermore, overexpression of HSP60 in the HFD group resulted in inhibited release of mitochondrial dsRNA (mt-dsRNA) compared to WT mice. In addition, overexpression of HSP60 also inhibited the activation of toll-like receptor 3 (TLR3), melanoma differentiation-associated gene 5 (MDA5), and phosphorylated-interferon regulatory factor 3 (p-IRF3), as well as inflammatory biomarkers such as mRNA of il-1β and il-6 expression in the liver in response to HFD. The in vitro study also confirmed that the addition of HSP-60 mimics in HepG2 cells led to upregulated expression level of HSP60 and restricted release of mt-dsRNA, as well as downregulated expression levels of TLR3, MDA5, and pIRF3. This study provides novel insight into a hepatoprotective effect, whereby HSP60 inhibits the release of dsRNA to repress the TLR3/MDA5/pIRF3 pathway in the context of NAFLD or hepatic inflammation. Therefore, HSP60 may serve as a possible therapeutic target for improving NAFLD.
Differential Effects of Platelet Factor 4 (CXCL4) and Its Non-Allelic Variant (CXCL4L1) on Cultured Human Vascular Smooth Muscle Cells
Authors: Kaczor Dawid M. , Kramann Rafael , Hackeng Tilman M. , Schurgers Leon J. , Koenen Rory R.
Published: January 2022

Platelet factor 4 (CXCL4) is a chemokine abundantly stored in platelets. Upon injury and during atherosclerosis, CXCL4 is transported through the vessel wall where it modulates the function of vascular smooth muscle cells (VSMCs) by affecting proliferation, migration, gene expression and cytokine release. Variant CXCL4L1 is distinct from CXCL4 in function and expression pattern, despite a minor three-amino acid difference. Here, the effects of CXCL4 and CXCL4L1 on the phenotype and function of human VSMCs were compared in vitro. VSMCs were found to constitutively express CXCL4L1 and only exogenously added CXCL4 was internalized by VSMCs. Pre-treatment with heparin completely blocked CXCL4 uptake. A role of the putative CXCL4 receptors CXCR3 and DARC in endocytosis was excluded, but LDL receptor family members appeared to be involved in the uptake of CXCL4. Incubation of VSMCs with both CXCL4 and CXCL4L1 resulted in decreased expression of contractile marker genes and increased mRNA levels of KLF4 and NLRP3 transcription factors, yet only CXCL4 stimulated proliferation and calcification of VSMCs. In conclusion, CXCL4 and CXCL4L1 both modulate gene expression, yet only CXCL4 increases the division rate and formation of calcium-phosphate crystals in VSMCs. CXCL4 and CXCL4L1 may play distinct roles during vascular remodeling in which CXCL4 induces proliferation and calcification while endogenously expressed CXCL4L1 governs cellular homeostasis. The latter notion remains a subject for future investigation.
In Vitro Evaluation of Bis-3-Chloropiperidines as RNA Modulators Targeting TAR and TAR-Protein Interaction
Authors: Sosic Alice , Olivato Giulia , Carraro Caterina , Göttlich Richard , Fabris Dan , Gatto Barbara
Published: January 2022

After a long limbo, RNA has gained its credibility as a druggable target, fully earning its deserved role in the next generation of pharmaceutical R&D. We have recently probed the trans-activation response (TAR) element, an RNA stem–bulge–loop domain of the HIV-1 genome with bis-3-chloropiperidines (B-CePs), and revealed the compounds unique behavior in stabilizing TAR structure, thus impairing in vitro the chaperone activity of the HIV-1 nucleocapsid (NC) protein. Seeking to elucidate the determinants of B-CePs inhibition, we have further characterized here their effects on the target TAR and its NC recognition, while developing quantitative analytical approaches for the study of multicomponent RNA-based interactions.
Anti-Inflammatory Effects of Rhamnetin on Bradykinin-Induced Matrix Metalloproteinase-9 Expression and Cell Migration in Rat Brain Astrocytes
Authors: Yang Chien-Chung , Hsiao Li-Der , Shih Ya-Fang , Yu Zih-Yao , Yang Chuen-Mao
Published: January 2022

Bradykinin (BK) has been shown to induce matrix metalloproteinase (MMP)-9 expression and participate in neuroinflammation. The BK/MMP-9 axis can be a target for managing neuroinflammation. Our previous reports have indicated that reactive oxygen species (ROS)-mediated nuclear factor-kappaB (NF-κB) activity is involved in BK-induced MMP-9 expression in rat brain astrocytes (RBA-1). Rhamnetin (RNT), a flavonoid compound, possesses antioxidant and anti-inflammatory effects. Thus, we proposed RNT could attenuate BK-induced response in RBA-1. This study aims to approach mechanisms underlying RNT regulating BK-stimulated MMP-9 expression, especially ROS and NF-κB. We used pharmacological inhibitors and siRNAs to dissect molecular mechanisms. Western blotting and gelatin zymography were used to evaluate protein and MMP-9 expression. Real-time PCR was used for gene expression. Wound healing assay was applied for cell migration. 2ʹ,7ʹ-dichlorodihydrofluorescein diacetate (H2DCF-DA) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) were used for ROS generation and NOX activity, respectively. Promoter luciferase assay and chromatin immunoprecipitation (ChIP) assay were applied to detect gene transcription. Our results showed that RNT inhibits BK-induced MMP-9 protein and mRNA expression, promoter activity, and cell migration in RBA-1 cells. Besides, the levels of phospho-PKCδ, NOX activity, ROS, phospho-ERK1/2, phospho-p65, and NF-κB p65 binding to MMP-9 promoter were attenuated by RNT. In summary, RNT attenuates BK-enhanced MMP-9 upregulation through inhibiting PKCδ/NOX/ROS/ERK1/2-dependent NF-κB activity in RBA-1.
Brain Tissue-Derived Extracellular Vesicle Mediated Therapy in the Neonatal Ischemic Brain
Authors: Nguyen Nam Phuong , Helmbrecht Hawley , Ye Ziming , Adebayo Tolulope , Hashi Najma , Doan My-Anh , Nance Elizabeth
Published: January 2022

Hypoxic-Ischemic Encephalopathy (HIE) in the brain is the leading cause of morbidity and mortality in neonates and can lead to irreparable tissue damage and cognition. Thus, investigating key mediators of the HI response to identify points of therapeutic intervention has significant clinical potential. Brain repair after HI requires highly coordinated injury responses mediated by cell-derived extracellular vesicles (EVs). Studies show that stem cell-derived EVs attenuate the injury response in ischemic models by releasing neuroprotective, neurogenic, and anti-inflammatory factors. In contrast to 2D cell cultures, we successfully isolated and characterized EVs from whole brain rat tissue (BEV) to study the therapeutic potential of endogenous EVs. We showed that BEVs decrease cytotoxicity in an ex vivo oxygen glucose deprivation (OGD) brain slice model of HI in a dose- and time-dependent manner. The minimum therapeutic dosage was determined to be 25 μg BEVs with a therapeutic application time window of 4–24 h post-injury. At this therapeutic dosage, BEV treatment increased anti-inflammatory cytokine expression. The morphology of microglia was also observed to shift from an amoeboid, inflammatory phenotype to a restorative, anti-inflammatory phenotype between 24–48 h of BEV exposure after OGD injury, indicating a shift in phenotype following BEV treatment. These results demonstrate the use of OWH brain slices to facilitate understanding of BEV activity and therapeutic potential in complex brain pathologies for treating neurological injury in neonates.
Simulated Microgravity Increases the Permeability of HUVEC Monolayer through Up-Regulation of Rap1GAP and Decreased Rap2 Activation
Authors: Shi Shuliang , Li Jing , Li Erzhuo , Guo Wenqi , He Yao , Wang Jinpeng , Zhang Yao , Yue Lei , Wei Lijun
Published: January 2022

Space microgravity condition has great physiological influence on astronauts’ health. The interaction of endothelial cells, which control vascular permeability and immune responses, is sensitive to mechanical stress. However, whether microgravity has significant effects on the physiological function of the endothelium has not been investigated. In order to address such a question, a clinostat-based culture model with a HUVEC monolayer being inside the culture vessel under the simulated microgravity (SMG) was established. The transmittance of FITC-tagged dextran was used to estimate the change of integrity of the adherens junction of the HUVEC monolayer. Firstly, we found that the permeability of the HUVEC monolayer was largely increased after SMG treatment. To elucidate the mechanism of the increased permeability of the HUVEC monolayer under SMG, the levels of total expression and activated protein levels of Rap1 and Rap2 in HUVEC cells, which regulate the adherens junction of endothelial cells, were detected by WB and GST pull-down after SMG. As the activation of both Rap1 and Rap2 was significantly decreased under SMG, the expression of Rap1GEF1 (C3G) and Rap1GAP in HUVECs, which regulate the activation of them, was further determined. The results indicate that both C3G and Rap1GAP showed a time-dependent increase with the expression of Rap1GAP being dominant at 48 h after SMG. The down-regulation of the expression of junctional proteins, VE-cadherin and β-catenin, in HUVEC cells was also confirmed by WB and immunofluorescence after SMG. To clarify whether up-regulation of Rap1GAP is necessary for the increased permeability of the HUVEC monolayer after SMG, the expression of Rap1GAP was knocked down by Rap1GAP-shRNA, and the change of permeability of the HUVEC monolayer was detected. The results indicate that knock-down of Rap1GAP reduced SMG-induced leaking of the HUVEC monolayer in a time-dependent manner. In total, our results indicate that the Rap1GAP-Rap signal axis was necessary for the increased permeability of the HUVEC monolayer along with the down-regulation of junctional molecules including VE-cadherin and β-catenin.
Role of Palatine Tonsil and Epipharyngeal Lymphoid Tissue in the Development of Glomerular Active Lesions (Glomerular vasculitis) in Immunoglobulin A Nephropathy
Authors: Hotta Osamu , Ieiri Norio , Nagai Masaaki , Tanaka Ayaki , Harabuchi Yasuaki
Published: January 2022

Hematuria is an essential symptom of immunoglobulin A nephropathy (IgAN). Although the etiology of hematuria in IgAN has not been fully elucidated, it is thought that the rupture of the glomerular basement membranes caused by intra-capillary leukocyte influx, so-called glomerular vasculitis, is the pathological condition responsible for severe hematuria. Glomerular vasculitis are active lesions that exist in the glomeruli of acute phase IgAN and it is important because it is suspected to make the transition to segmental glomerular sclerosis (SGS) as a repair scar lesion in the chronic phase, and the progression of SGS would eventually lead to glomerular obsolescence. Worsening of hematuria concomitant with acute pharyngitis is common in patients with IgAN; therefore, elucidating the relationship between the immune system of Waldeyer’s ring, including the palatine tonsil and epipharyngeal lymphoid tissue, and the glomerular vasculitis may lead to understanding the nature of IgAN. The epipharynx is an immunologically activated site even under normal conditions, and enhanced activation of innate immunity is likely to occur in response to airborne infection. Hyperactivation of innate immunity via upregulation of Toll-like receptors in the interfollicular area of the palatine tonsil and epipharyngeal lymphoid tissue, followed by enhanced fractalkine/CX3CR1 interactions, appears to play an important role in the development of glomerular vasculitis in IgAN. As latent but significant epipharyngitis is present in most patients with IgAN, it is plausible that acute upper respiratory infection may contribute as a trigger for the innate epipharyngeal immune system, which is already upregulated in a chronically inflamed environment. Given that epipharyngitis and its effects on IgAN are not fully understood, we propose that the so-called “epipharynx–kidney axis” may provide an important focus for future research.
Enriching Roadside Safety Assessments Using LiDAR Technology: Disaggregate Collision-Level Data Fusion and Analysis
Authors: Gargoum Suliman , Karsten Lloyd , El-Basyouny Karim , Chen Xinyu
Published: January 2022

Fatalities and serious injuries still represent a significant portion of run-off-the-road (ROR) collisions on highways in North America. In order to address this issue and design safer and more forgiving roadside areas, more empirical evidence is required to understand the association between roadside elements and safety. The inability to gather that evidence has been attributed in many cases to limitations in data collection and data fusion capabilities. To help overcome such issues, this paper proposes using LiDAR datasets to extract the information required to analyze factors contributing to the severity of ROR collisions on a localized collision level. Specifically, the paper proposes a new method for extracting pole-like objects and tree canopies. Information about other roadside assets, including signposts, alignment attributes, and side slopes is also extracted from the LiDAR scans in a fully automated manner. The extracted information is then attached to individual collisions to perform a localized assessment. Logistic regression is then used to explore links between the extracted features and the severity of fixed-object collisions. The analysis is conducted on 80 km of roads from 10 different highways in Alberta, Canada. The results show that roadside attributes vary significantly for the different collisions along the 80 km analyzed, indicating the importance of utilizing LiDAR to extract such features on a disaggregate collision level. The regression results show that the steepness of side slopes and the offset of roadside objects had the most significant impacts on the severity of fixed-object collisions.
Joint Layout Design: Finding the Strongest Connections within Segmental Masonry Arched Forms
Authors: Mousavian Elham , Casapulla Claudia
Published: January 2022

Segmental arched forms composed of discrete units are among the most common construction systems, ranging from historic masonry vaults to contemporary precast concrete shells. Simple fabrication, transport, and assembly have particularly made these structural systems convenient choices to construct infrastructures such as bridges in challenging environmental conditions. The most important drawback of segmental vaults is basically the poor mechanical behaviour at the joints connecting their constituent segments. The influence of the joint shape and location on structural performances has been widely explored in the literature, including studies on different stereotomy, bond patterns, and interlocking joint shapes. To date, however, a few methods have been developed to design optimal joint layouts, but they are limited to extremely limited geometric parameters and material properties. To remedy this, this paper presents a novel method to design the strongest joint layout in 2D arched structures while allowing joints to take on a range of diverse shapes. To do so, a masonry arched form is represented as a layout of potential joints, and the optimization problems developed based on the two plastic methods of classic limit analysis and discontinuity layout optimization find the joint layout that corresponds to the maximum load-bearing capacity.
Remedies to Avoid Failure Mechanisms of Lithium-Metal Anode in Li-Ion Batteries
Authors: Mauger Alain , Julien Christian M.
Published: January 2022

Rechargeable lithium-metal batteries (LMBs), which have high power and energy density, are very attractive to solve the intermittence problem of the energy supplied either by wind mills or solar plants or to power electric vehicles. However, two failure modes limit the commercial use of LMBs, i.e., dendrite growth at the surface of Li metal and side reactions with the electrolyte. Substantial research is being accomplished to mitigate these drawbacks. This article reviews the different strategies for fabricating safe LMBs, aiming to outperform lithium-ion batteries (LIBs). They include modification of the electrolyte (salt and solvents) to obtain a highly conductive solid–electrolyte interphase (SEI) layer, protection of the Li anode by in situ and ex situ coatings, use of three-dimensional porous skeletons, and anchoring Li on 3D current collectors.
Numerical Study on Plastic Strain Distributions and Mechanical Behaviour of a Tube under Bending
Authors: Amaechi Chiemela Victor , Adefuye Emmanuel Folarin , Oyetunji Abiodun Kolawole , Ja’e Idris Ahmed , Adelusi Ibitoye , Odijie Agbomerie Charles , Wang Facheng
Published: January 2022

Tubular pipe structures have been used in various applications—domestic, aviation, marine, manufacturing and material testing. The applications of tubular pipes have been considered greatly in the installation of tubular pipes, marine risers and pipe bending. For the investigation of plastic strains and the mechanical behaviour of a tube under bending, considerations were made utilising an exponent model with assumptions on the plane strain. The bending moment, wall thickness effect, cross-sectional distribution, stresses during bending and neutral layer boundaries were all presented as necessary theoretical formulations on the physics of tubular pipe bending. This model was based on the analytical and numerical investigation. In principle, the application can be observed as the spooling of pipes, bending of pipes and reeling. Comparisons were made on two models developed on the finite element analysis in Simscale OpenFEA, namely the linear-elastic and the elasto-plastic models. This study presents visualization profiles using plastic strain to assess its effect on the tubular pipes. This can increase due to the limitation of plastic deformation on the composite materials selected.
Estimation of the Tower Shape Effect on the Stress–Strain Behavior of Wind Turbines Operating under Offshore Boundary Conditions
Authors: Diaconita Alexandra Ionelia , Andrei Gabriel , Rusu Eugen
Published: January 2022

The metal tower, or the pylon, is one of the most important elements in the construction of a wind turbine. It has the role of supporting the entire wind turbine, and it also allows access for inspection and conducting planned maintenance and repairs. Moreover, the tower ensures support for the structure and strengthens the whole assembly. It has a particularly important role, as it has to face very severe weather conditions. The present study aims to analyze the forces and moments resulting from the action of the wind on the tower of a wind turbine. Two important load cases are considered, namely, the load under operating conditions and the ultimate load under 50 year wind conditions. For this purpose, cylindrical and conical geometric shapes of the tower were chosen. These were analyzed under the action of both normal and extreme wind speeds. Then, the behavior of the two towers under the action of the wind speed for a location in the Black Sea was analyzed. Finally, in an attempt to make the structure more economical, the thickness of the shell was reduced.
Electrocardiographic Characteristics and Their Correlation with Echocardiographic Alterations in Fabry Disease
Authors: Zada Matthew , Lo Queenie , Trivedi Siddharth J. , Harapoz Mehmet , Boyd Anita C. , Devine Kerry , Sadick Norman , Tchan Michel C. , Thomas Liza
Published: January 2022

Fabry disease (FD) is an X-linked disorder with α-galactosidase A deficiency. Males (>30 years) and females (>40 years) often present with cardiac manifestations, predominantly left ventricular hypertrophy (LVH). The aim of this study was to evaluate electrocardiographic (ECG) characteristics within FD patients to identify gender related differences, and to additionally explore the association of ECG parameters with structural and functional alterations on transthoracic echocardiography (TTE). Retrospective cross-sectional analysis of 45 FD patients with contemporaneous ECG and TTE was performed and compared to age and gender matched healthy controls. FD patients demonstrated alterations in several ECG parameters particularly in males, including prolonged P-wave duration (91 vs. 81 ms, p = 0.022), prolonged QRS duration (96 vs. 84 ms, p < 0.001), increased R-wave amplitude in lead I (8.1 vs. 5.7 mV, p = 0.047), increased Sokolow–Lyon index (25 vs. 19 mV, p = 0.002) and were more likely to meet LVH criteria (31% vs. 7%, p = 0.006). FD patients with impaired basal longitudinal strain (LS) on TTE were more likely to meet LVH criteria (41% vs. 0%, p = 0.018). Those with more advanced FD (increased LV wall thickness on TTE) were more likely to meet LVH criteria but additionally demonstrated prolonged ventricular depolarization (QRS duration 101 vs. 88 ms, p = 0.044). Therefore, alterations on ECG demonstrating delayed atrial activation, delayed ventricular depolarization and evidence of LVH were more often seen in male FD patients. Impaired basal LS, a TTE marker of early cardiac involvement, correlated with ECG abnormalities. Increased LV wall thickness on TTE, a marker of more advanced FD, was associated with more severe ECG abnormalities.
The Role of Multimodality Imaging in Left-Sided Prosthetic Valve Dysfunction
Authors: Muratori Manuela , Fusini Laura , Mancini Maria Elisabetta , Tamborini Gloria , Ghulam Ali Sarah , Gripari Paola , Doldi Marco , Frappampina Antonio , Teruzzi Giovanni , Pontone Gianluca , Montorsi Piero , Pepi Mauro
Published: January 2022

Prosthetic valve (PV) dysfunction (PVD) is a complication of mechanical or biological PV. Etiologic mechanisms associated with PVD include fibrotic pannus ingrowth, thrombosis, structural valve degeneration, and endocarditis resulting in different grades of obstruction and/or regurgitation. PVD can be life threatening and often challenging to diagnose due to the similarities between the clinical presentations of different causes. Nevertheless, identifying the cause of PVD is critical to treatment administration (thrombolysis, surgery, or percutaneous procedure). In this report, we review the role of multimodality imaging in the diagnosis of PVD. Specifically, this review discusses the characteristics of advanced imaging modalities underlying the importance of an integrated approach including 2D/3D transthoracic and transesophageal echocardiography, fluoroscopy, and computed tomography. In this scenario, it is critical to understand the strengths and weaknesses of each modality according to the suspected cause of PVD. In conclusion, for patients with suspected or known PVD, this stepwise imaging approach may lead to a simplified, more rapid, accurate and specific workflow and management.
The Use of Machine Learning Algorithms in the Evaluation of the Effectiveness of Resynchronization Therapy
Authors: Krzowski Bartosz , Rokicki Jakub , Główczyńska Renata , Fajkis-Zajączkowska Nikola , Barczewska Katarzyna , Mąsior Mariusz , Grabowski Marcin , Balsam Paweł
Published: January 2022

Background: Cardiovascular disease remains the leading cause of death in the European Union and worldwide. Constant improvement in cardiac care is leading to an increased number of patients with heart failure, which is a challenging condition in terms of clinical management. Cardiac resynchronization therapy is becoming more popular because of its grounded position in guidelines and clinical practice. However, some patients do not respond to treatment as expected. One way of assessing cardiac resynchronization therapy is with ECG analysis. Artificial intelligence is increasing in terms of everyday usability due to the possibility of everyday workflow improvement and, as a result, shortens the time required for diagnosis. A special area of artificial intelligence is machine learning. AI algorithms learn on their own based on implemented data. The aim of this study was to evaluate using artificial intelligence algorithms for detecting inadequate resynchronization therapy. Methods: A total of 1241 ECG tracings were collected from 547 cardiac department patients. All ECG signals were analyzed by three independent cardiologists. Every signal event (QRS-complex) and rhythm was manually classified by the medical team and fully reviewed by additional cardiologists. The results were divided into two parts: 80% of the results were used to train the algorithm, and 20% were used for the test (Cardiomatics, Cracow, Poland). Results: The required level of detection sensitivity of effective cardiac resynchronization therapy stimulation was achieved: 99.2% with a precision of 92.4%. Conclusions: Artificial intelligence algorithms can be a useful tool in assessing the effectiveness of resynchronization therapy.
3D Printing under High Ambient Pressures and Improvement of Mechanical Properties of Printed Parts
Authors: Shaik Yousuf Pasha , Schuster Jens , Katherapalli Harshavardhan Reddy , Shaik Aarif
Published: January 2022

Contrary to other polymer processing methods, additive manufacturing processes do not require any pressure during the consolidation of layers. This study investigates the effect of high ambient pressure on the consolidation of layers during the FDM process and their analysis of mechanical properties. An experimental setup was arranged, consisting of a 3D printer integrated into a customized Autoclave, to achieve high strength properties for 3D printed parts as like injection-molded specimens. The autoclave can maintain 135 bar of pressure and a maximum temperature of 185 °C. 3D printing with PLA was carried out at 0 bar, 5 bar, and 10 bar. Tensile, flexural, and Charpy tests were conducted on printed specimens, and the effect of pressure and temperature on 3D-printed samples were analyzed. It could be shown that autoclave preheating before printing and autoclave pressure during printing improves the consolidation of layers immensely. The pressure inside the autoclave provokes a more intimate contact between the layer surfaces and results in higher mechanical properties such as yield strength, Young’s modulus, and impact strength. The properties could be raised 100%.
Lower Limb Kinematic Coordination during the Running Motion of Stroke Patient: A Single Case Study
Authors: Chiba Noboru , Minamisawa Tadayoshi
Published: January 2022

The purpose of this study was to clarify the lower limb joint motor coordination of para-athletes during running motion from frequency characteristics and to propose this as a method for evaluating their performance. The subject used was a 43-year-old male para-athlete who had suffered a left cerebral infarction. Using a three-dimensional motion analysis system, the angles of the hip, knee, and ankle joints were measured during 1 min of running at a speed of 8 km/h on a treadmill. Nine inter- and intra-limb joint angle pairs were analyzed by coherence and phase analyses. The main characteristic of the stroke patient was that there were joint pairs with absent or increased coherence peaks in the high-frequency band above 4 Hz that were not found in healthy subjects. Interestingly, these features were also observed on the non-paralyzed side. Furthermore, a phase analysis showed different phase differences between the joint motions of the stroke patient and healthy subjects in some joint pairs. Thus, we concluded there was a widespread functional impairment of joint motion in the stroke patient that has not been revealed by conventional methods. The coherence analysis of joint motion may be useful for identifying joint motion problems in para-athletes.
Towards a First-Person Perspective Mixed Reality Guidance System for Needle Interventions
Authors: Groves Leah , Li Natalie , Peters Terry M. , Chen Elvis C. S.
Published: January 2022

While ultrasound (US) guidance has been used during central venous catheterization to reduce complications, including the puncturing of arteries, the rate of such problems remains non-negligible. To further reduce complication rates, mixed-reality systems have been proposed as part of the user interface for such procedures. We demonstrate the use of a surgical navigation system that renders a calibrated US image, and the needle and its trajectory, in a common frame of reference. We compare the effectiveness of this system, whereby images are rendered on a planar monitor and within a head-mounted display (HMD), to the standard-of-care US-only approach, via a phantom-based user study that recruited 31 expert clinicians and 20 medical students. These users performed needle-insertions into a phantom under the three modes of visualization. The success rates were significantly improved under HMD-guidance as compared to US-guidance, for both expert clinicians (94% vs. 70%) and medical students (70% vs. 25%). Users more consistently positioned their needle closer to the center of the vessel’s lumen under HMD-guidance compared to US-guidance. The performance of the clinicians when interacting with this monitor system was comparable to using US-only guidance, with no significant difference being observed across any metrics. The results suggest that the use of an HMD to align the clinician’s visual and motor fields promotes successful needle guidance, highlighting the importance of continued HMD-guidance research.