bluuebunny/crossref_metadata_2025 huggingface dataset:
ELECTROCHEMICAL INVESTIGATIONS OF THE INTERACTION OF CAFFEINIUM COMPOUNDS WITH POLYANІОNES OF Мо AND W WITH OF 1,3,5 - TRIPHENYL VERDAZYL RADICAL
Authors: Panteleieva Olha , Plyasovskaya Kateryna , Shtemenko Olexandr
Published: January 2021

The work continues the study on the peculiarities of the interaction of 1,3,7-trimethylxanthine (caffeine) compounds with polyoxometalates of molybdenum and tungsten with the artificial radical of 1,3,5- triphenylverdazyl (TFV). Using the example of a model reaction with the TFV radical, these compounds showed a special antiradical action. Based on the research results, it was found that the nature of the destruction of the radical when interacting with (HСaf)3[PМ12O40]∙6H2O (where М = Мо, W) differs from most known systems, which are characterized by a mechanism of disproportionation. The data obtained confirmed the previously made assumption about the chemical nature of these interactions. To establish the stoichiometry of the reaction between TFV and (HСaf)3[PW12O40], electrochemical studies were conducted which showed that the activity of the radical is restored after exceeding the concentration ratio of 12 : 1, respectively. The synergism of the components of the compound (HСaf)3[PW12O40] is shown: when TFV interacts with H3[PW12O40], the maximum cathode current characteristic of TFV occurs at a concentration ratio of 4 : 1, respectively, while caffeine has no antiradical effect at all. Previously obtained data from X-ray diffraction analysis of compounds (HСaf)3[PMo12O40]∙6H2O, (HСaf)3[PW12O40]∙6H2O prove that the orientation of protonated caffeine relative to polyoxamethalate-anion is possible due to hydrogen bonds =O…H–N=. This process can result in the delocalization of the charge over the entire O-enriched surface, by all twelve groups [О–Ме–О]-, which are part of the POM, making the latter active centers capable of interacting with TFV.

Therefore, the data presented correlate with the previously obtained results of spectrophotometric analysis and X-ray diffraction data and confirm the previously made conclusions.
MAHKOTA SIGER SEBAGAI SARANA AKULTURASI TATA RIAS JAWA DAN SUNDA: KAJIAN BUDAYA
Authors: Pangesti Cita Raras Nindya , Sabardila Atiqa
Published: January 2021

Penelitian ini bertujuan untuk (1) mendeksripsikan latar belakang terjadinya akulturasi tata rias Jawa dan Sunda, (2) mendeksripsikan anggota masyarakat yang memilih akulturasi tata rias Jawa dan Sunda, (3) mendeksripsikan bentuk akulturasi tata rias Jawa dan Sunda. Penelitian ini merupakan penelitian kualitatif. Data penelitian ini diperoleh dari studi lapangan untuk melakukan observasi, wawancara, serta teknik dokumentasi. Wawancara dilakukan kepada salah satu make-up artist dan sejumlah masyarakat di kabupaten Blora, Jawa Tengah. Data yang telah dikumpulkan dianalisis dengan menggunakan analisis deskriptif. Hasil penelitian menunjukkan bahwa latar belakang adanya percampuran atau akulturasi tata rias Jawa dan Sunda adalah karena pengaruh dari teknologi yaitu melalui peranan media sosial. Dari 30 responden, masyarakat yang paling banyak memilih tata rias Sunda siger adalah masyarakat asli dari Kabupaten Blora maupun dari kabupaten/kota di Jawa Timur. Data menunjukkan sejumlah 28 pengantin yang berdomisili Jawa dengan persentase 93%. Bentuk akulturasi dari tata rias Jawa dan Sunda adalah lebih menonjolkan pada penggunaan siger Sunda. Untuk busana sebagian besar masih menggunakan kebaya beludru atau kebaya biasa dengan ciri khas dari kebaya pengantin Solo Putri. Pada hasil tata rias yang sudah terpengaruhi oleh Sunda Siger yaitu pada warna blush on. Blush on mengikuti tata rias Sunda siger yang berwarna merah samar, berbeda dengan tata rias Solo Putri yang menggunakan warna merah merona.
НАСЛЕДИЕ ОБЫЧНОГО ПРАВА В РУССКОЙ ПОСТСОВЕТСКОЙ ДЕРЕВНЕ
Authors: Крюкова Светлана Станиславовна
Published: January 2021

Аннотация. В статье рассматривается комплекс обычно-правовых коммуникаций в русской постсоветской деревне с точки зрения преемственности традиции. Автор приходит к выводу, что специфика механизмов социальной коммуникации в сельской среде заложена как самим характером земледельческого труда, требующим коллективного участия в нем, так и всем укладом деревенской жизни, покоящимся не на законодательных нормах, а на обычаях/традициях – на коллективном опыте устного регулирования и разрешения разных проблем деревенской жизни. Неформальные и по большей части не фиксируемые в письменном виде, но имеющие нормативно-правовую основу соглашения и обязательства растворены в привычной для сельчан повседневности. Их соблюдение сопровождается набором специфических норм и установок, знание которых формируется в атмосфере и в результате постоянного общения в среде длительного совместного проживания.
Ключевые слова: русская деревня, обычай, традиция, землепользование, неформальное право, соционормативные коммуникации.

Abstract. The article examines the complex of customary legal communications in the Russian post-Soviet village from the point of view of the continuity of tradition. The author comes to the conclusion that the specificity of the mechanisms of social communication in the rural environment is laid down both by the very nature of agricultural labor, which requires collective participation in it, and by the whole way of village life, which rests not on legislative norms, but on customs / traditions, - on the collective experience of nonwritten regulation and solution of various problems of village life. Informal and for the most part not fixed in writing, but having a legal basis, agreements and obligations are dissolved in the everyday life familiar to villagers. Their observance is accompanied by a set of specific norms and attitudes, the knowledge of which is formed in the atmosphere and as a result of constant communication in an environment of long cohabitation.
Key words: Russian village, custom, tradition, land use, informal law, socionormative communications.
ПРОФЕССОР КИЕВСКОЙ ДУХОВНОЙ АКАДЕМИИ А. И. БУЛГАКОВ (1859–1907)
Authors: Лабынцев Юрий Андреевич , Щавинская Лариса Леонидовна
Published: January 2021

Аннотация. В статье на основе различных литературных и архивных материалов рассказывается о жизни, научной и просветительской работе Афанасия Ивановича Булгакова – отца известного русского писателя М. А. Булгакова. Особое внимание уделено полемической и проповеднической деятельности А. И. Булгакова – православного ученого богослова, в том числе рассчитанной на самые широкие слои населения Российской империи, включая простонародные. В приложении публикуется рукописная автобиография А. И. Булгакова.
Ключевые слова: православие, А. И. Булгаков, М. А. Булгаков, Киевская духовная академия, богословие.
Abstract. The article is based on various literary and archival materials and tells about the life, scientific and educational work of Afanasy Ivanovich Bulgakov, the father of the famous Russian writer M.A. Bulgakov. Special attention is paid to the polemical and preaching activities of the Orthodox scholar theologian A.I. Bulgakov. Its activities were designed for the broadest segments of the population of the Russian Empire, including the common people. The Application contains a handwritten autobiography of A.I. Bulgakov.
Key words: Orthodoxy, A.I. Bulgakov, M.A. Bulgakov, Kiev Theological Academy, theology
Corneal Biomechanical Properties in Varying Severities of Myopia
Authors: Sedaghat Mohammad-Reza , Momeni-Moghaddam Hamed , Azimi Abbas , Fakhimi Zohreh , Ziaei Mohammed , Danesh Zeynad , Roberts Cynthia J. , Monfared Naeemeh , Jamali Alireza
Published: January 2021

Purpose: To investigate corneal biomechanical response parameters in varying degrees of myopia and their correlation with corneal geometrical parameters and axial length.

Methods: In this prospective cross-sectional study, 172 eyes of 172 subjects, the severity degree of myopia was categorized into mild, moderate, severe, and extreme myopia. Cycloplegic refraction, corneal tomography using Pentacam HR, corneal biomechanical assessment using Corvis ST and Ocular Response Analyser (ORA), and ocular biometry using IOLMaster 700 were performed for all subjects. A general linear model was used to compare biomechanical parameters in various degrees of myopia, while central corneal thickness (CCT) and biomechanically corrected intraocular pressure (bIOP) were considered as covariates. Multiple linear regression was used to investigate the relationship between corneal biomechanical parameters with spherical equivalent (SE), axial length (AXL), bIOP, mean keratometry (Mean KR), and CCT.

Results: Corneal biomechanical parameters assessed by Corvis ST that showed significant differences among the groups were second applanation length (AL2, p = 0.035), highest concavity radius (HCR, p < 0.001), deformation amplitude (DA, p < 0.001), peak distance (PD, p = 0.022), integrated inverse radius (IR, p < 0.001) and DA ratio (DAR, p = 0.004), while there were no significant differences in the means of pressure-derived parameters of ORA between groups. Multiple regression analysis showed all parameters of Corvis ST have significant relationships with level of myopia (SE, AXL, Mean KR), except AL1 and AL2. Significant biomechanical parameters showed progressive reduction in corneal stiffness with increasing myopia (either with greater negative SE or greater AXL), independent of IOP and CCT. Also, corneal hysteresis (CH) or ability to dissipate energy from the ORA decreased with increasing level of myopia.

Conclusions: Dynamic corneal response assessed by Corvis ST shows evidence of biomechanical changes consistent with decreasing stiffness with increasing levels of myopia in multiple parameters. The strongest correlations were with highest concavity parameters where the sclera influence is maximal.
Developing a Sustainable and Circular Bio-Based Economy in EU: By Partnering Across Sectors, Upscaling and Using New Knowledge Faster, and For the Benefit of Climate, Environment & Biodiversity, and People & Business
Authors: Lange Lene , Connor Kevin O. , Arason Sigurjon , Bundgård-Jørgensen Uffe , Canalis Antonella , Carrez Dirk , Gallagher Joe , Gøtke Niels , Huyghe Christian , Jarry Bruno , Llorente Pilar , Marinova Mariya , Martins Ligia O. , Mengal Philippe , Paiano Paola , Panoutsou Calliope , Rodrigues Ligia , Stengel Dagmar B. , van der Meer Yvonne , Vieira Helena
Published: January 2021

This paper gives an overview of development of the EU-bioeconomy, 2014–2020. The Vision of the new Circular Bio-based Economy, CBE is presented: Unlocking the full potential of all types of sustainably sourced biomass, crop residues, industrial side-streams, and wastes by transforming it into value-added products. The resulting product portfolio consists of a wide spectrum of value-added products, addressing societal and consumer needs. Food and feed, bio-based chemicals, materials, health-promoting products; and bio-based fuels. The pillars of CBE are described, including biotechnology, microbial production, enzyme technology, green chemistry, integrated physical/chemical processing, policies, conducive framework conditions and public private partnerships. Drivers of CBE are analyzed: Biomass supply, biorefineries, value chain clusters, rural development, farmers, foresters and mariners; urgent need for climate change mitigation and adaptation, and stopping biodiversity loss. Improved framework conditions can be drivers but also obstacles if not updated to the era of circularity. Key figures, across the entire BBI-JU project portfolio (2014–2020) are provided, including expansion into biomass feedstocks, terrestrial and aquatic, and an impressive broadening of bio-based product portfolio, including higher-value, health-promoting products for man, animal, plants and soil. Parallel to this, diversification of industrial segments and types of funding instruments developed, reflecting industrial needs and academic research involvement. Impact assessment is highlighted. A number of specific recommendations are given; e.g., including international win/win CBE-collaborations, as e.g., expanding African EU collaboration into CBE. In contrast to fossil resources biological resources are found worldwide. In its outset, circular bio-based economy, can be implemented all over, in a just manner, not the least stimulating rural development.
The Role of Neutrophils and Neutrophil Extracellular Traps in Acute Pancreatitis
Authors: Wan Jianhua , Ren Yuping , Yang Xiaoyu , Li Xueyang , Xia Liang , Lu Nonghua
Published: January 2021

Leukocyte invasion (neutrophils and monocytes/macrophages) is closely related to the severity of acute pancreatitis (AP) and plays an important role in the systemic inflammatory response and other organ injuries secondary to AP. Increased and sustained activation of neutrophils are major determinants of pancreatic injury and inflammation. After the onset of AP, the arrival of the first wave of neutrophils occurs due to a variety of triggers and is critical for the exacerbation of inflammation. In this review, we summarize the functional characteristics of neutrophils, elastase, and heparin-binding proteins in granules, the mechanisms of neutrophil recruitment and the role of neutrophil extracellular traps (NETs) in AP.
BRG1 Mediates Nephronectin Activation in Hepatocytes to Promote T Lymphocyte Infiltration in ConA-Induced Hepatitis
Authors: Hong Wenxuan , Kong Ming , Qi Mengwen , Bai Hui , Fan Zhiwen , Zhang Ziyu , Sun Aijun , Fan Xiangshan , Xu Yong
Published: January 2021

Fulminant hepatitis (FH) is a major cause of acute liver failure. Concanavalin A (ConA) belongs to the lectin family and is frequently used as an inducer of FH in animal models. ConA induced FH is characterized by massive accumulation of T lymphocytes in the liver. A host of chemoattractive substances are known to promote T cell homing to the liver during acute hepatitis. Here we investigated the involvement of Brahma-related gene 1 (BRG1), a chromatin remodeling protein, in FH. BRG1-flox mice were crossed to Alb-Cre mice to generate hepatocyte conditional BRG1 knockout (LKO) mice. The mice were peritoneally injected with a single dose of ConA to induce FH. BRG1 deficiency mitigated ConA-induced FH in mice. Consistently, there were fewer T lymphocyte infiltrates in the LKO livers compared to the wild type (WT) livers paralleling downregulation of T cell specific cytokines. Further analysis revealed that BRG1 deficiency repressed the expression of several chemokines critical for T cell homing including nephronectin (Npnt). BRG1 knockdown blocked the induction of Npnt in hepatocytes and attenuated T lymphocyte migration in vitro, which was reversed by the addition of recombinant nephronectin. Mechanistically, BRG1 interacted with β-catenin to directly bind to the Npnt promoter and activate Npnt transcription. Importantly, a positive correlation between infiltration of CD3+ T lymphocyes and nephronectin expression was detected in human acute hepatitis biopsy specimens. In conclusion, our data identify a novel role for BRG1 as a promoter of T lymphocyte trafficking by activating Npnt transcription in hepatocytes. Targeting the BRG1-Npnt axis may yield novel therapeutic solutions for FH.
A Novel m6A Gene Signature Associated With Regulatory Immune Function for Prognosis Prediction in Clear-Cell Renal Cell Carcinoma
Authors: Chen Siteng , Zhang Ning , Zhang Encheng , Wang Tao , Jiang Liren , Wang Xiang , Zheng Junhua
Published: January 2021

The important role of N6-methyladenosine (m6A) RNA methylation regulator in carcinogenesis and progression of clear-cell renal cell carcinoma (ccRCC) is poorly understood by now. In this study, we performed comprehensive analyses of m6A RNA methylation regulators in 975 ccRCC samples and 332 adjacent normal tissues and identified ccRCC-related m6A regulators. Moreover, the m6A diagnostic score based on ccRCC-related m6A regulators could accurately distinguish ccRCC from normal tissue in the Meta-cohort, which was further validated in the independent GSE-cohort and The Cancer Genome Atlas-cohort, with an area under the curve of 0.924, 0.867, and 0.795, respectively. Effective survival prediction of ccRCC by m6A risk score was also identified in the Cancer Genome Atlas training cohort and verified in the testing cohort and the independent GSE22541 cohort, with hazard ratio values of 3.474, 1.679, and 2.101 in the survival prognosis, respectively. The m6A risk score was identified as a risk factor of overall survival in ccRCC patients by the univariate Cox regression analysis, which was further verified in both the training cohort and the independent validation cohort. The integrated nomogram combining m6A risk score and predictable clinicopathologic factors could accurately predict the survival status of the ccRCC patients, with an area under the curve values of 85.2, 82.4, and 78.3% for the overall survival prediction in 1-, 3- and 5-year, respectively. Weighted gene co-expression network analysis with functional enrichment analysis indicated that m6A RNA methylation might affect clinical prognosis through regulating immune functions in patients with ccRCC.
Combining Miconazole and Domiphen Bromide Results in Excess of Reactive Oxygen Species and Killing of Biofilm Cells
Authors: Tits Jana , Berman Judith , Cammue Bruno P. A. , Thevissen Karin
Published: January 2021

Fungal biofilm-related infections are increasingly occurring. We previously identified a fungicidal antibiofilm combination, consisting of miconazole (MCZ) and the quaternary ammonium compound domiphen bromide (DB). DB eliminates tolerance rather than altering the susceptibility to MCZ of variousCandidaspp. Here we studied the mode of action of the MCZ-DB combination in more detail. We found that DB's action increases the permeability of the plasma membrane as well as that of the vacuolar membrane ofCandidaspp. Furthermore, the addition of DB affects the intracellular azole distribution. MCZ is a fungicidal azole that, apart from its well-known inhibition of ergosterol biosynthesis, also induces accumulation of reactive oxygen species (ROS). Interestingly, the MCZ-DB combination induced significantly more ROS inC. albicansbiofilms as compared to single compound treatment. Co-administration of the antioxidant ascorbic acid resulted in abolishment of the ROS generated by MCZ-DB combination as well as its fungicidal action. In conclusion, increased intracellular MCZ availability due to DB's action results in excess of ROS and enhanced fungal cell killing.
Ectonucleotidase Modulation of Lymphocyte Function in Gut and Liver
Authors: Savio Luiz Eduardo Baggio , Robson Simon C. , Longhi Maria Serena
Published: January 2021

Imbalance between regulatory and effector T lymphocytes contributes to loss of immunotolerance and plays a permissive role in the initiation, perpetuation, and progression of chronic inflammatory diseases and autoimmune disorders. Regulatory/effector cell balance is governed by the CD39 ectonucleotidase, the prototype member of the NTPDase family that hydrolyzes ATP and ADP into AMP, subsequently converted into adenosine by CD73. Generation of adenosine impacts T-cell function as it contributes to the mechanism of suppression of Tregs and confers regulatory properties to pathogenic Th17-cells. CD39 cell distribution, mechanism of regulation and impact on inflammatory and regulatory signaling pathways are also discussed here. Innovative therapeutic strategies to boost CD39 levels and activity by either administering soluble ADPases or interfering with CD39 inhibitory signals are reviewed. Restoration of CD39 levels and function has enormous translational and clinical implications and should be regarded as an additional form of treatment to be deployed in the chronic inflammatory setting. The key role of CD39 in immunoregulation in the context of Crohn's disease, one of the most frequent manifestations of inflammatory bowel disease, and autoimmune hepatitis, an autoimmune disorder of the liver, is reviewed and discussed here.
Multi-Omics Analysis of Acute Lymphoblastic Leukemia Identified the Methylation and Expression Differences Between BCP-ALL and T-ALL
Authors: Li Jin-Fan , Ma Xiao-Jing , Ying Lin-Lin , Tong Ying-hui , Xiang Xue-ping
Published: January 2021

Acute lymphoblastic leukemia (ALL) as a common cancer is a heterogeneous disease which is mainly divided into BCP-ALL and T-ALL, accounting for 80–85% and 15–20%, respectively. There are many differences between BCP-ALL and T-ALL, including prognosis, treatment, drug screening, gene research and so on. In this study, starting with methylation and gene expression data, we analyzed the molecular differences between BCP-ALL and T-ALL and identified the multi-omics signatures using Boruta and Monte Carlo feature selection methods. There were 7 expression signature genes (CD3D, VPREB3, HLA-DRA, PAX5, BLNK, GALNT6, SLC4A8) and 168 methylation sites corresponding to 175 methylation signature genes. The overall accuracy, accuracy of BCP-ALL, accuracy of T-ALL of the RIPPER (Repeated Incremental Pruning to Produce Error Reduction) classifier using these signatures evaluated with 10-fold cross validation repeated 3 times were 0.973, 0.990, and 0.933, respectively. Two overlapped genes between 175 methylation signature genes and 7 expression signature genes were CD3D and VPREB3. The network analysis of the methylation and expression signature genes suggested that their common gene, CD3D, was not only different on both methylation and expression levels, but also played a key regulatory role as hub on the network. Our results provided insights of understanding the underlying molecular mechanisms of ALL and facilitated more precision diagnosis and treatment of ALL.
Extracellular Vesicles in Neuroinflammation
Authors: Marostica Giulia , Gelibter Stefano , Gironi Maira , Nigro Annamaria , Furlan Roberto
Published: January 2021

Extracellular vesicles (EVs) are a heterogenous group of membrane-bound particles that play a pivotal role in cell–cell communication, not only participating in many physiological processes, but also contributing to the pathogenesis of several diseases. The term EVs defines many and different vesicles based on their biogenesis and release pathway, including exosomes, microvesicles (MVs), and apoptotic bodies. However, their classification, biological function as well as protocols for isolation and detection are still under investigation. Recent evidences suggest the existence of novel subpopulations of EVs, increasing the degree of heterogeneity between EV types and subtypes. EVs have been shown to have roles in the CNS as biomarkers and vehicles of drugs and other therapeutic molecules. They are known to cross the blood brain barrier, allowing CNS EVs to be detectable in peripheral fluids, and their cargo may give information on parental cells and the pathological process they are involved in. In this review, we summarize the knowledge on the function of EVs in the pathogenesis of multiple sclerosis (MS) and discuss recent evidences for their potential applications as diagnostic biomarkers and therapeutic targets.
The Role of Mitochondria in Pyroptosis
Authors: Li Qian , Shi Nengxian , Cai Chen , Zhang Mingming , He Jing , Tan Ying , Fu Weijun
Published: January 2021

Pyroptosis is a recently discovered aspartic aspart-specific cysteine protease (Caspase-1/4/5/11) dependent mode of gene-regulated cell death cell death, which is represented by the rupture of cell membrane perforations and the production of proinflammatory mediaters like interleukin-18(IL-18) and interleukin-1β (IL-1β). Mitochondria also play an important role in apoptotic cell death. When it comes to apoptosis of mitochondrion, mitochondrial outer membrane permeabilization (MOMP) is commonly known to cause cell death. As a downstream pathological process of apoptotic signaling, MOMP participates in the leakage of cytochrome-c from mitochondrion to the cytosol and subsequently activate caspase proteases. Hence, targeting MOMP for the sake of manipulating cell death presents potential therapeutic effects among various types of diseases, such as autoimmune disorders, neurodegenerative diseases, and cancer. In this review, we highlights the roles and significance of mitochondria in pyroptosis to provide unexplored strategies that target the mitochondria to regulate cell death for clinical benefits.
Circular RNA CircCOL5A1 Sponges the MiR-7-5p/Epac1 Axis to Promote the Progression of Keloids Through Regulating PI3K/Akt Signaling Pathway
Authors: Lv Wenchang , Liu Shengxuan , Zhang Qi , Hu Weijie , Wu Yiping , Ren Yuping
Published: January 2021

Keloids, as a result of abnormal wound healing in susceptible individuals, are characterized by the hyper-proliferation of fibroblasts and exaggerated deposition of extracellular matrix. Current surgical and therapeutic modalities provide limited satisfactory results. Growing evidence has highlighted the roles of circRNAs in acting as miRNA sponges. However, up to date, the regulatory mechanism of circRNAs in the pathological process of keloids has rarely been reported. In this study, cell proliferation, cell migration, flow cytometry, western blotting, fluorescence in situ hybridization, dual-luciferase activity, and immunohistochemistry assays were applied to explore the roles and mechanisms of the circCOL5A1/miR-7-5p/Epac1 axis in the keloid. The therapeutic potential of circCOL5A1 was investigated by establishing keloid implantation models. The RT-qPCR result revealed that circCOL5A1 expression was obviously higher in keloid tissues and keloid fibroblasts. Subsequent cellular experiments demonstrated that circCOL5A1 knockdown repressed the proliferation, migration, extracellular matrix (ECM) deposition, whereas promoted cell apoptosis, through the PI3K/Akt signaling pathway. Furthermore, RNA-fluorescence in situ hybridization (RNA-FISH) illustrated that both circCOL5A1 and miR-7-5p were located in the cytoplasm. The luciferase reporter gene assay confirmed that exact binding sites were present between circCOL5A1 and miR-7-5p, as well as between miR-7-5p and Epac1. Collectively, the present study revealed that circCOL5A1 functioned as competing endogenous RNA (ceRNA) by adsorbing miR-7-5p to release Epac1, which contributed to pathological hyperplasia of keloids through activating the PI3K/Akt signaling pathway. Our data indicated that circCOL5A1 might serve as a novel promising therapeutic target and represent a new avenue to understand underlying pathogenesis for keloids.
Characteristics and Biomarkers of Ferroptosis
Authors: Chen Xin , Comish Paul B. , Tang Daolin , Kang Rui
Published: January 2021

The induction and consequences of regulated cell death (RCD) are accompanied by changes in gene and protein expression, biochemical pathways, as well as cell morphology and size. Such RCDs have a significant impact on development, tissue homeostasis, and the occurrence and progression of disease. Among different forms of RCD, ferroptosis appears to be the main cause of tissue damage driven by iron overload and lipid peroxidation. In fact, the dysfunctional ferroptotic response is implicated in a variety of pathological conditions and diseases, such as neurodegenerative diseases, tissue ischemia-reperfusion injury, tumorigenesis, infections, and immune diseases. Ferroptotic response can be fine-tuned through various oxidative stress and antioxidant defense pathways, coupling with metabolism, gene transcription, and protein degradation machinery. Accordingly, a series of ferroptosis inducers or inhibitors targeting redox- or iron metabolism-related proteins or signal transduction have been developed. Although this kind of RCD has recently attracted great interest in basic and clinical research, detecting and monitoring a ferroptotic response still faces challenges. In this mini-review, we not only summarize the latest knowledge about the characteristics of ferroptosis in vitro and in vivo, but also discuss the specificity and limitations of current biomarkers of ferroptosis.
Host Responses in an Ex Vivo Human Skin Model Challenged With Malassezia sympodialis
Authors: Corzo-León Dora E. , MacCallum Donna M. , Munro Carol A.
Published: January 2021

Malassezia species are a major part of the normal mycobiota and colonize mainly sebum-rich skin regions of the body. This group of fungi cause a variety of infections such as pityriasis versicolor, folliculitis, and fungaemia. In particular, Malassezia sympodialis and its allergens have been associated with non-infective inflammatory diseases such as seborrheic dermatitis and atopic eczema. The aim of this study was to investigate the host response to M. sympodialis on oily skin (supplemented with oleic acid) and non-oily skin using an ex vivo human skin model. Host-pathogen interactions were analyzed by SEM, histology, gene expression, immunoassays and dual species proteomics. The skin response to M. sympodialis was characterized by increased expression of the genes encoding β-defensin 3 and RNase7, and by high levels of S100 proteins in tissue. Supplementation of oleic acid onto skin was associated with direct contact of yeasts with keratinocytes and epidermal damage. In oily conditions, there was increased expression of IL18 but no expression of antimicrobial peptide genes in the skin’s response to M. sympodialis. In supernatants from inoculated skin plus oleic acid, TNFα, IL-6, and IL1-β levels were decreased and IL-18 levels were significantly increased.
Umbilical Cord Pericytes Provide a Viable Alternative to Mesenchymal Stem Cells for Neonatal Vascular Engineering
Authors: Cathery William , Faulkner Ashton , Jover Eva , Rodriguez-Arabaolaza Iker , Thomas Anita C. , Avolio Elisa , Caputo Massimo , Madeddu Paolo
Published: January 2021

Reconstructive surgery of congenital heart disease (CHD) remains inadequate due to the inability of prosthetic grafts to match the somatic growth of pediatric patients. Functionalization of grafts with mesenchymal stem cells (MSCs) may provide a solution. However, MSCs represent a heterogeneous population characterized by wide diversity across different tissue sources. Here we investigated the suitability of umbilical cord pericytes (UCPs) in neonatal vascular engineering. Explant outgrowth followed by immunomagnetic sorting was used to isolate neural/glial antigen 2 (NG2)+/CD31− UCPs. Expanded NG2 UCPs showed consistent antigenic phenotype, including expression of mesenchymal and stemness markers, and high proliferation rate. They could be induced to a vascular smooth muscle cell-like phenotype after exposure to differentiation medium, as evidenced by the expression of transgelin and smooth muscle myosin heavy chain. Analysis of cell monolayers and conditioned medium revealed production of extracellular matrix proteins and the secretion of major angiocrine factors, which conferred UCPs with ability to promote endothelial cell migration and tube formation. Decellularized swine-derived grafts were functionalized using UCPs and cultured under static and dynamic flow conditions. UCPs were observed to integrate into the outer layer of the graft and modify the extracellular environment, resulting in improved elasticity and rupture strain in comparison with acellular grafts. These findings demonstrate that a homogeneous pericyte-like population can be efficiently isolated and expanded from human cords and integrated in acellular grafts currently used for repair of CHD. Functional assays suggest that NG2 UCPs may represent a viable option for neonatal tissue engineering applications.
Case Report: Primary Hypothyroidism Associated With Lutetium 177-DOTATATE Therapy for Metastatic Paraganglioma
Authors: Gubbi Sriram , Al-Jundi Mohammad , Del Rivero Jaydira , Jha Abhishek , Knue Marianne , Zou Joy , Turkbey Baris , Carrasquillo Jorge Amilcar , Lin Emily , Pacak Karel , Klubo-Gwiezdzinska Joanna , Lin Frank I-Kai
Published: January 2021

Background

Lutetium 177 (177Lu) - DOTATATE is a form of peptide receptor radionuclide therapy (PRRT) utilized in the treatment of neuroendocrine tumors. Data on 177Lu-DOTATATE-induced thyroid dysfunction is limited.

Case Description

A 29-year-old male with SDHB positive metastatic paraganglioma enrolled under the 177Lu-DOTATATE trial (NCT03206060) underwent thyroid function test (TFT) evaluation comprised of thyroid stimulating hormone (TSH) and free thyroxine (FT4) immunoassay measurements per protocol prior to 177Lu-DOTATATE therapy. The TSH was suppressed [<0.01 µIU/ml (0.27–4.2 µIU/ml)], and FT4 was normal [1.3 ng/dl (0.9–1.7 ng/dl)]. The TSH receptor antibody and thyroid stimulating immunoglobulin index were undetectable [<1 IU/L (≤1.75 IU/L), and <1 (≤1.3) respectively], while the anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies were elevated [605 IU/ml (0.0–34.9 IU/ml), and 178 IU/ml (0.0-40.0 IU/ml) respectively]. Mass spectrometry on a stored (-80°C) plasma sample obtained one-month pre-PRRT revealed elevated total triiodothyronine (TT3) [235 ng/dl (65–193 ng/dl)] and FT4 [3.9 ng/dl (1.2–2.9 ng/dl)] levels. The patient was diagnosed with Hashimoto’s thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi 177Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 µIU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87–169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to 177Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of 177Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient’s symptoms resolved.

We report, for the first time, a patient with asymptomatic primary hyperthyroidism who rapidly developed symptomatic primary hypothyroidism 1 month after 177Lu-DOTATATE therapy, accompanied by marked changes in TFTs and thyroid auto-antibody titers, with functional imaging evidence of diffuse uptake of 177Lu-DOTATATE in the thyroid gland.

Conclusions

Thyroid dysfunction can be associated with PRRT. Thyroid uptake patterns on pre-treatment diagnostic somatostatin analog scans might predict individual susceptibility to PRRT-associated TFT disruption. Therefore, periodic evaluation of TFTs should be considered in patients receiving PRRT.
Androgen Receptor Is Dispensable for X-Zone Regression in the Female Adrenal but Regulates Post-Partum Corticosterone Levels and Protects Cortex Integrity
Authors: Gannon Anne-Louise , O’Hara Laura , Mason Ian J. , Jørgensen Anne , Frederiksen Hanne , Curley Michael , Milne Laura , Smith Sarah , Mitchell Rod T. , Smith Lee B.
Published: January 2021

Adrenal androgens are fundamental mediators of ovarian folliculogenesis, embryonic implantation, and breast development. Although adrenal androgen function in target tissues are well characterized, there is little research covering the role of androgen-signaling within the adrenal itself. Adrenal glands express AR which is essential for the regression of the X-zone in male mice. Female mice also undergo X-zone regression during their first pregnancy, however whether this is also controlled by AR signaling is unknown. To understand the role of the androgen receptor (AR) in the female adrenal, we utilized a Cyp11a1-Cre to specifically ablate AR from the mouse adrenal cortex. Results show that AR-signaling is dispensable for adrenal gland development in females, and for X-zone regression during pregnancy, but is required to suppress elevation of corticosterone levels post-partum. Additionally, following disruption to adrenal AR, aberrant spindle cell development is observed in young adult females. These results demonstrate sexually dimorphic regulation of the adrenal X-zone by AR and point to dysfunctional adrenal androgen signaling as a possible mechanism in the early development of adrenal spindle cell hyperplasia.
Natural Compounds in Sex Hormone-Dependent Cancers: The Role of Triterpenes as Therapeutic Agents
Authors: Şoica Codruţa , Voicu Mirela , Ghiulai Roxana , Dehelean Cristina , Racoviceanu Roxana , Trandafirescu Cristina , Roșca Oana-Janina , Nistor Gabriela , Mioc Marius , Mioc Alexandra
Published: January 2021

Sex hormone-dependent cancers currently contribute to the high number of cancer-related deaths worldwide. The study and elucidation of the molecular mechanisms underlying the progression of these tumors was a double-edged sword, leading to the expansion and development of new treatment options, with the cost of triggering more aggressive, therapy resistant relapses. The interaction of androgen, estrogen and progesterone hormones with specific receptors (AR, ER, PR) has emerged as a key player in the development and progression of breast, ovarian, prostate and endometrium cancers. Sex hormone-dependent cancers share a common and rather unique carcinogenesis mechanism involving the active role of endogenous and exogenous sex hormones to maintain high mitotic rates and increased cell proliferation thus increasing the probability of aberrant gene occurrence and accumulation highly correlated with abnormal cell division and the occurrence of malignant phenotypes. Cancer related hormone therapy has evolved, currently being associated with the blockade of other signaling pathways often associated with carcinogenesis and tumor progression in cancers, with promising results. However, despite the established developments, there are still several shortcomings to be addressed. Triterpenes are natural occurring secondary metabolites biosynthesized by various pathways starting from squalene cyclization. Due to their versatile therapeutic potential, including the extensively researched antiproliferative effect, these compounds are most definitely a cornerstone in the research and development of new natural/semisynthetic anticancer therapies. The present work thoroughly describes the ongoing research related to the antitumor activity of triterpenes in sex hormone-dependent cancers. Also, the current review highlights both the biological activity of various triterpenoid compounds and their featured mechanisms of action correlated with important chemical structural features.
The Pontastacus leptodactylus (Astacidae) Repeatome Provides Insight Into Genome Evolution and Reveals Remarkable Diversity of Satellite DNA
Authors: Boštjančić Ljudevit Luka , Bonassin Lena , Anušić Lucija , Lovrenčić Leona , Besendorfer Višnja , Maguire Ivana , Grandjean Frederic , Austin Christopher M. , Greve Carola , Hamadou Alexander Ben , Mlinarec Jelena
Published: January 2021

Pontastacus leptodactylus is a native European crayfish species found in both freshwater and brackish environments. It has commercial importance for fisheries and aquaculture industries. Up till now, most studies concerning P. leptodactylus have focused onto gaining knowledge about its phylogeny and population genetics. However, little is known about the chromosomal evolution and genome organization of this species. Therefore, we performed clustering analysis of a low coverage genomic dataset to identify and characterize repetitive DNA in the P. leptodactylus genome. In addition, the karyogram of P. leptodactylus (2n = 180) is presented here for the first time consisting of 75 metacentric, 14 submetacentric, and a submetacentric/metacentric heteromorphic chromosome pair. We determined the genome size to be at ~18.7 gigabase pairs. Repetitive DNA represents about 54.85% of the genome. Satellite DNA repeats are the most abundant type of repetitive DNA, making up to ~28% of the total amount of repetitive elements, followed by the Ty3/Gypsy retroelements (~15%). Our study established a surprisingly high diversity of satellite repeats in P. leptodactylus. The genome of P. leptodactylus is by far the most satellite-rich genome discovered to date with 258 satellite families described. Of the five mapped satellite DNA families on chromosomes, PlSAT3-411 co-localizes with the AT-rich DAPI positive probable (peri)centromeric heterochromatin on all chromosomes, while PlSAT14-79 co-localizes with the AT-rich DAPI positive (peri)centromeric heterochromatin on one chromosome and is also located subterminally and intercalary on some chromosomes. PlSAT1-21 is located intercalary in the vicinity of the (peri)centromeric heterochromatin on some chromosomes, while PlSAT6-70 and PlSAT7-134 are located intercalary on some P. leptodactylus chromosomes. The FISH results reveal amplification of interstitial telomeric repeats (ITRs) in P. leptodactylus. The prevalence of repetitive elements, especially the satellite DNA repeats, may have provided a driving force for the evolution of the P. leptodactylus genome.
l-Isoaspartyl Methyltransferase Deficiency in Zebrafish Leads to Impaired Calcium Signaling in the Brain
Authors: Soliman Remon , Cordero-Maldonado Maria Lorena , Martins Teresa G. , Moein Mahsa , Conrotte Jean-François , Warmack Rebeccah A. , Skupin Alexander , Crawford Alexander D. , Clarke Steven G. , Linster Carole L.
Published: January 2021

Isomerization of l-aspartyl and l-asparaginyl residues to l-isoaspartyl residues is one type of protein damage that can occur under physiological conditions and leads to conformational changes, loss of function, and enhanced protein degradation. Protein l-isoaspartyl methyltransferase (PCMT) is a repair enzyme whose action initiates the reconversion of abnormal l-isoaspartyl residues to normal l-aspartyl residues in proteins. Many lines of evidence support a crucial role for PCMT in the brain, but the mechanisms involved remain poorly understood. Here, we investigated PCMT activity and function in zebrafish, a vertebrate model that is particularly well-suited to analyze brain function using a variety of techniques. We characterized the expression products of the zebrafish PCMT homologous genes pcmt and pcmtl. Both zebrafish proteins showed a robust l-isoaspartyl methyltransferase activity and highest mRNA transcript levels were found in brain and testes. Zebrafish morphant larvae with a knockdown in both the pcmt and pcmtl genes showed pronounced morphological abnormalities, decreased survival, and increased isoaspartyl levels. Interestingly, we identified a profound perturbation of brain calcium homeostasis in these morphants. An abnormal calcium response upon ATP stimulation was also observed in mouse hippocampal HT22 cells knocked out for Pcmt1. This work shows that zebrafish is a promising model to unravel further facets of PCMT function and demonstrates, for the first time in vivo, that PCMT plays a pivotal role in the regulation of calcium fluxes.
Telomere Length as a Marker of Biological Age: State-of-the-Art, Open Issues, and Future Perspectives
Authors: Vaiserman Alexander , Krasnienkov Dmytro
Published: January 2021

Telomere shortening is a well-known hallmark of both cellular senescence and organismal aging. An accelerated rate of telomere attrition is also a common feature of age-related diseases. Therefore, telomere length (TL) has been recognized for a long time as one of the best biomarkers of aging. Recent research findings, however, indicate that TL per se can only allow a rough estimate of aging rate and can hardly be regarded as a clinically important risk marker for age-related pathologies and mortality. Evidence is obtained that other indicators such as certain immune parameters, indices of epigenetic age, etc., could be stronger predictors of the health status and the risk of chronic disease. However, despite these issues and limitations, TL remains to be very informative marker in accessing the biological age when used along with other markers such as indices of homeostatic dysregulation, frailty index, epigenetic clock, etc. This review article is aimed at describing the current state of the art in the field and at discussing recent research findings and divergent viewpoints regarding the usefulness of leukocyte TL for estimating the human biological age.
A Novel Framework to Predict Breast Cancer Prognosis Using Immune-Associated LncRNAs
Authors: Huang Zhijian , Xiao Chen , Zhang Fushou , Zhou Zhifeng , Yu Liang , Ye Changsheng , Huang Weiwei , Li Nani
Published: January 2021

Background: Breast cancer (BC) is one of the most frequently diagnosed malignancies among females. As a huge heterogeneity of malignant tumor, it is important to seek reliable molecular biomarkers to carry out the stratification for patients with BC. We surveyed immune- associated lncRNAs that may be used as potential therapeutic targets in BC.

Methods: LncRNA expression data and clinical information of BC patients were downloaded from the TCGA database for a comprehensive analysis of candidate genes. A model consisting of immune-related lncRNAs enriched in BC cancerous tissues was established using the univariate Cox regression analysis and the iterative Lasso Cox regression analysis. The prognostic performance of this model was validated in two independent cohorts (GSE21653 and BC-KR), and compared with known prognostic biomarkers. A nomogram that integrated the immune-related lncRNA signature and clinicopathological factors was constructed to accurately assess the prognostic value of this signature. The correlation between the signature and immune cell infiltration in BC was also analyzed.

Results: The Kaplan-Meier analysis showed that the OS of Patients in the low-risk group had significantly better survival than those in the high-risk group, Clinical subgroup analysis showed that the predictive ability was independent of clinicopathological factors. Univariate/multivariate Cox regression analysis showed immune lncRNA signature is an important prognostic factor and an independent prognostic marker. In addition, GSEA and GSVA analysis as well as comprehensive analysis of immune cells showed that the signature was significantly correlated with the infiltration of immune cells.

Conclusion: We successfully constructed an immune-associated lncRNA signature that can accurately predict BC prognosis.
Dietary Indole-3-Carbinol Activates AhR in the Gut, Alters Th17-Microbe Interactions, and Exacerbates Insulitis in NOD Mice
Authors: Kahalehili Heather M. , Newman Nolan K. , Pennington Jamie M. , Kolluri Siva K. , Kerkvliet Nancy I. , Shulzhenko Natalia , Morgun Andrey , Ehrlich Allison K.
Published: January 2021

The diet represents one environmental risk factor controlling the progression of type 1 diabetes (T1D) in genetically susceptible individuals. Consequently, understanding which specific nutritional components promote or prevent the development of disease could be used to make dietary recommendations in prediabetic individuals. In the current study, we hypothesized that the immunoregulatory phytochemcial, indole-3-carbinol (I3C) which is found in cruciferous vegetables, will regulate the progression of T1D in nonobese diabetic (NOD) mice. During digestion, I3C is metabolized into ligands for the aryl hydrocarbon receptor (AhR), a transcription factor that when systemically activated prevents T1D. In NOD mice, an I3C-supplemented diet led to strong AhR activation in the small intestine but minimal systemic AhR activity. In the absence of this systemic response, the dietary intervention led to exacerbated insulitis. Consistent with the compartmentalization of AhR activation, dietary I3C did not alter T helper cell differentiation in the spleen or pancreatic draining lymph nodes. Instead, dietary I3C increased the percentage of CD4+RORγt+Foxp3- (Th17 cells) in the lamina propria, intraepithelial layer, and Peyer’s patches of the small intestine. The immune modulation in the gut was accompanied by alterations to the intestinal microbiome, with changes in bacterial communities observed within one week of I3C supplementation. A transkingdom network was generated to predict host-microbe interactions that were influenced by dietary I3C. Within the phylum Firmicutes, several genera (Intestinimonas, Ruminiclostridium 9, and unclassified Lachnospiraceae) were negatively regulated by I3C. Using AhR knockout mice, we validated that Intestinimonas is negatively regulated by AhR. I3C-mediated microbial dysbiosis was linked to increases in CD25high Th17 cells. Collectively, these data demonstrate that site of AhR activation and subsequent interactions with the host microbiome are important considerations in developing AhR-targeted interventions for T1D.