bluuebunny/crossref_metadata_2025 huggingface dataset:
Soil Formation, Subaerial Sedimentation Processes and Ancient Cultures during MIS 2 and the Deglaciation Phase MIS 1 in the Baikal–Yenisei Siberia (Russia)
Authors: Vorobieva Galina , Vashukevich Nadezhda , Berdnikova Natalia , Berdnikov Ivan , Zolotarev Dmitry , Kuklina Svetlana , Lipnina Ekaterina
Published: July 2021

The time of Sartan glaciation in the Baikal–Yenisei Siberia, is comparable with that of MIS 2 and the deglaciation phase MIS 1. Loess loams, aeolian–colluvial sands and sandy loams represent subaerial sediments. There are four subhorizons (sr1, sr2, sr3 and sr4) in the Sartan horizon (sr). Sedimentary and soil-forming processes at different stratigraphic levels are considered. Differing soil formation types of cold periods are distinguished. Soils of the interstadial type with the A-C profile are represented only in the Early Sartan section of this paper. The soils of the pleniglacial type are discussed throughout the section. Their initial profile is O-C, TJ-C and W-C. Plant detritus remnants or poor thin humus horizons are preserved in places from the upper horizons. We propose for the first time for the interphasial soil formation type of cold stages to be distinguished. This is represented in the sections by the preserved BCm, BCg, Cm and Cg horizons of 15–20 cm thick. The upper horizons are absent in most sections. According to the surviving fragments, these were organogenous (O, TJ and T) and organomineral (AO and W) horizons. The sedimentation and soil formation features are considered from the perspective reconstruction of the Sartan natural and climatic conditions. Buried Sartan soils often contain cultural layers. Soil formation shows a well-defined periodicity of natural condition stabilization, which allowed ancient populations to adapt actively to various situations. Archaeologists’ interest in fossil soils is based on the ability of soils to “record” information about the natural and climatic conditions of human habitation.
Radiofrequency Exposure Levels from Mobile Phone Base Stations in Outdoor Environments and an Underground Shopping Mall in Japan
Authors: Onishi Teruo , Ikuyo Miwa , Tobita Kazuhiro , Liu Sen , Taki Masao , Watanabe Soichi
Published: July 2021

Recent progress in wireless technologies has made human exposure to electromagnetic fields (EMFs) increasingly complex. The situation can increase public concerns related to possible health effects due to EMF exposure. Monitoring EMF exposure levels and characterizing them are indispensable for risk communications of human exposure to EMFs. From this background, a project on the acquisition, accumulation, and applications of EMF exposure monitoring data in Japan was started in 2019. One of the objectives of this project is to obtain a comprehensive picture of EMF exposure in actual daily lives. In 2019 and 2020, we measured the electric field (E-field) strength from mainly mobile phone base stations in the same areas as those in measurements conducted in 2006 and 2007 by the Ministry of Internal Affairs and Communications (MIC), Japan, and compared the data to investigate the time-course of the EMF environment. The number of measured points was 100 (10 × 10 grids) in an area of 1 km × 1 km in two urban and two suburban areas, and that in an underground shopping mall was 158. This large-scale study is the first in Japan. As a result, we found that the measured E-field strengths tended to be higher in 2019 and 2020 than those in 2006 and 2007, especially in the mall. However, the median ratios to the Japanese radio wave protection guideline values for urban areas and malls are lower than −40 dB.
Barriers and Facilitators to Promoting Resilience to HIV/AIDS: A Qualitative Study on the Lived Experiences of HIV-Positive, Racial and Ethnic Minority, Middle-Aged and Older Men Who Have Sex with Men from Ontario, Canada
Authors: Liboro Renato M. , Bell Sherry , Ranuschio Brandon , Barnes Lianne , Despres Jenna , Sedere Aruna , Puno Trinity , Shuper Paul A.
Published: July 2021

Evidence-based research has highlighted the need for exploring factors that support the mental health of men who have sex with men living with HIV/AIDS (MSMLWH), and environmental influences that promote their resilience to HIV/AIDS. This exploratory study utilized a community-based participatory research approach to investigate barriers and facilitators to promoting resilience to HIV/AIDS, specifically among racial and ethnic minority, middle-aged and older MSMLWH, a population that continues to be significantly impacted by HIV/AIDS today. This collaborative, qualitative study recruited participants who identified as racial or ethnic minority MSMLWH, were aged 40 or older, and resided in Ontario, Canada. Participants (n = 24) discussed in their interviews barriers and facilitators to promoting resilience to HIV/AIDS, which they recognized from their lived experiences. Utilizing thematic analysis, themes related to barriers and facilitators to promoting resilience to HIV/AIDS were identified. Themes related to identified barriers included: (1) language proficiency, (2) racism, (3) pernicious norms in North American gay culture, and (4) HIV stigma. Themes related to identified facilitators included: (1) compartmentalization, (2) perseverance, and (3) community-based health and social services. This article discusses the implications of the study’s findings, particularly on how they may influence the development of future services for racial and ethnic minority, middle-aged and older MSMLWH.
The Impact of Income Inequality on Subjective Environmental Pollution: Individual Evidence from China
Authors: Li Baoxi , Xiao De
Published: July 2021

Numerous studies have investigated the relationship between income inequality and objective environmental pollution, but few focus on the nexus between income inequality and subjective environmental pollution (SEP). Using micro data from the Chinese General Society Survey (CGSS) in 2013 and official statistical data at the provincial level, this paper tests the impact of individual-level income inequality on subjective environmental pollution in China. The results show that individual-level income inequality has an inverted U-shape relationship with subjective environmental pollution, which indicates that increasing the income inequality at the individual level will first rise and then reduce their perceived subjective environmental pollution after reaching the peak. For about 84% of respondents, their subjective environmental pollution decreases with the increase of individual-level income inequality. Furthermore, the heterogeneity analyses show that the income inequality of urban residents and of the locals have an inverted U-shape effect on SEP, and the SEP of females and of individuals with positive environmental attitude are more sensitive to the effect of income inequality. Additionally, we find that subjective well-being plays a mediating role in the relation between income inequality and SEP. Individual income inequality decreases their self-reported well-being, and an increase in well-being has a negative effect on their subjectively perceived environmental quality. We also find non-television media exposures, such as newspaper, magazine, broadcasting, Internet, and mobile custom messages, will amplify the effect of individual-level income inequality on subjective environmental pollution.
COVID-19 Misinformation Online and Health Literacy: A Brief Overview
Authors: Bin Naeem Salman , Kamel Boulos Maged N.
Published: July 2021

Low digital health literacy affects large percentages of populations around the world and is a direct contributor to the spread of COVID-19-related online misinformation (together with bots). The ease and ‘viral’ nature of social media sharing further complicate the situation. This paper provides a quick overview of the magnitude of the problem of COVID-19 misinformation on social media, its devastating effects, and its intricate relation to digital health literacy. The main strategies, methods and services that can be used to detect and prevent the spread of COVID-19 misinformation, including machine learning-based approaches, health literacy guidelines, checklists, mythbusters and fact-checkers, are then briefly reviewed. Given the complexity of the COVID-19 infodemic, it is very unlikely that any of these approaches or tools will be fully effective alone in stopping the spread of COVID-19 misinformation. Instead, a mixed, synergistic approach, combining the best of these strategies, methods, and services together, is highly recommended in tackling online health misinformation, and mitigating its negative effects in COVID-19 and future pandemics. Furthermore, techniques and tools should ideally focus on evaluating both the message (information content) and the messenger (information author/source) and not just rely on assessing the latter as a quick and easy proxy for the trustworthiness and truthfulness of the former. Surveying and improving population digital health literacy levels are also essential for future infodemic preparedness.
Effect of Exposure Angulation on the Occupational Radiation Exposure during Cardiac Angiography: Simulation Study
Authors: Roh Younghoon , Kim Jungsu , Park Hyemin , Kim Jungmin , Ryu Dongryeol , Chun Kwangjin , Seo Jeonghun , Lee Bongki , Cho Byungryul , Yoon Yongsu
Published: July 2021

Cardiac angiography to visualize the cardiac coronary artery for lesions causes a lot of radiation exposure dose to the interventional cardiologist. We evaluated the occupational radiation exposure to the interventional cardiologist based on changes to the angle of the X-ray tube used in cardiac angiography and calculated the conversion factor for effective dose in this study. To evaluate the occupational radiation exposure resulting from scattered radiation to interventional cardiologists, organ doses for eyeball, thyroid, and heart were calculated using Monte Carlo simulation with korean typical man(KTMAN) phantom at the left anterior oblique (LAO)30/cranial (CRAN)30, CRAN40, right anterior oblique (RAO)30/CRAN30, RAO30/caudal(CAUD)20, CAUD39, LAO40/CAUD35, and LAO40 positions in the femoral and the radial artery puncture. In this study, analysis of the different angles showed the highest radiation exposure on LAO30/CRAN30 and CRAN40 position, which were 150.65% and 135.3%, respectively, compared to AP angles. Therefore, to reduce occupational dose for interventional cardiologists, it is recommended that radiation protection, such as using radiation shield and personal protective equipment (PPE), be used at LAO30/CRAN30 and CRAN40 angulation, and the conversion factor for calculating the organ dose received by the interventional cardiologists based on patient dose can be applied for improved occupational dose management.
Association of Addictive Substance Use with Polyvictimization and Acceptance of Violence in Adolescent Couples
Authors: Gordillo Isabel Cuadrado , Parra Guadalupe Martín-Mora , Antelo Inmaculada Fernández
Published: July 2021

Theoretical framework: The objectives of this study were to analyse the possible influence that some variables such as substance use (alcohol and marijuana) might have on relevant aspects related to violence in adolescent dating (victimization, frequency of violence and acceptance of violence). Methods: The sample included 2577 adolescents between the ages of 14 and 18. The instruments used were two questionnaires. The first identified and analysed the types and frequency of violence experienced by the victims, and their acceptance of violence. The second analysed the use of alcohol and marijuana in adolescents. Results: The results indicate that victims frequently take on the role of polyvictims, suffering aggression in up to more than five different forms at the same time. Furthermore, it was found that this phenomenon is precipitated by substance use, the frequency of abuse and the acceptance of violence in a cycle of mutual interaction.
Fatty Acid Synthesis in Glial Cells of the CNS
Authors: Garcia Corrales Aida V. , Haidar Mansour , Bogie Jeroen F. J. , Hendriks Jerome J. A.
Published: July 2021

Fatty acids (FAs) are of crucial importance for brain homeostasis and neural function. Glia cells support the high demand of FAs that the central nervous system (CNS) needs for its proper functioning. Additionally, FAs can modulate inflammation and direct CNS repair, thereby contributing to brain pathologies such Alzheimer’s disease or multiple sclerosis. Intervention strategies targeting FA synthesis in glia represents a potential therapeutic opportunity for several CNS diseases.
Leukemia-Induced Cellular Senescence and Stemness Alterations in Mesenchymal Stem Cells Are Reversible upon Withdrawal of B-Cell Acute Lymphoblastic Leukemia Cells
Authors: Vanegas Natalia-Del Pilar , Ruiz-Aparicio Paola Fernanda , Uribe Gloria Inés , Linares-Ballesteros Adriana , Vernot Jean-Paul
Published: July 2021

Leukemic cell growth in the bone marrow (BM) induces a very stressful condition. Mesenchymal stem cells (MSC), a key component of this BM niche, are affected in several ways with unfavorable consequences on hematopoietic stem cells favoring leukemic cells. These alterations in MSC during B-cell acute lymphoblastic leukemia (B-ALL) have not been fully studied. In this work, we have compared the modifications that occur in an in vitro leukemic niche (LN) with those observed in MSC isolated from B-ALL patients. MSC in this LN niche showed features of a senescence process, i.e., altered morphology, increased senescence-associated β-Galactosidase (SA-βGAL) activity, and upregulation of p53 and p21 (without p16 expression), cell-cycle arrest, reduced clonogenicity, and some moderated changes in stemness properties. Importantly, almost all of these features were found in MSC isolated from B-ALL patients. These alterations rendered B-ALL cells susceptible to the chemotherapeutic agent dexamethasone. The senescent process seems to be transient since when leukemic cells are removed, normal MSC morphology is re-established, SA-βGAL expression is diminished, and MSC are capable of re-entering cell cycle. In addition, few cells showed low γH2AX phosphorylation that was reduced to basal levels upon cultivation. The reversibility of the senescent process in MSC must impinge important biological and clinical significance depending on cell interactions in the bone marrow at different stages of disease progression in B-ALL.
Cisplatin Plus Cetuximab Inhibits Cisplatin-Resistant Human Oral Squamous Cell Carcinoma Cell Migration and Proliferation but Does Not Enhance Apoptosis
Authors: Choi Hyeong Sim , Kim Young-Kyun , Yun Pil-Young
Published: July 2021

Cisplatin is among the most widely used anticancer drugs used in the treatment of several malignancies, including oral cancer. However, cisplatin treatment often promotes chemical resistance, subsequently causing treatment failure. Several studies have shown that epidermal growth factor receptors (EGFRs) play a variety of roles in cancer progression and overcoming cisplatin resistance. Therefore, this study focused on EGFR inhibitors used in novel targeted therapies as a method to overcome this resistance. We herein aimed to determine whether the combined effects of cisplatin and cetuximab could enhance cisplatin sensitivity by inhibiting the epithelial-to-mesenchymal transition (EMT) process in cisplatin-resistant cells. In vitro analyses of three cisplatin-resistant oral squamous cell carcinoma cells, which included cell proliferation assay, combination index calculation, cell cytotoxicity assay, live/dead cell count assay, Western blot assay, propidium iodide staining assay, scratch assay, and qRT-PCR assay were then conducted. Our results showed that a cisplatin/cetuximab combination treatment inhibited cell proliferation, cell motility, and N-cadherin protein expression but induced E-cadherin and claudin-1 protein expression. Although the combination of cisplatin and cetuximab did not induce apoptosis of cisplatin-resistant cells, it may be useful in treating oral cancer patients with cisplatin resistance given that it controls cell motility and EMT-related proteins.
Stereoselective Synthesis of Novel Sphingoid Bases Utilized for Exploring the Secrets of Sphinx
Authors: Saied Essa M. , Arenz Christoph
Published: July 2021

Sphingolipids are ubiquitous in eukaryotic plasma membranes and play major roles in human and animal physiology and disease. This class of lipids is usually defined as being derivatives of sphingosine, a long-chain 1,3-dihydroxy-2-amino alcohol. Various pathological conditions such as diabetes or neuropathy have been associated with changes in the sphingolipidome and an increased biosynthesis of structurally altered non-canonical sphingolipid derivatives. These unusual or non-canonical sphingolipids hold great promise as potential diagnostic markers. However, due to their low concentrations and the unavailability of suitable standards, the research to explore the secret of this class of ‘Sphinx’ lipids is ultimately hampered. Therefore, the development of efficient and facile syntheses of standard compounds is a key endeavor. Here, we present various chemical approaches for stereoselective synthesis and in-depth chemical characterization of a set of novel sphingoid bases which were recently utilized as valuable tools to explore the metabolism and biophysical properties of sphingolipids, but also to develop efficient analytical methods for their detection and quantification.
Characterization of the Heat-Stable Proteome during Seed Germination in Arabidopsis with Special Focus on LEA Proteins
Authors: Ginsawaeng Orarat , Gorka Michal , Erban Alexander , Heise Carolin , Brueckner Franziska , Hoefgen Rainer , Kopka Joachim , Skirycz Aleksandra , Hincha Dirk K. , Zuther Ellen
Published: July 2021

During seed germination, desiccation tolerance is lost in the radicle with progressing radicle protrusion and seedling establishment. This process is accompanied by comprehensive changes in the metabolome and proteome. Germination of Arabidopsis seeds was investigated over 72 h with special focus on the heat-stable proteome including late embryogenesis abundant (LEA) proteins together with changes in primary metabolites. Six metabolites in dry seeds known to be important for seed longevity decreased during germination and seedling establishment, while all other metabolites increased simultaneously with activation of growth and development. Thermo-stable proteins were associated with a multitude of biological processes. In the heat-stable proteome, a relatively similar proportion of fully ordered and fully intrinsically disordered proteins (IDP) was discovered. Highly disordered proteins were found to be associated with functional categories development, protein, RNA and stress. As expected, the majority of LEA proteins decreased during germination and seedling establishment. However, four germination-specific dehydrins were identified, not present in dry seeds. A network analysis of proteins, metabolites and amino acids generated during the course of germination revealed a highly connected LEA protein network.
Heme Burden and Ensuing Mechanisms That Protect the Kidney: Insights from Bench and Bedside
Authors: Balla József , Zarjou Abolfazl
Published: July 2021

With iron at its core, the tetrapyrrole heme ring is a cardinal prosthetic group made up of many proteins that participate in a wide array of cellular functions and metabolism. Once released, due to its pro-oxidant properties, free heme in sufficient amounts can result in injurious effects to the kidney and other organs. Heme oxygenase-1 (HO-1) has evolved to promptly attend to such injurious potential by facilitating degradation of heme into equimolar amounts of carbon monoxide, iron, and biliverdin. HO-1 induction is a beneficial response to tissue injury in diverse animal models of diseases, including those that affect the kidney. These protective attributes are mainly due to: (i) prompt degradation of heme leading to restraining potential hazardous effects of free heme, and (ii) generation of byproducts that along with induction of ferritin have proven beneficial in a number of pathological conditions. This review will focus on describing clinical aspects of some of the conditions with the unifying end-result of increased heme burden and will discuss the molecular mechanisms that ensue to protect the kidneys.
Ncx3-Induced Mitochondrial Dysfunction in Midbrain Leads to Neuroinflammation in Striatum of A53t-α-Synuclein Transgenic Old Mice
Authors: Di Martino Rossana , Sisalli Maria , Sirabella Rossana , Della Notte Salvatore , Borzacchiello Domenica , Feliciello Antonio , Annunziato Lucio , Scorziello Antonella
Published: July 2021

The exact mechanism underlying selective dopaminergic neurodegeneration is not completely understood. The complex interplay among toxic alpha-synuclein aggregates, oxidative stress, altered intracellular Ca2+-homeostasis, mitochondrial dysfunction and disruption of mitochondrial integrity is considered among the pathogenic mechanisms leading to dopaminergic neuronal loss. We herein investigated the molecular mechanisms leading to mitochondrial dysfunction and its relationship with activation of the neuroinflammatory process occurring in Parkinson’s disease. To address these issues, experiments were performed in vitro and in vivo in mice carrying the human mutation of α-synuclein A53T under the prion murine promoter. In these models, the expression and activity of NCX isoforms, a family of important transporters regulating ionic homeostasis in mammalian cells working in a bidirectional way, were evaluated in neurons and glial cells. Mitochondrial function was monitored with confocal microscopy and fluorescent dyes to measure mitochondrial calcium content and mitochondrial membrane potential. Parallel experiments were performed in 4 and 16-month-old A53T-α-synuclein Tg mice to correlate the functional data obtained in vitro with mitochondrial dysfunction and neuroinflammation through biochemical analysis. The results obtained demonstrated: 1. in A53T mice mitochondrial dysfunction occurs early in midbrain and later in striatum; 2. mitochondrial dysfunction occurring in the midbrain is mediated by the impairment of NCX3 protein expression in neurons and astrocytes; 3. mitochondrial dysfunction occurring early in midbrain triggers neuroinflammation later into the striatum, thus contributing to PD progression during mice aging.
The Development of Molecular Biology of Osteoporosis
Authors: Gao Yongguang , Patil Suryaji , Jia Jingxian
Published: July 2021

Osteoporosis is one of the major bone disorders that affects both women and men, and causes bone deterioration and bone strength. Bone remodeling maintains bone mass and mineral homeostasis through the balanced action of osteoblasts and osteoclasts, which are responsible for bone formation and bone resorption, respectively. The imbalance in bone remodeling is known to be the main cause of osteoporosis. The imbalance can be the result of the action of various molecules produced by one bone cell that acts on other bone cells and influence cell activity. The understanding of the effect of these molecules on bone can help identify new targets and therapeutics to prevent and treat bone disorders. In this article, we have focused on molecules that are produced by osteoblasts, osteocytes, and osteoclasts and their mechanism of action on these cells. We have also summarized the different pharmacological osteoporosis treatments that target different molecular aspects of these bone cells to minimize osteoporosis.
AMD-Like Substrate Causes Epithelial Mesenchymal Transition in iPSC-Derived Retinal Pigment Epithelial Cells Wild Type but Not C3-Knockout
Authors: Chinchilla Blanca , Fernandez-Godino Rosario
Published: July 2021

The Bruch’s membrane (BrM) is a five-layered extracellular matrix (ECM) that supports the retinal pigment epithelium (RPE). Normal age-related changes in the BrM may lead to RPE cell damage and ultimately to the onset and progression of age-related macular degeneration (AMD), which is the most common cause of visual loss among the elderly. A role for the complement system in AMD pathology has been established, but the disease mechanisms are poorly understood, which hampers the design of efficient therapies to treat millions of patients. In an effort to identify the mechanisms that lead from normal aging to pathology, we have developed a cell-based model using complement deficient human induced pluripotent stem cell (iPSC)-derived RPE cells cultured on an AMD-like ECM that mimics BrM. The data present evidence that changes in the ECM result in loss of differentiation and promote epithelial mesenchymal transition (EMT) of healthy RPE cells. This pathological process is mediated by complement activation and involves the formation of a randomly oriented collagen meshwork that drives the dedifferentiation of the RPE monolayer. Genetic ablation of complement component 3 has a protective effect against EMT but does not prevent the abnormal deposition of collagens. These findings offer new insights into the sequence of events that initiate AMD and may guide the design of efficient therapies to treat this disease with unmet medical needs.
The Rice Cation/H+ Exchanger Family Involved in Cd Tolerance and Transport
Authors: Zou Wenli , Chen Jingguang , Meng Lijun , Chen Dandan , He Haohua , Ye Guoyou
Published: July 2021

Cadmium (Cd), a heavy metal toxic to humans, easily accumulates in rice grains. Rice with unacceptable Cd content has become a serious food safety problem in many rice production regions due to contaminations by industrialization and inappropriate waste management. The development of rice varieties with low grain Cd content is seen as an economic and long-term solution of this problem. The cation/H+ exchanger (CAX) family has been shown to play important roles in Cd uptake, transport and accumulation in plants. Here, we report the characterization of the rice CAX family. The six rice CAX genes all have homologous genes in Arabidopsis thaliana. Phylogenetic analysis identified two subfamilies with three rice and three Arabidopsis thaliana genes in both of them. All rice CAX genes have trans-member structures. OsCAX1a and OsCAX1c were localized in the vacuolar while OsCAX4 were localized in the plasma membrane in rice cell. The consequences of qRT-PCR analysis showed that all the six genes strongly expressed in the leaves under the different Cd treatments. Their expression in roots increased in a Cd dose-dependent manner. GUS staining assay showed that all the six rice CAX genes strongly expressed in roots, whereas OsCAX1c and OsCAX4 also strongly expressed in rice leaves. The yeast (Saccharomyces cerevisiae) cells expressing OsCAX1a, OsCAX1c and OsCAX4 grew better than those expressing the vector control on SD-Gal medium containing CdCl2. OsCAX1a and OsCAX1c enhanced while OsCAX4 reduced Cd accumulation in yeast. No auto-inhibition was found for all the rice CAX genes. Therefore, OsCAX1a, OsCAX1c and OsCAX4 are likely to involve in Cd uptake and translocation in rice, which need to be further validated.
Nuclear Transfer Arrest Embryos Show Massive Dysregulation of Genes Involved in Transcription Pathways
Authors: Long Chunshen , Li Hanshuang , Li Xinru , Yang Wuritu , Zuo Yongchun
Published: July 2021

Somatic cell nuclear transfer (SCNT) technology can reprogram terminally differentiated cell nuclei into a totipotent state. However, the underlying molecular barriers of SCNT embryo development remain incompletely elucidated. Here, we observed that transcription-related pathways were incompletely activated in nuclear transfer arrest (NTA) embryos compared to normal SCNT embryos and in vivo fertilized (WT) embryos, which hinders the development of SCNT embryos. We further revealed the transcription pathway associated gene regulatory networks (GRNs) and found the aberrant transcription pathways can lead to the massive dysregulation of genes in NTA embryos. The predicted target genes of transcription pathways contain a series of crucial factors in WT embryos, which play an important role in catabolic process, pluripotency regulation, epigenetic modification and signal transduction. In NTA embryos, however, these genes were varying degrees of inhibition and show a defect in synergy. Overall, our research found that the incomplete activation of transcription pathways is another potential molecular barrier for SCNT embryos besides the incomplete reprogramming of epigenetic modifications, broadening the understanding of molecular mechanism of SCNT embryonic development.
Near-UV Light Induced ROS Production Initiates Spatial Ca2+ Spiking to Fire NFATc3 Translocation
Authors: Oflaz Furkan E. , Koshenov Zhanat , Hirtl Martin , Rost Rene , Bachkoenig Olaf A. , Gottschalk Benjamin , Madreiter-Sokolowski Corina T. , Malli Roland , Graier Wolfgang F.
Published: July 2021

Ca2+-dependent gene regulation controls several functions to determine the fate of the cells. Proteins of the nuclear factor of activated T-cells (NFAT) family are Ca2+ sensitive transcription factors that control the cell growth, proliferation and insulin secretion in β-cells. Translocation of NFAT proteins to the nucleus occurs in a sequence of events that starts with activating calmodulin-dependent phosphatase calcineurin in a Ca2+-dependent manner, which dephosphorylates the NFAT proteins and leads to their translocation to the nucleus. Here, we examined the role of IP3-generating agonists and near-UV light in the induction of NFATc3 migration to the nucleus in the pancreatic β-cell line INS-1. Our results show that IP3 generation yields cytosolic Ca2+ rise and NFATc3 translocation. Moreover, near-UV light exposure generates reactive oxygen species (ROS), resulting in cytosolic Ca2+ spiking via the L-type Ca2+ channel and triggers NFATc3 translocation to the nucleus. Using the mitochondria as a Ca2+ buffering tool, we showed that ROS-induced cytosolic Ca2+ spiking, not the ROS themselves, was the triggering mechanism of nuclear import of NFATc3. Collectively, this study reveals the mechanism of near-UV light induced NFATc3 migration.
Regulatory Network Analysis in Estradiol-Treated Human Endothelial Cells
Authors: Pérez-Cremades Daniel , Paes Ana B. , Vidal-Gómez Xavier , Mompeón Ana , Hermenegildo Carlos , Novella Susana
Published: July 2021

Background/Aims: Estrogen has been reported to have beneficial effects on vascular biology through direct actions on endothelium. Together with transcription factors, miRNAs are the major drivers of gene expression and signaling networks. The objective of this study was to identify a comprehensive regulatory network (miRNA–transcription factor–downstream genes) that controls the transcriptomic changes observed in endothelial cells exposed to estradiol. Methods: miRNA/mRNA interactions were assembled using our previous microarray data of human umbilical vein endothelial cells (HUVEC) treated with 17β-estradiol (E2) (1 nmol/L, 24 h). miRNA–mRNA pairings and their associated canonical pathways were determined using Ingenuity Pathway Analysis software. Transcription factors were identified among the miRNA-regulated genes. Transcription factor downstream target genes were predicted by consensus transcription factor binding sites in the promoter region of E2-regulated genes by using JASPAR and TRANSFAC tools in Enrichr software. Results: miRNA–target pairings were filtered by using differentially expressed miRNAs and mRNAs characterized by a regulatory relationship according to miRNA target prediction databases. The analysis identified 588 miRNA–target interactions between 102 miRNAs and 588 targets. Specifically, 63 upregulated miRNAs interacted with 295 downregulated targets, while 39 downregulated miRNAs were paired with 293 upregulated mRNA targets. Functional characterization of miRNA/mRNA association analysis highlighted hypoxia signaling, integrin, ephrin receptor signaling and regulation of actin-based motility by Rho among the canonical pathways regulated by E2 in HUVEC. Transcription factors and downstream genes analysis revealed eight networks, including those mediated by JUN and REPIN1, which are associated with cadherin binding and cell adhesion molecule binding pathways. Conclusion: This study identifies regulatory networks obtained by integrative microarray analysis and provides additional insights into the way estradiol could regulate endothelial function in human endothelial cells.
Emerging hiPSC Models for Drug Discovery in Neurodegenerative Diseases
Authors: Trudler Dorit , Ghatak Swagata , Lipton Stuart A.
Published: July 2021

Neurodegenerative diseases affect millions of people worldwide and are characterized by the chronic and progressive deterioration of neural function. Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), represent a huge social and economic burden due to increasing prevalence in our aging society, severity of symptoms, and lack of effective disease-modifying therapies. This lack of effective treatments is partly due to a lack of reliable models. Modeling neurodegenerative diseases is difficult because of poor access to human samples (restricted in general to postmortem tissue) and limited knowledge of disease mechanisms in a human context. Animal models play an instrumental role in understanding these diseases but fail to comprehensively represent the full extent of disease due to critical differences between humans and other mammals. The advent of human-induced pluripotent stem cell (hiPSC) technology presents an advantageous system that complements animal models of neurodegenerative diseases. Coupled with advances in gene-editing technologies, hiPSC-derived neural cells from patients and healthy donors now allow disease modeling using human samples that can be used for drug discovery.
Aerobic and Anaerobic Bacterial and Fungal Degradation of Pyrene: Mechanism Pathway Including Biochemical Reaction and Catabolic Genes
Authors: Elyamine Ali Mohamed , Kan Jie , Meng Shanshan , Tao Peng , Wang Hui , Hu Zhong
Published: July 2021

Microbial biodegradation is one of the acceptable technologies to remediate and control the pollution by polycyclic aromatic hydrocarbon (PAH). Several bacteria, fungi, and cyanobacteria strains have been isolated and used for bioremediation purpose. This review paper is intended to provide key information on the various steps and actors involved in the bacterial and fungal aerobic and anaerobic degradation of pyrene, a high molecular weight PAH, including catabolic genes and enzymes, in order to expand our understanding on pyrene degradation. The aerobic degradation pathway by Mycobacterium vanbaalenii PRY-1 and Mycobactetrium sp. KMS and the anaerobic one, by the facultative bacteria anaerobe Pseudomonas sp. JP1 and Klebsiella sp. LZ6 are reviewed and presented, to describe the complete and integrated degradation mechanism pathway of pyrene. The different microbial strains with the ability to degrade pyrene are listed, and the degradation of pyrene by consortium is also discussed. The future studies on the anaerobic degradation of pyrene would be a great initiative to understand and address the degradation mechanism pathway, since, although some strains are identified to degrade pyrene in reduced or total absence of oxygen, the degradation pathway of more than 90% remains unclear and incomplete. Additionally, the present review recommends the use of the combination of various strains of anaerobic fungi and a fungi consortium and anaerobic bacteria to achieve maximum efficiency of the pyrene biodegradation mechanism.
Identification of an IL-22-Dependent Gene Signature as a Pharmacodynamic Biomarker
Authors: Rae Julie , Hackney Jason , Huang Kevin , Keir Mary , Herman Ann
Published: July 2021

Interleukin-22 (IL-22) plays a role in epithelial barrier function and repair, and may provide benefits in conditions like inflammatory bowel disease. However, limited human data are available to assess the clinical effect of IL-22 administration. This study used a human intestinal cell line to identify an IL-22-dependent gene signature that could serve as a pharmacodynamic biomarker for IL-22 therapy. The response to IL-22Fc (UTTR1147A, an Fc-stabilized version of IL-22) was assessed in HT-29 cells by microarray, and the selected responsive genes were confirmed by qPCR. HT-29 cells demonstrated dose-dependent increases in STAT3 phosphorylation and multiple gene expression changes in response to UTTR1147A. Genes were selected that were upregulated by UTTR1147A, but to a lesser extent by IL-6, which also signals via STAT3. IL-1R1 was highly upregulated by UTTR1147A, and differential gene expression patterns were observed in response to IL-22Fc in the presence of IL-1β. An IL-22-dependent gene signature was identified that could serve as a pharmacodynamic biomarker in intestinal biopsies to support the clinical development of an IL-22 therapeutic. The differential gene expression pattern in the presence of IL-1β suggests that an inflammatory cytokine milieu in the disease setting could influence the clinical responses to IL-22.
Hormonal Regulation and Crosstalk of Auxin/Cytokinin Signaling Pathways in Potatoes In Vitro and in Relation to Vegetation or Tuberization Stages
Authors: Kolachevskaya Oksana O. , Myakushina Yulia A. , Getman Irina A. , Lomin Sergey N. , Deyneko Igor V. , Deigraf Svetlana V. , Romanov Georgy A.
Published: July 2021

Auxins and cytokinins create versatile regulatory network controlling virtually all aspects of plant growth and development. These hormonal systems act in close contact, synergistically or antagonistically, determining plant phenotype, resistance and productivity. However, the current knowledge about molecular interactions of these systems is still scarce. Our study with potato plants aimed at deciphering potential interactions between auxin and cytokinin signaling pathways at the level of respective gene expression. Potato plants grown on sterile medium with 1.5% (vegetation) or 5% (tuberization) sucrose were treated for 1 h with auxin or cytokinin. Effects of these two hormones on expression profiles of genes belonging to main signaling pathways of auxin and cytokinin were quantified by RT-qPCR. As a result, several signaling genes were found to respond to auxin and/or cytokinin by up- or down-regulation. The observed effects were largely organ-specific and depended on sucrose content. Auxin strongly reduced cytokinin perception apparatus while reciprocal cytokinin effect was ambiguous and sucrose-dependent. In many cases, functional clustering of genes of the same family was observed. Promoters in some clusters are enriched with canonic hormone-response cis-elements supporting their direct sensitivity to hormones. Collectively, our data shed new light on the crosstalk between auxin- and cytokinin signaling pathways.
Innovative Biomaterials for the Treatment of Bone Cancer
Authors: Ambrosio Luca , Raucci Maria Grazia , Vadalà Gianluca , Ambrosio Luigi , Papalia Rocco , Denaro Vincenzo
Published: July 2021

Bone cancer is a demanding challenge for contemporary medicine due to its high frequency of presentation and significant heterogeneity of malignant lesions developing within the bone. To date, available treatments are rarely curative and are primarily aimed at prolonging patients’ survival and ameliorating their quality of life. Furthermore, both pharmacological and surgical therapies are aggravated by a consistent burden of adverse events and subsequent disability due to the loss of healthy bone structural and functional properties. Therefore, great research efforts are being made to develop innovative biomaterials able to selectively inhibit bone cancer progression while reducing the loss of bone structural properties secondary to local tissue invasion. In this review, we describe the state of the art of innovative biomaterials for the treatment of bone cancer. Along with physiological bone remodeling, the development of bone metastasis and osteosarcoma will be depicted. Subsequently, recent advances on nanocarrier-based drug delivery systems, as well as the application of novel, multifunctional biomaterials for the treatment of bone cancer will be discussed. Eventually, actual limitations and promising future perspectives regarding the employment of such approaches in the clinical scenario will be debated.
CYP2E1 in Alcoholic and Non-Alcoholic Liver Injury. Roles of ROS, Reactive Intermediates and Lipid Overload
Authors: Harjumäki Riina , Pridgeon Chris S. , Ingelman-Sundberg Magnus
Published: July 2021

CYP2E1 is one of the fifty-seven cytochrome P450 genes in the human genome and is highly conserved. CYP2E1 is a unique P450 enzyme because its heme iron is constitutively in the high spin state, allowing direct reduction of, e.g., dioxygen, causing the formation of a variety of reactive oxygen species and reduction of xenobiotics to toxic products. The CYP2E1 enzyme has been the focus of scientific interest due to (i) its important endogenous function in liver homeostasis, (ii) its ability to activate procarcinogens and to convert certain drugs, e.g., paracetamol and anesthetics, to cytotoxic end products, (iii) its unique ability to effectively reduce dioxygen to radical species causing liver injury, (iv) its capability to reduce compounds, often generating radical intermediates of direct toxic or indirect immunotoxic properties and (v) its contribution to the development of alcoholic liver disease, steatosis and NASH. In this overview, we present the discovery of the enzyme and studies in humans, 3D liver systems and genetically modified mice to disclose its function and clinical relevance. Induction of the CYP2E1 enzyme either by alcohol or high-fat diet leads to increased severity of liver pathology and likelihood to develop ALD and NASH, with subsequent influence on the occurrence of hepatocellular cancer. Thus, fat-dependent induction of the enzyme might provide a link between steatosis and fibrosis in the liver. We conclude that CYP2E1 has many important physiological functions and is a key enzyme for hepatic carcinogenesis, drug toxicity and liver disease.
Immunohistochemical Characteristics of the Human Carotid Body in the Antenatal and Postnatal Periods of Development
Authors: Otlyga Dmitry , Tsvetkova Ekaterina , Junemann Olga , Saveliev Sergey
Published: July 2021

The evolutionary and ontogenetic development of the carotid body is still understudied. Research aimed at studying the comparative morphology of the organ at different periods in the individual development of various animal species should play a crucial role in understanding the physiology of the carotid body. However, despite more than two centuries of study, the human carotid body remains poorly understood. There are many knowledge gaps in particular related to the antenatal development of this structure. The aim of our work is to study the morphological and immunohistochemical characteristics of the human carotid body in the antenatal and postnatal periods of development. We investigated the human carotid bodies from 1 embryo, 20 fetuses and 13 adults of different ages using samples obtained at autopsy. Immunohistochemistry revealed expression of βIII-tubulin and tyrosine hydroxylase in the type I cells and nerve fibers at all periods of ontogenesis; synaptophysin and PGP9.5 in the type I cells in some of the antenatal cases and all of the postnatal cases; 200 kDa neurofilaments in nerve fibers in some of the antenatal cases and all of the postnatal cases; and GFAP and S100 in the type II cells and Schwann cells in some of the antenatal cases and all of the postnatal cases. A high level of tyrosine hydroxylase in the type I cells was a distinctive feature of the antenatal carotid bodies. On the contrary, in the type I cells of adults, the expression of tyrosine hydroxylase was significantly lower. Our data suggest that the human carotid body may perform an endocrine function in the antenatal period, while in the postnatal period of development, it loses this function and becomes a chemosensory organ.
Deferoxamine Reduces Inflammation and Osteoclastogenesis in Avulsed Teeth
Authors: Lee Ko Eun , Mo Seunghan , Lee Hyo-Seol , Jeon Mijeong , Song Je Seon , Choi Hyung-Jun , Cho Hyunsoo , Kang Chung-Min
Published: July 2021

Replacement and inflammatory resorption are serious complications associated with the delayed replantation of avulsed teeth. In this study, we aimed to assess whether deferoxamine (DFO) can suppress inflammation and osteoclastogenesis in vitro and attenuate inflammation and bone resorption in a replanted rat tooth model. Cell viability and inflammation were evaluated in RAW264.7 cells. Osteoclastogenesis was confirmed by tartrate-resistant acid phosphatase staining, reactive oxygen species (ROS) measurement, and quantitative reverse transcriptase–polymerase chain reaction in teeth exposed to different concentrations of DFO. In vivo, molars of 31 six-week-old male Sprague–Dawley rats were extracted and stored in saline (n = 10) or DFO solution (n = 21) before replantation. Micro-computed tomography (micro-CT) imaging and histological analysis were performed to evaluate inflammation and root and alveolar bone resorption. DFO downregulated the genes related to inflammation and osteoclastogenesis. DFO also reduced ROS production and regulated specific pathways. Furthermore, the results of the micro-CT and histological analyses provided evidence of the decrease in inflammation and hard tissue resorption in the DFO group. Overall, these results suggest that DFO reduces inflammation and osteoclastogenesis in a tooth replantation model, and thus, it has to be further investigated as a root surface treatment option for an avulsed tooth.
Generation of Hepatobiliary Cell Lineages from Human Induced Pluripotent Stem Cells: Applications in Disease Modeling and Drug Screening
Authors: Pasqua Mattia , Di Gesù Roberto , Chinnici Cinzia Maria , Conaldi Pier Giulio , Francipane Maria Giovanna
Published: July 2021

The possibility to reproduce key tissue functions in vitro from induced pluripotent stem cells (iPSCs) is offering an incredible opportunity to gain better insight into biological mechanisms underlying development and disease, and a tool for the rapid screening of drug candidates. This review attempts to summarize recent strategies for specification of iPSCs towards hepatobiliary lineages —hepatocytes and cholangiocytes—and their use as platforms for disease modeling and drug testing. The application of different tissue-engineering methods to promote accurate and reliable readouts is discussed. Space is given to open questions, including to what extent these novel systems can be informative. Potential pathways for improvement are finally suggested.
Methods of Attenuating Ischemia-Reperfusion Injury in Liver Transplantation for Hepatocellular Carcinoma
Authors: Masior Łukasz , Grąt Michał
Published: July 2021

Hepatocellular carcinoma (HCC) is one of the most frequent indications for liver transplantation. However, the transplantation is ultimately associated with the occurrence of ischemia-reperfusion injury (IRI). It affects not only the function of the graft but also significantly worsens the oncological results. Various methods have been used so far to manage IRI. These include the non-invasive approach (pharmacotherapy) and more advanced options encompassing various types of liver conditioning and machine perfusion. Strategies aimed at shortening ischemic times and better organ allocation pathways are still under development as well. This article presents the mechanisms responsible for IRI, its impact on treatment outcomes, and strategies to mitigate it. An extensive review of the relevant literature using MEDLINE (PubMed) and Scopus databases until September 2020 was conducted. Only full-text articles written in English were included. The following search terms were used: “ischemia reperfusion injury”, “liver transplantation”, “hepatocellular carcinoma”, “preconditioning”, “machine perfusion”.