Publisher: MDPI   (Total: 233 journals)

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Showing 1 - 200 of 233 Journals sorted alphabetically
Acoustics     Open Access   (Followers: 4)
Actuators     Open Access   (Followers: 4)
Administrative Sciences     Open Access   (Followers: 6)
Aerospace     Open Access   (Followers: 60, SJR: 0.305, CiteScore: 1)
Agriculture     Open Access   (Followers: 9, SJR: 0.33, CiteScore: 2)
AgriEngineering     Open Access   (Followers: 1)
Agronomy     Open Access   (Followers: 14, SJR: 0.695, CiteScore: 2)
Algorithms     Open Access   (Followers: 13, SJR: 0.217, CiteScore: 1)
Allergies     Open Access   (Followers: 2)
Animals     Open Access   (Followers: 15, SJR: 0.744, CiteScore: 2)
Antibiotics     Open Access   (Followers: 9, SJR: 1.063, CiteScore: 3)
Antibodies     Open Access   (Followers: 2, SJR: 0.931, CiteScore: 3)
Antioxidants     Open Access   (Followers: 5, SJR: 0.847, CiteScore: 3)
Applied Sciences     Open Access   (Followers: 6, SJR: 0.303, CiteScore: 2)
Applied System Innovation     Open Access  
Arts     Open Access   (Followers: 9)
Atmosphere     Open Access   (Followers: 26)
Atoms     Open Access   (Followers: 1)
Axioms     Open Access   (Followers: 1)
Batteries     Open Access   (Followers: 10)
Behavioral Sciences     Open Access   (Followers: 4)
Beverages     Open Access   (Followers: 1)
Big Data and Cognitive Computing     Open Access   (Followers: 7)
Bioengineering     Open Access   (Followers: 4)
Biology     Open Access   (Followers: 4, SJR: 1.324, CiteScore: 3)
Biomedicines     Open Access   (Followers: 1)
Biomimetics     Open Access  
Biomolecules     Open Access   (Followers: 1, SJR: 2.552, CiteScore: 6)
Biosensors     Open Access   (Followers: 3, SJR: 0.829, CiteScore: 4)
Brain Sciences     Open Access   (Followers: 5, SJR: 1.047, CiteScore: 3)
Buildings     Open Access   (Followers: 8)
C - J. of Carbon Research     Open Access   (Followers: 5)
Cancers     Open Access   (Followers: 3, SJR: 2.243, CiteScore: 6)
Catalysts     Open Access   (Followers: 14)
Cells     Open Access   (Followers: 4, SJR: 2.742, CiteScore: 6)
Ceramics     Open Access  
Challenges     Open Access   (Followers: 2)
ChemEngineering     Open Access  
Chemistry     Open Access  
Chemosensors     Open Access   (Followers: 1)
Children     Open Access   (Followers: 2)
Chromatography     Open Access   (Followers: 3)
Clean Technologies     Open Access  
Climate     Open Access   (Followers: 6)
Clocks & Sleep     Open Access   (Followers: 2)
Coatings     Open Access   (Followers: 4)
Colloids and Interfaces     Open Access  
Computation     Open Access   (Followers: 1)
Computers     Open Access   (Followers: 2)
Condensed Matter     Open Access   (Followers: 3)
Corrosion and Materials Degradation     Open Access   (Followers: 1)
Cosmetics     Open Access   (Followers: 5)
Cryptography     Open Access  
Crystals     Open Access   (Followers: 5, SJR: 0.566, CiteScore: 2)
Dairy     Open Access   (Followers: 3)
Data     Open Access   (Followers: 4)
Dentistry J.     Open Access   (Followers: 6)
Designs     Open Access  
Diagnostics     Open Access   (Followers: 1, SJR: 0.669, CiteScore: 2)
Diseases     Open Access  
Diversity     Open Access   (Followers: 5)
Drones     Open Access   (Followers: 5)
Econometrics     Open Access   (Followers: 12)
Economies     Open Access   (Followers: 1)
Education     Open Access   (Followers: 13)
Electronics     Open Access   (Followers: 112, SJR: 0.548, CiteScore: 3)
Energies     Open Access   (Followers: 6, SJR: 0.67, CiteScore: 3)
Entropy     Open Access   (Followers: 8, SJR: 0.592, CiteScore: 2)
Environments     Open Access  
Epigenomes     Open Access  
European J. of Burn Care     Open Access  
European J. of Investigation in Health, Psychology and Education     Open Access   (Followers: 5)
Fermentation     Open Access   (Followers: 3)
Fibers     Open Access   (Followers: 7)
Fire     Open Access  
Fishes     Open Access  
Fluids     Open Access   (Followers: 1)
Foods     Open Access  
Forecasting     Open Access   (Followers: 1)
Forests     Open Access   (Followers: 2, SJR: 0.812, CiteScore: 2)
Fractal and Fractional     Open Access  
Future Internet     Open Access   (Followers: 177, SJR: 0.219, CiteScore: 1)
Galaxies     Open Access   (Followers: 6)
Games     Open Access   (Followers: 4, SJR: 0.242, CiteScore: 1)
Gastrointestinal Disorders     Open Access  
Gels     Open Access  
Genealogy     Open Access   (Followers: 1)
Genes     Open Access   (Followers: 2, SJR: 1.82, CiteScore: 3)
GeoHazards     Open Access   (Followers: 2)
Geosciences     Open Access   (Followers: 3, SJR: 0.451, CiteScore: 2)
Geriatrics     Open Access   (Followers: 4)
Healthcare     Open Access   (Followers: 3)
Hearts     Open Access   (Followers: 3)
Heritage     Open Access  
High-Throughput     Open Access  
Histories     Open Access   (Followers: 2)
Horticulturae     Open Access   (Followers: 2)
Humanities     Open Access   (Followers: 15)
Hydrology     Open Access   (Followers: 5)
Informatics     Open Access   (Followers: 4)
Information     Open Access   (Followers: 48, SJR: 0.222, CiteScore: 1)
Infrastructures     Open Access  
Inorganics     Open Access   (Followers: 3)
Insects     Open Access   (Followers: 2, SJR: 0.897, CiteScore: 2)
Instruments     Open Access  
Intl. J. of Environmental Research and Public Health     Open Access   (Followers: 27, SJR: 0.735, CiteScore: 2)
Intl. J. of Financial Studies     Open Access   (Followers: 5)
Intl. J. of Molecular Sciences     Open Access   (Followers: 3, SJR: 1.26, CiteScore: 4)
Intl. J. of Neonatal Screening     Open Access   (Followers: 4)
Intl. J. of Turbomachinery, Propulsion and Power     Open Access   (Followers: 11)
Inventions     Open Access  
IoT     Open Access   (Followers: 1)
ISPRS Intl. J. of Geo-Information     Open Access   (Followers: 5, SJR: 0.493, CiteScore: 2)
J : Multidisciplinary Scientific J.     Open Access  
J. of Cardiovascular Development and Disease     Open Access   (Followers: 1)
J. of Clinical Medicine     Open Access   (Followers: 3)
J. of Composites Science     Open Access   (Followers: 3)
J. of Cybersecurity and Privacy     Open Access   (Followers: 2)
J. of Developmental Biology     Open Access   (Followers: 2)
J. of Functional Biomaterials     Open Access   (Followers: 3, SJR: 0.685, CiteScore: 3)
J. of Functional Morphology and Kinesiology     Open Access  
J. of Fungi     Open Access   (Followers: 3)
J. of Imaging     Open Access   (Followers: 3)
J. of Intelligence     Open Access   (Followers: 2)
J. of Low Power Electronics and Applications     Open Access   (Followers: 10, SJR: 0.222, CiteScore: 1)
J. of Manufacturing and Materials Processing     Open Access  
J. of Marine Science and Engineering     Open Access   (Followers: 2)
J. of Nanotheranostics     Open Access   (Followers: 1)
J. of Open Innovation : Technology, Market, and Complexity     Open Access   (Followers: 1)
J. of Otorhinolaryngology, Hearing and Balance Medicine     Open Access   (Followers: 1)
J. of Personalized Medicine     Open Access   (Followers: 3, SJR: 1.269, CiteScore: 3)
J. of Risk and Financial Management     Open Access   (Followers: 9)
J. of Sensor and Actuator Networks     Open Access   (Followers: 13)
J. of Xenobiotics     Open Access  
Land     Open Access   (Followers: 4)
Languages     Open Access   (Followers: 4)
Laws     Open Access   (Followers: 2)
Life     Open Access   (Followers: 2, SJR: 1.625, CiteScore: 3)
Literature     Open Access  
Logistics     Open Access   (Followers: 3)
Lubricants     Open Access   (Followers: 2)
Machine Learning and Knowledge Extraction     Open Access   (Followers: 7)
Machines     Open Access   (Followers: 3)
Magnetochemistry     Open Access  
Marine Drugs     Open Access   (Followers: 3, SJR: 0.978, CiteScore: 5)
Materials     Open Access   (Followers: 6)
Mathematical and Computational Applications     Open Access   (Followers: 2)
Mathematics     Open Access   (Followers: 2)
Medical Sciences     Open Access   (Followers: 2)
Medicina     Open Access   (Followers: 1, SJR: 0.422, CiteScore: 1)
Medicines     Open Access   (Followers: 1)
Membranes     Open Access   (Followers: 5, SJR: 0.645, CiteScore: 3)
Metabolites     Open Access   (Followers: 2, SJR: 1.026, CiteScore: 3)
Metals     Open Access   (Followers: 5, SJR: 0.55, CiteScore: 2)
Methods and Protocols     Open Access   (Followers: 1)
Microarrays     Open Access  
Micromachines     Open Access   (Followers: 3, SJR: 0.493, CiteScore: 2)
Microorganisms     Open Access   (Followers: 6)
Minerals     Open Access   (Followers: 2, SJR: 0.462, CiteScore: 2)
Molbank     Open Access   (Followers: 1, SJR: 0.12, CiteScore: 0)
Molecules     Open Access   (Followers: 7, SJR: 0.855, CiteScore: 3)
Multimodal Technologies and Interaction     Open Access  
Nanomaterials     Open Access   (Followers: 6)
Neuroglia     Open Access   (Followers: 1)
Nitrogen     Open Access   (Followers: 2)
Non-Coding RNA     Open Access  
Nursing Reports     Open Access   (Followers: 3)
Nutrients     Open Access   (Followers: 11, SJR: 1.557, CiteScore: 4)
Oceans     Open Access  
Particles     Open Access  
Pathogens     Open Access   (Followers: 4, SJR: 1.421, CiteScore: 4)
Pharmaceuticals     Open Access   (Followers: 6, SJR: 1.293, CiteScore: 4)
Pharmaceutics     Open Access   (Followers: 4, SJR: 0.949, CiteScore: 4)
Pharmacy     Open Access   (Followers: 7)
Philosophies     Open Access  
Photonics     Open Access   (Followers: 6, SJR: 0.709, CiteScore: 2)
Physics     Open Access  
Plants     Open Access   (SJR: 1.39, CiteScore: 3)
Plasma     Open Access   (Followers: 5)
Polymers     Open Access   (Followers: 21, SJR: 0.852, CiteScore: 3)
Proceedings     Open Access   (Followers: 1)
Processes     Open Access  
Projects     Open Access   (Followers: 2)
Prosthesis     Open Access  
Proteomes     Open Access  
Psych     Open Access   (Followers: 1)
Publications     Open Access   (Followers: 7)
Quantum Beam Science     Open Access   (Followers: 1)
Quantum Reports     Open Access  
Quaternary     Open Access  
Reactions     Open Access   (Followers: 1)
Recycling     Open Access  
Religions     Open Access   (Followers: 4, SJR: 0.232, CiteScore: 1)
Remote Sensing     Open Access   (Followers: 55, SJR: 1.386, CiteScore: 4)
Reports     Open Access  
Resources     Open Access   (SJR: 0.688, CiteScore: 3)
Risks     Open Access  
Robotics     Open Access   (Followers: 9)
Safety     Open Access   (Followers: 2)
Sci     Open Access  

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Journal Cover
Cells
Journal Prestige (SJR): 2.742
Citation Impact (citeScore): 6
Number of Followers: 4  

  This is an Open Access Journal Open Access journal
ISSN (Online) 2073-4409
Published by MDPI Homepage  [233 journals]
  • Cells, Vol. 10, Pages 1035: Protective Effects of Necrostatin-1 in Acute
           Pancreatitis: Partial Involvement of Receptor Interacting Protein Kinase 1
           

    • Authors: Yulin Ouyang, Li Wen, Jane A. Armstrong, Michael Chvanov, Diane Latawiec, Wenhao Cai, Mohammad Awais, Rajarshi Mukherjee, Wei Huang, Peter J. Gough, John Bertin, Alexei V. Tepikin, Robert Sutton, David N. Criddle
      First page: 1035
      Abstract: Acute pancreatitis (AP) is a severe and potentially fatal disease caused predominantly by alcohol excess and gallstones, which lacks a specific therapy. The role of Receptor-Interacting Protein Kinase 1 (RIPK1), a key component of programmed necrosis (Necroptosis), is unclear in AP. We assessed the effects of RIPK1 inhibitor Necrostatin-1 (Nec-1) and RIPK1 modification (RIPK1K45A: kinase dead) in bile acid (TLCS-AP), alcoholic (FAEE-AP) and caerulein hyperstimulation (CER-AP) mouse models. Involvement of collateral Nec-1 target indoleamine 2,3-dioxygenase (IDO) was probed with the inhibitor Epacadostat (EPA). Effects of Nec-1 and RIPK1K45A were also compared on pancreatic acinar cell (PAC) fate in vitro and underlying mechanisms explored. Nec-1 markedly ameliorated histological and biochemical changes in all models. However, these were only partially reduced or unchanged in RIPK1K45A mice. Inhibition of IDO with EPA was protective in TLCS-AP. Both Nec-1 and RIPK1K45A modification inhibited TLCS- and FAEE-induced PAC necrosis in vitro. Nec-1 did not affect TLCS-induced Ca2+ entry in PACs, however, it inhibited an associated ROS elevation. The results demonstrate protective actions of Nec-1 in multiple models. However, RIPK1-dependent necroptosis only partially contributed to beneficial effects, and actions on targets such as IDO are likely to be important.
      Citation: Cells
      PubDate: 2021-04-27
      DOI: 10.3390/cells10051035
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1036: Complexity and Specificity of
           Sec61-Channelopathies: Human Diseases Affecting Gating of the Sec61
           Complex

    • Authors: Mark Sicking, Sven Lang, Florian Bochen, Andreas Roos, Joost P. H. Drenth, Muhammad Zakaria, Richard Zimmermann, Maximilian Linxweiler
      First page: 1036
      Abstract: The rough endoplasmic reticulum (ER) of nucleated human cells has crucial functions in protein biogenesis, calcium (Ca2+) homeostasis, and signal transduction. Among the roughly one hundred components, which are involved in protein import and protein folding or assembly, two components stand out: The Sec61 complex and BiP. The Sec61 complex in the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER and provides a conduit for Ca2+ ions from the ER lumen to the cytosol. The second component, the Hsp70-type molecular chaperone immunoglobulin heavy chain binding protein, short BiP, plays central roles in protein folding and assembly (hence its name), protein import, cellular Ca2+ homeostasis, and various intracellular signal transduction pathways. For the purpose of this review, we focus on these two components, their relevant allosteric effectors and on the question of how their respective functional cycles are linked in order to reconcile the apparently contradictory features of the ER membrane, selective permeability for precursor polypeptides, and impermeability for Ca2+. The key issues are that the Sec61 complex exists in two conformations: An open and a closed state that are in a dynamic equilibrium with each other, and that BiP contributes to its gating in both directions in cooperation with different co-chaperones. While the open Sec61 complex forms an aqueous polypeptide-conducting- and transiently Ca2+-permeable channel, the closed complex is impermeable even to Ca2+. Therefore, we discuss the human hereditary and tumor diseases that are linked to Sec61 channel gating, termed Sec61-channelopathies, as disturbances of selective polypeptide-impermeability and/or aberrant Ca2+-permeability.
      Citation: Cells
      PubDate: 2021-04-27
      DOI: 10.3390/cells10051036
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1037: Age-Dependent Microglial Response to Systemic
           Infection

    • Authors: Brianna Cyr, Juan Pablo de Rivero Vaccari
      First page: 1037
      Abstract: Inflammation is part of the aging process, and the inflammatory innate immune response is more exacerbated in older individuals when compared to younger individuals. Similarly, there is a difference in the response to systemic infection that varies with age. In a recent article by Hoogland et al., the authors studied the microglial response to systemic infection in young (2 months) and middle-aged mice (13–14 months) that were challenged with live Escherichia coli to investigate whether the pro- and anti-inflammatory responses mounted by microglia after systemic infection varies with age. Here, we comment on this study and its implications on how inflammation in the brain varies with age.
      Citation: Cells
      PubDate: 2021-04-28
      DOI: 10.3390/cells10051037
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1038: The ECM Modulator ITIH5 Affects Cell Adhesion,
           Motility and Chemotherapeutic Response of Basal/Squamous-Like (BASQ)
           Bladder Cancer Cells

    • Authors: Michael Rose, Erik Noetzel, Jennifer Kistermann, Julian Eschenbruch, Sandra Rushrush, Lin Gan, Ruth Knüchel, Nadine T. Gaisa, Edgar Dahl
      First page: 1038
      Abstract: This study aims at characterizing the role of the putative tumor suppressor ITIH5 in basal-type bladder cancers (BLCA). By sub-classifying TCGA BLCA data, we revealed predominant loss of ITIH5 expression in the basal/squamous-like (BASQ) subtype. ITIH5 expression inversely correlated with basal-type makers such as KRT6A and CD44. Interestingly, Kaplan–Meier analyses showed longer recurrence-free survival in combination with strong CD44 expression, which is thought to mediate ITIH-hyaluronan (HA) binding functions. In vitro, stable ITIH5 overexpression in two basal-type BLCA cell lines showing differential CD44 expression levels, i.e., with (SCaBER) and without squamous features (HT1376), demonstrated clear inhibition of cell and colony growth of BASQ-type SCaBER cells. ITIH5 further enhanced HA-associated cell-matrix attachment, indicated by altered size and number of focal adhesion sites resulting in reduced cell migration capacities. Transcriptomic analyses revealed enrichment of pathways and processes involved in ECM organization, differentiation and cell signaling. Finally, we provide evidence that ITIH5 increase sensitivity of SCaBER cells to chemotherapeutical agents (cisplatin and gemcitabine), whereas responsiveness of HT1376 cells was not affected by ITIH5 expression. Thus, we gain further insights into the putative role of ITIH5 as tumor suppressor highlighting an impact on drug response potentially via the HA-CD44 axis in BASQ-type BLCA.
      Citation: Cells
      PubDate: 2021-04-28
      DOI: 10.3390/cells10051038
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1039: The Small GTPases in Fungal Signaling
           Conservation and Function

    • Authors: Mitzuko Dautt-Castro, Montserrat Rosendo-Vargas, Sergio Casas-Flores
      First page: 1039
      Abstract: Monomeric GTPases, which belong to the Ras superfamily, are small proteins involved in many biological processes. They are fine-tuned regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Several families have been identified in organisms from different kingdoms. Overall, the most studied families are Ras, Rho, Rab, Ran, Arf, and Miro. Recently, a new family named Big Ras GTPases was reported. As a general rule, the proteins of all families have five characteristic motifs (G1–G5), and some specific features for each family have been described. Here, we present an exhaustive analysis of these small GTPase families in fungi, using 56 different genomes belonging to different phyla. For this purpose, we used distinct approaches such as phylogenetics and sequences analysis. The main functions described for monomeric GTPases in fungi include morphogenesis, secondary metabolism, vesicle trafficking, and virulence, which are discussed here. Their participation during fungus–plant interactions is reviewed as well.
      Citation: Cells
      PubDate: 2021-04-28
      DOI: 10.3390/cells10051039
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1040: Affinity Selection in Germinal Centers:
           Cautionary Tales and New Opportunities

    • Authors: Jose Faro, Mario Castro
      First page: 1040
      Abstract: Our current quantitative knowledge of the kinetics of antibody-mediated immunity is partly based on idealized experiments throughout the last decades. However, new experimental techniques often render contradictory quantitative outcomes that shake previously uncontroversial assumptions. This has been the case in the field of T-cell receptors, where recent techniques for measuring the 2-dimensional rate constants of T-cell receptor–ligand interactions exposed results contradictory to those obtained with techniques measuring 3-dimensional interactions. Recently, we have developed a mathematical framework to rationalize those discrepancies, focusing on the proper fine-grained description of the underlying kinetic steps involved in the immune synapse. In this perspective article, we apply this approach to unveil potential blind spots in the case of B-cell receptors (BCR) and to rethink the interactions between B cells and follicular dendritic cells (FDC) during the germinal center (GC) reaction. Also, we elaborate on the concept of “catch bonds” and on the recent observations that B-cell synapses retract and pull antigen generating a “retracting force”, and propose some testable predictions that can lead to future research.
      Citation: Cells
      PubDate: 2021-04-28
      DOI: 10.3390/cells10051040
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1041: The Endothelium Is Both a Target and a Barrier
           of HDL’s Protective Functions

    • Authors: Jérôme Robert, Elena Osto, Arnold von Eckardstein
      First page: 1041
      Abstract: The vascular endothelium serves as a barrier between the intravascular and extravascular compartments. High-density lipoproteins (HDL) have two kinds of interactions with this barrier. First, bloodborne HDL must pass the endothelium to access extravascular tissues, for example the arterial wall or the brain, to mediate cholesterol efflux from macrophages and other cells or exert other functions. To complete reverse cholesterol transport, HDL must even pass the endothelium a second time to re-enter circulation via the lymphatics. Transendothelial HDL transport is a regulated process involving scavenger receptor SR-BI, endothelial lipase, and ATP binding cassette transporters A1 and G1. Second, HDL helps to maintain the integrity of the endothelial barrier by (i) promoting junction closure as well as (ii) repair by stimulating the proliferation and migration of endothelial cells and their progenitor cells, and by preventing (iii) loss of glycocalix, (iv) apoptosis, as well as (v) transmigration of inflammatory cells. Additional vasoprotective functions of HDL include (vi) the induction of nitric oxide (NO) production and (vii) the inhibition of reactive oxygen species (ROS) production. These vasoprotective functions are exerted by the interactions of HDL particles with SR-BI as well as specific agonists carried by HDL, notably sphingosine-1-phophate (S1P), with their specific cellular counterparts, e.g., S1P receptors. Various diseases modify the protein and lipid composition and thereby the endothelial functionality of HDL. Thorough understanding of the structure–function relationships underlying the multiple interactions of HDL with endothelial cells is expected to elucidate new targets and strategies for the treatment or prevention of various diseases.
      Citation: Cells
      PubDate: 2021-04-28
      DOI: 10.3390/cells10051041
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1042: Dual Impact of a Benzimidazole Resistant
           β-Tubulin on Microtubule Behavior in Fission Yeast

    • Authors: Mamika Minagawa, Minamo Shirato, Mika Toya, Masamitsu Sato
      First page: 1042
      Abstract: The cytoskeleton microtubule consists of polymerized αβ-tubulin dimers and plays essential roles in many cellular events. Reagents that inhibit microtubule behaviors have been developed as antifungal, antiparasitic, and anticancer drugs. Benzimidazole compounds, including thiabendazole (TBZ), carbendazim (MBC), and nocodazole, are prevailing microtubule poisons that target β-tubulin and inhibit microtubule polymerization. The molecular basis, however, as to how the drug acts on β-tubulin remains controversial. Here, we characterize the S. pombe β-tubulin mutant nda3-TB101, which was previously isolated as a mutant resistance to benzimidazole. The mutation site tyrosine at position 50 is located in the interface of two lateral β-tubulin proteins and at the gate of a putative binging pocket for benzimidazole. Our observation revealed two properties of the mutant tubulin. First, the dynamics of cellular microtubules comprising the mutant β-tubulin were stabilized in the absence of benzimidazole. Second, the mutant protein reduced the affinity to benzimidazole in vitro. We therefore conclude that the mutant β-tubulin Nda3-TB101 exerts a dual effect on microtubule behaviors: the mutant β-tubulin stabilizes microtubules and is insensitive to benzimidazole drugs. This notion fine-tunes the current elusive molecular model regarding binding of benzimidazole to β-tubulin.
      Citation: Cells
      PubDate: 2021-04-28
      DOI: 10.3390/cells10051042
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1043: Influence of Hypothermic Storage Fluids on
           Mesenchymal Stem Cell Stability: A Comprehensive Review and Personal
           Experience

    • Authors: Aneta Ścieżyńska, Marta Soszyńska, Patrycja Szpak, Natalia Krześniak, Jacek Malejczyk, Ilona Kalaszczyńska
      First page: 1043
      Abstract: Mesenchymal stem cells have generated a great deal of interest due to their potential use in regenerative medicine and tissue engineering. Examples illustrating their therapeutic value across various in vivo models are demonstrated in the literature. However, some clinical trials have not proved their therapeutic efficacy, showing that translation into clinical practice is considerably more difficult and discrepancies in clinical protocols can be a source of failure. Among the critical factors which play an important role in MSCs’ therapeutic efficiency are the method of preservation of the stem cell viability and various characteristics during their storage and transportation from the GMP production facility to the patient’s bedside. The cell storage medium should be considered a key factor stabilizing the environment and greatly influencing cell viability and potency and therefore the effectiveness of advanced therapy medicinal product (ATMP) based on MSCs. In this review, we summarize data from 826 publications concerning the effect of the most frequently used cell preservation solutions on MSC potential as cell-based therapeutic medicinal products.
      Citation: Cells
      PubDate: 2021-04-28
      DOI: 10.3390/cells10051043
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1044: The Effect and Regulatory Mechanism of High
           Mobility Group Box-1 Protein on Immune Cells in Inflammatory Diseases

    • Authors: Yun Ge, Man Huang, Yong-ming Yao
      First page: 1044
      Abstract: High mobility group box-1 protein (HMGB1), a member of the high mobility group protein superfamily, is an abundant and ubiquitously expressed nuclear protein. Intracellular HMGB1 is released by immune and necrotic cells and secreted HMGB1 activates a range of immune cells, contributing to the excessive release of inflammatory cytokines and promoting processes such as cell migration and adhesion. Moreover, HMGB1 is a typical damage-associated molecular pattern molecule that participates in various inflammatory and immune responses. In these ways, it plays a critical role in the pathophysiology of inflammatory diseases. Herein, we review the effects of HMGB1 on various immune cell types and describe the molecular mechanisms by which it contributes to the development of inflammatory disorders. Finally, we address the therapeutic potential of targeting HMGB1.
      Citation: Cells
      PubDate: 2021-04-28
      DOI: 10.3390/cells10051044
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1045: Extracellular Vesicle Surface Signatures in
           IPF Patients: A Multiplex Bead-Based Flow Cytometry Approach

    • Authors: Miriana d’Alessandro, Piera Soccio, Laura Bergantini, Paolo Cameli, Giulia Scioscia, Maria Pia Foschino Barbaro, Donato Lacedonia, Elena Bargagli
      First page: 1045
      Abstract: Background: Extracellular vesicles (EVs) are secreted by cells from their membrane within circulation and body fluids. Knowledge of the involvement of EVs in pathogenesis of lung diseases is increasing. The present study aimed to evaluate the expression of exosomal surface epitopes in a cohort of idiopathic pulmonary fibrosis (IPF) patients followed in two Italian Referral Centres for Interstitial Lung Diseases, comparing them with a group of healthy volunteers. Materials and Methods: Ninety IPF patients (median age and interquartile range (IQR) 71 (66–75) years; 69 males) were selected retrospectively. Blood samples were obtained from patients before starting antifibrotic therapy. A MACSPlex Exosome Kit, human, (Miltenyi Biotec, Bergisch-Gladbach, Germany), to detect 37 exosomal surface epitopes, was used. Results: CD19, CD69, CD8, and CD86 were significantly higher in IPF patients than in controls (p = 0.0023, p = 0.0471, p = 0.0082, and p = 0.0143, respectively). CD42a was lower in IPF subjects than in controls (p = 0.0153), while CD209, Cd133/1, MCSP, and ROR1 were higher in IPF patients than in controls (p = 0.0007, p = 0.0050, p = 0.0139, and p = 0.0335, respectively). Kaplan-Meier survival analysis for IPF patients: for median values and a cut-off of 0.48 for CD25, the two subgroups showed a significant difference in survival rate (p = 0.0243, hazard ratio: 0.52 (95%CI 0.29–0.92); the same was true for CD8 (cut-off 1.53, p = 0.0309, hazard ratio: 1.39 (95%CI 0.75–2.53). Conclusion: Our multicenter study showed for the first time the expression of surface epitopes on EVs from IPF patients, providing interesting data on the communication signatures/exosomal profile in serum from IPF patients and new insights into the pathogenesis of the disease and a promising reliability in predicting mid-term survival of IPF patients.
      Citation: Cells
      PubDate: 2021-04-28
      DOI: 10.3390/cells10051045
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1046: The Dynamic Interaction between Extracellular
           Matrix Remodeling and Breast Tumor Progression

    • Authors: Jorge Martinez, Patricio C. Smith
      First page: 1046
      Abstract: Desmoplastic tumors correspond to a unique tissue structure characterized by the abnormal deposition of extracellular matrix. Breast tumors are a typical example of this type of lesion, a property that allows its palpation and early detection. Fibrillar type I collagen is a major component of tumor desmoplasia and its accumulation is causally linked to tumor cell survival and metastasis. For many years, the desmoplastic phenomenon was considered to be a reaction and response of the host tissue against tumor cells and, accordingly, designated as “desmoplastic reaction”. This notion has been challenged in the last decades when desmoplastic tissue was detected in breast tissue in the absence of tumor. This finding suggests that desmoplasia is a preexisting condition that stimulates the development of a malignant phenotype. With this perspective, in the present review, we analyze the role of extracellular matrix remodeling in the development of the desmoplastic response. Importantly, during the discussion, we also analyze the impact of obesity and cell metabolism as critical drivers of tissue remodeling during the development of desmoplasia. New knowledge derived from the dynamic remodeling of the extracellular matrix may lead to novel targets of interest for early diagnosis or therapy in the context of breast tumors.
      Citation: Cells
      PubDate: 2021-04-29
      DOI: 10.3390/cells10051046
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1047: Molecular Evolution of CatSper in Mammals and
           Function of Sperm Hyperactivation in Gray Short-Tailed Opossum

    • Authors: Jae Yeon Hwang, Jamie Maziarz, Günter P. Wagner, Jean-Ju Chung
      First page: 1047
      Abstract: Males have evolved species-specifical sperm morphology and swimming patterns to adapt to different fertilization environments. In eutherians, only a small fraction of the sperm overcome the diverse obstacles in the female reproductive tract and successfully migrate to the fertilizing site. Sperm arriving at the fertilizing site show hyperactivated motility, a unique motility pattern displaying asymmetric beating of sperm flagella with increased amplitude. This motility change is triggered by Ca2+ influx through the sperm-specific ion channel, CatSper. However, the current understanding of the CatSper function and its molecular regulation is limited in eutherians. Here, we report molecular evolution and conservation of the CatSper channel in the genome throughout eutherians and marsupials. Sequence analyses reveal that CatSper proteins are slowly evolved in marsupials. Using an American marsupial, gray short-tailed opossum (Monodelphis domestica), we demonstrate the expression of CatSper in testes and its function in hyperactivation and unpairing of sperm. We demonstrate that a conserved IQ-like motif in CatSperζ is required for CatSperζ interaction with the pH-tuned Ca2+ sensor, EFCAB9, for regulating CatSper activity. Recombinant opossum EFCAB9 can interact with mouse CatSperζ despite high sequence divergence of CatSperζ among CatSper subunits in therians. Our finding suggests that molecular characteristics and functions of CatSper are evolutionarily conserved in gray short-tailed opossum, unraveling the significance of sperm hyperactivation and fertilization in marsupials for the first time.
      Citation: Cells
      PubDate: 2021-04-29
      DOI: 10.3390/cells10051047
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1048: Hepatic Wnt1 Inducible Signaling Pathway
           Protein 1 (WISP-1/CCN4) Associates with Markers of Liver Fibrosis in
           Severe Obesity

    • Authors: Olga Pivovarova-Ramich, Jennifer Loske, Silke Hornemann, Mariya Markova, Nicole Seebeck, Anke Rosenthal, Frederick Klauschen, José Castro, René Buschow, Tilman Grune, Volker Lange, Natalia Rudovich, D. Ouwens
      First page: 1048
      Abstract: Liver fibrosis is a critical complication of obesity-induced fatty liver disease. Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4), a novel adipokine associated with visceral obesity and insulin resistance, also contributes to lung and kidney fibrosis. The aim of the present study was to investigate the role of CCN4 in liver fibrosis in severe obesity. For this, human liver biopsies were collected from 35 severely obese humans (BMI 42.5 ± 0.7 kg/m2, age 46.7 ± 1.8 y, 25.7% males) during bariatric surgery and examined for the expression of CCN4, fibrosis, and inflammation markers. Hepatic stellate LX-2 cells were treated with human recombinant CCN4 alone or in combination with LPS or transforming growth factor beta (TGF-β) and examined for fibrosis and inflammation markers. CCN4 mRNA expression in the liver positively correlated with BMI and expression of fibrosis markers COL1A1, COL3A1, COL6A1, αSMA, TGFB1, extracellular matrix turnover enzymes TIMP1 and MMP9, and the inflammatory marker ITGAX/CD11c. In LX-2 cells, the exposure to recombinant CCN4 caused dose-dependent induction of MMP9 and MCP1. CCN4 potentiated the TGF-β-mediated induction of COL3A1, TIMP1, and MCP1 but showed no interaction with LPS treatment. Our results suggest a potential contribution of CCN4 to the early pathogenesis of obesity-associated liver fibrosis.
      Citation: Cells
      PubDate: 2021-04-29
      DOI: 10.3390/cells10051048
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1049: Anti-VEGF-Resistant Retinal Diseases: A Review
           of the Latest Treatment Options

    • Authors: Josh O. Wallsh, Ron P. Gallemore
      First page: 1049
      Abstract: Anti-vascular endothelial growth factor (anti-VEGF) therapy currently plays a central role in the treatment of numerous retinal diseases, most notably exudative age-related macular degeneration (eAMD), diabetic retinopathy and retinal vein occlusions. While offering significant functional and anatomic benefits in most patients, there exists a subset of 15–40% of eyes that fail to respond or only partially respond. For these cases, various treatment options have been explored with a range of outcomes. These options include steroid injections, laser treatment (both thermal therapy for retinal vascular diseases and photodynamic therapy for eAMD), abbreviated anti-VEGF treatment intervals, switching anti-VEGF agents and topical medications. In this article, we review the effectiveness of these treatment options along with a discussion of the current research into future directions for anti-VEGF-resistant eyes.
      Citation: Cells
      PubDate: 2021-04-29
      DOI: 10.3390/cells10051049
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1050: Structure and Development of the
           Legume-Rhizobial Symbiotic Interface in Infection Threads

    • Authors: Anna V. Tsyganova, Nicholas J. Brewin, Viktor E. Tsyganov
      First page: 1050
      Abstract: The intracellular infection thread initiated in a root hair cell is a unique structure associated with Rhizobium-legume symbiosis. It is characterized by inverted tip growth of the plant cell wall, resulting in a tunnel that allows invasion of host cells by bacteria during the formation of the nitrogen-fixing root nodule. Regulation of the plant-microbial interface is essential for infection thread growth. This involves targeted deposition of the cell wall and extracellular matrix and tight control of cell wall remodeling. This review describes the potential role of different actors such as transcription factors, receptors, and enzymes in the rearrangement of the plant-microbial interface and control of polar infection thread growth. It also focuses on the composition of the main polymers of the infection thread wall and matrix and the participation of reactive oxygen species (ROS) in the development of the infection thread. Mutant analysis has helped to gain insight into the development of host defense reactions. The available data raise many new questions about the structure, function, and development of infection threads.
      Citation: Cells
      PubDate: 2021-04-29
      DOI: 10.3390/cells10051050
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1051: Molecular Functions of WWOX Potentially
           Involved in Cancer Development

    • Authors: Karim Taouis, Keltouma Driouch, Rosette Lidereau, François Lallemand
      First page: 1051
      Abstract: The WW domain-containing oxidoreductase gene (WWOX) was cloned 21 years ago as a putative tumor suppressor gene mapping to chromosomal fragile site FRA16D. The localization of WWOX in a chromosomal region frequently altered in human cancers has initiated multiple current studies to establish its role in this disease. All of this work suggests that WWOX, due to its ability to interact with a large number of partners, exerts its tumor suppressive activity through a wide variety of molecular actions that are mostly cell specific.
      Citation: Cells
      PubDate: 2021-04-29
      DOI: 10.3390/cells10051051
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1052: Remdesivir and Ledipasvir among the
           FDA-Approved Antiviral Drugs Have Potential to Inhibit SARS-CoV-2
           Replication

    • Authors: Rameez Hassan Pirzada, Muhammad Haseeb, Maria Batool, MoonSuk Kim, Sangdun Choi
      First page: 1052
      Abstract: The rapid spread of the virus, the surge in the number of deaths, and the unavailability of specific SARS-CoV-2 drugs thus far necessitate the identification of drugs with anti-COVID-19 activity. SARS-CoV-2 enters the host cell and assembles a multisubunit RNA-dependent RNA polymerase (RdRp) complex of viral nonstructural proteins that plays a substantial role in the transcription and replication of the viral genome. Therefore, RdRp is among the most suitable targets in RNA viruses. Our aim was to investigate the FDA approved antiviral drugs having potential to inhibit the viral replication. The methodology adopted was virtual screening and docking of FDA-approved antiviral drugs into the RdRp protein. Top hits were selected and subjected to molecular dynamics simulations to understand the dynamics of RdRp in complex with these drugs. The antiviral activity of the drugs against SARS-CoV-2 was assessed in Vero E6 cells. Notably, both remdesivir (half-maximal effective concentration (EC50) 6.6 μM, 50% cytotoxicity concentration (CC50) > 100 µM, selectivity index (SI) = 15) and ledipasvir (EC50 34.6 μM, CC50 > 100 µM, SI > 2.9) exerted antiviral action. This study highlights the use of direct-acting antiviral drugs, alone or in combination, for better treatments of COVID-19.
      Citation: Cells
      PubDate: 2021-04-29
      DOI: 10.3390/cells10051052
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1053: 1,3,4-Thiadiazoles Effectively Inhibit
           Proliferation of Toxoplasma gondii

    • Authors: Lidia Węglińska, Adrian Bekier, Katarzyna Dzitko, Barbara Pacholczyk-Sienicka, Łukasz Albrecht, Tomasz Plech, Piotr Paneth, Agata Paneth
      First page: 1053
      Abstract: Congenital and acquired toxoplasmosis caused by the food- and water-born parasite Toxoplasma gondii (T. gondii) is one of the most prevalent zoonotic infection of global importance. T. gondii is an obligate intracellular parasite with limited capacity for extracellular survival, thus a successful, efficient and robust host cell invasion process is crucial for its survival, proliferation and transmission. In this study, we screened a series of novel 1,3,4-thiadiazole-2-halophenylamines functionalized at the C5 position with the imidazole ring (1b–12b) for their effects on T. gondii host cell invasion and proliferation. To achieve this goal, these compounds were initially subjected to in vitro assays to assess their cytotoxicity on human fibroblasts and then antiparasitic efficacy. Results showed that all of them compare favorably to control drugs sulfadiazine and trimethoprim in terms of T. gondii growth inhibition (IC50) and selectivity toward the parasite, expressed as selectivity index (SI). Subsequently, the most potent of them with meta-fluoro 2b, meta-chloro 5b, meta-bromo 8b, meta-iodo 11b and para-iodo 12b substitution were tested for their efficacy in inhibition of tachyzoites invasion and subsequent proliferation by direct action on established intracellular infection. All the compounds significantly inhibited the parasite invasion and intracellular proliferation via direct action on both tachyzoites and parasitophorous vacuoles formation. The most effective was para-iodo derivative 12b that caused reduction in the percentage of infected host cells by 44% and number of tachyzoites per vacuole by 93% compared to non-treated host cells. Collectively, these studies indicate that 1,3,4-thiadiazoles 1b–12b, especially 12b with IC50 of 4.70 µg/mL and SI of 20.89, could be considered as early hit compounds for future design and synthesis of anti-Toxoplasma agents that effectively and selectively block the invasion and subsequent proliferation of T. gondii into host cells.
      Citation: Cells
      PubDate: 2021-04-29
      DOI: 10.3390/cells10051053
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1054: Manifestations of Age on Autophagy, Mitophagy
           and Lysosomes in Skeletal Muscle

    • Authors: Matthew Triolo, David A. Hood
      First page: 1054
      Abstract: Sarcopenia is the loss of both muscle mass and function with age. Although the molecular underpinnings of sarcopenia are not fully understood, numerous pathways are implicated, including autophagy, in which defective cargo is selectively identified and degraded at the lysosome. The specific tagging and degradation of mitochondria is termed mitophagy, a process important for the maintenance of an organelle pool that functions efficiently in energy production and with relatively low reactive oxygen species production. Emerging data, yet insufficient, have implicated various steps in this pathway as potential contributors to the aging muscle atrophy phenotype. Included in this is the lysosome, the end-stage organelle possessing a host of proteolytic and degradative enzymes, and a function devoted to the hydrolysis and breakdown of defective molecular complexes and organelles. This review provides a summary of our current understanding of how the autophagy-lysosome system is regulated in aging muscle, highlighting specific areas where knowledge gaps exist. Characterization of the autophagy pathway with a particular focus on the lysosome will undoubtedly pave the way for the development of novel therapeutic strategies to combat age-related muscle loss.
      Citation: Cells
      PubDate: 2021-04-29
      DOI: 10.3390/cells10051054
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1055: Development of a Decellularized Porcine
           Esophageal Matrix for Potential Applications in Cancer Modeling

    • Authors: Hersh Chaitin, Michael L. Lu, Michael B. Wallace, Yunqing Kang
      First page: 1055
      Abstract: Many decellularized extracellular matrix-derived whole organs have been widely used in studies of tissue engineering and cancer models. However, decellularizing porcine esophagus to obtain decellularized esophageal matrix (DEM) for potential biomedical applications has not been widely investigated. In this study a modified decellularization protocol was employed to prepare a porcine esophageal DEM for the study of cancer cell growth. The cellular removal and retention of matrix components in the porcine DEM were fully characterized. The microstructure of the DEM was observed using scanning electronic microscopy. Human esophageal squamous cell carcinoma (ESCC) and human primary esophageal fibroblast cells (FBCs) were seeded in the DEM to observe their growth. Results show that the decellularization process did not cause significant loss of mechanical properties and that blood ducts and lymphatic vessels in the submucosa layer were also preserved. ESCC and FBCs grew on the DEM well and the matrix did not show any toxicity to cells. When FBS and ESCC were cocultured on the matrix, they secreted more periostin, a protein that supports cell adhesion on matrix. This study shows that the modified decellularization protocol can effectively remove the cell materials and maintain the microstructure of the porcine esophageal matrix, which has the potential application of studying cell growth and migration for esophageal cancer models.
      Citation: Cells
      PubDate: 2021-04-29
      DOI: 10.3390/cells10051055
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1056: Mechanisms of Metabolic Reprogramming in
           Cancer Cells Supporting Enhanced Growth and Proliferation

    • Authors: Chelsea Schiliro, Bonnie L. Firestein
      First page: 1056
      Abstract: Cancer cells alter metabolic processes to sustain their characteristic uncontrolled growth and proliferation. These metabolic alterations include (1) a shift from oxidative phosphorylation to aerobic glycolysis to support the increased need for ATP, (2) increased glutaminolysis for NADPH regeneration, (3) altered flux through the pentose phosphate pathway and the tricarboxylic acid cycle for macromolecule generation, (4) increased lipid uptake, lipogenesis, and cholesterol synthesis, (5) upregulation of one-carbon metabolism for the production of ATP, NADH/NADPH, nucleotides, and glutathione, (6) altered amino acid metabolism, (7) metabolism-based regulation of apoptosis, and (8) the utilization of alternative substrates, such as lactate and acetate. Altered metabolic flux in cancer is controlled by tumor-host cell interactions, key oncogenes, tumor suppressors, and other regulatory molecules, including non-coding RNAs. Changes to metabolic pathways in cancer are dynamic, exhibit plasticity, and are often dependent on the type of tumor and the tumor microenvironment, leading in a shift of thought from the Warburg Effect and the “reverse Warburg Effect” to metabolic plasticity. Understanding the complex nature of altered flux through these multiple pathways in cancer cells can support the development of new therapies.
      Citation: Cells
      PubDate: 2021-04-29
      DOI: 10.3390/cells10051056
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1057: Oral Administration of Lactobacillus rhamnosus
           Ameliorates the Progression of Osteoarthritis by Inhibiting Joint Pain and
           Inflammation

    • Authors: JooYeon Jhun, Keun-Hyung Cho, Dong-Hwan Lee, Ji Ye Kwon, Jin Seok Woo, Jiyoung Kim, Hyun Sik Na, Sung-Hwan Park, Seok Jung Kim, Mi-La Cho
      First page: 1057
      Abstract: Osteoarthritis (OA) is the most common form of arthritis and age-related degenerative joint disorder, which adversely affects quality of life and causes disability. However, the pathogenesis of OA remains unclear. This study was performed to examine the effects of Lactobacillus rhamnosus in OA progression. OA was induced in 6-week-old male Wistar rats by monosodium iodoacetate (MIA) injection, and the effects of oral administration of L. rhamnosus were examined in this OA rat model. Pain severity, cartilage destruction, and inflammation were measured in MIA-induced OA rats. The small intestines were isolated from OA rats, and the intestinal structure and inflammation were measured. Protein expression in the dorsal root ganglion was analyzed by immunohistochemistry. The effects of L. rhamnosus on mRNA and protein expression in chondrocytes stimulated with interleukin (IL)-1β and lipopolysaccharide (LPS) were analyzed by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Pain severity was decreased in L. rhamnosus-treated MIA-induced OA rats. The levels of expression of MCP-1, a potential inflammatory cytokine, and its receptor, CCR2, were decreased, and GABA and PPAR-γ expression were increased in L. rhamnosus-treated OA rats. The inflammation, as determined by IL-1β, and cartilage destruction, as determined by MMP3, were also significantly decreased by L. rhamnosus in OA rats. Additionally, intestinal damage and inflammation were improved by L. rhamnosus. In human OA chondrocytes, TIMP1, TIMP3, SOX9, and COL2A1 which are tissue inhibitors of MMP, and IL-10, an anti-inflammatory cytokine, were increased by L. rhamnosus. L. rhamnosus treatment led to decreased pain severity and cartilage destruction in a rat model of OA. Intestinal damage and inflammation were also decreased by L. rhamnosus treatment. Our findings suggested the therapeutic potential of L. rhamnosus in OA.
      Citation: Cells
      PubDate: 2021-04-29
      DOI: 10.3390/cells10051057
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1058: Enhancing a Natural Killer: Modification of NK
           Cells for Cancer Immunotherapy

    • Authors: Rasa Islam, Aleta Pupovac, Vera Evtimov, Nicholas Boyd, Runzhe Shu, Richard Boyd, Alan Trounson
      First page: 1058
      Abstract: Natural killer (NK) cells are potent innate immune system effector lymphocytes armed with multiple mechanisms for killing cancer cells. Given the dynamic roles of NK cells in tumor surveillance, they are fast becoming a next-generation tool for adoptive immunotherapy. Many strategies are being employed to increase their number and improve their ability to overcome cancer resistance and the immunosuppressive tumor microenvironment. These include the use of cytokines and synthetic compounds to bolster propagation and killing capacity, targeting immune-function checkpoints, addition of chimeric antigen receptors (CARs) to provide cancer specificity and genetic ablation of inhibitory molecules. The next generation of NK cell products will ideally be readily available as an “off-the-shelf” product and stem cell derived to enable potentially unlimited supply. However, several considerations regarding NK cell source, genetic modification and scale up first need addressing. Understanding NK cell biology and interaction within specific tumor contexts will help identify necessary NK cell modifications and relevant choice of NK cell source. Further enhancement of manufacturing processes will allow for off-the-shelf NK cell immunotherapies to become key components of multifaceted therapeutic strategies for cancer.
      Citation: Cells
      PubDate: 2021-04-29
      DOI: 10.3390/cells10051058
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1059: Comparative Study between Exogenously Applied
           Plant Growth Hormones versus Metabolites of Microbial Endophytes as Plant
           Growth-Promoting for Phaseolus vulgaris L.

    • Authors: Mohamed A. Ismail, Mohamed A. Amin, Ahmed M. Eid, Saad El-Din Hassan, Hany A. M. Mahgoub, Islam Lashin, Abdelrhman T. Abdelwahab, Ehab Azab, Adil A. Gobouri, Amr Elkelish, Amr Fouda
      First page: 1059
      Abstract: Microbial endophytes organize symbiotic relationships with the host plant, and their excretions contain diverse plant beneficial matter such as phytohormones and bioactive compounds. In the present investigation, six bacterial and four fungal strains were isolated from the common bean (Phaseolus vulgaris L.) root plant, identified using molecular techniques, and their growth-promoting properties were reviewed. All microbial isolates showed varying activities to produce indole-3-acetic acid (IAA) and different hydrolytic enzymes such as amylase, cellulase, protease, pectinase, and xylanase. Six bacterial endophytic isolates displayed phosphate-solubilizing capacity and ammonia production. We conducted a field experiment to evaluate the promotion activity of the metabolites of the most potent endophytic bacterial (Bacillus thuringiensis PB2 and Brevibacillus agri PB5) and fungal (Alternaria sorghi PF2 and, Penicillium commune PF3) strains in comparison to two exogenously applied hormone, IAA, and benzyl adenine (BA), on the growth and biochemical characteristics of the P. vulgaris L. Interestingly, our investigations showed that bacterial and fungal endophytic metabolites surpassed the exogenously applied hormones in increasing the plant biomass, photosynthetic pigments, carbohydrate and protein contents, antioxidant enzyme activity, endogenous hormones and yield traits. Our findings illustrate that the endophyte Brevibacillus agri (PB5) provides high potential as a stimulator for the growth and productivity of common bean plants.
      Citation: Cells
      PubDate: 2021-04-29
      DOI: 10.3390/cells10051059
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1060: Modulation of microRNome by Human
           Cytomegalovirus and Human Herpesvirus 6 Infection in Human Dermal
           Fibroblasts: Possible Significance in the Induction of Fibrosis in
           Systemic Sclerosis

    • Authors: Irene Soffritti, Maria D’Accolti, Gloria Ravegnini, Maria-Cristina Arcangeletti, Clara Maccari, Flora De Conto, Adriana Calderaro, Elisabetta Caselli
      First page: 1060
      Abstract: Human cytomegalovirus (HCMV) and Human herpesvirus 6 (HHV-6) have been reportedly suggested as triggers of the onset and/or progression of systemic sclerosis (SSc), a severe autoimmune disorder characterized by multi-organ fibrosis. The etiology and pathogenesis of SSc are still largely unknown but virological and immunological observations support a role for these beta-herpesviruses, and we recently observed a direct impact of HCMV and HHV-6 infection on the expression of cell factors associated with fibrosis at the cell level. Since miRNA expression has been found profoundly deregulated at the tissue level, here we aimed to investigate the impact on cell microRNome (miRNome) of HCMV and HHV-6 infection in in vitro infected primary human dermal fibroblasts, which represent one of the main SSc target cells. The analysis, performed by Taqman arrays detecting and quantifying 754 microRNAs (miRNAs), showed that both herpesviruses significantly modulated miRNA expression in infected cells, with evident early and late effects and deep modulation (>10 fold) of >40 miRNAs at each time post infection, including those previously recognized for their key function in fibrosis. The correlation between these in vitro results with in vivo observations is strongly suggestive of a role of HCMV and/or HHV-6 in the multistep pathogenesis of fibrosis in SSc and in the induction of fibrosis-signaling pathways finally leading to tissue fibrosis. The identification of specific miRNAs may open the way to their use as biomarkers for SSc diagnosis, assessment of disease progression and possible antifibrotic therapies.
      Citation: Cells
      PubDate: 2021-04-29
      DOI: 10.3390/cells10051060
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1061: HDL in Immune-Inflammatory Responses:
           Implications beyond Cardiovascular Diseases

    • Authors: Fabrizia Bonacina, Angela Pirillo, Alberico L. Catapano, Giuseppe D. Norata
      First page: 1061
      Abstract: High density lipoproteins (HDL) are heterogeneous particles composed by a vast array of proteins and lipids, mostly recognized for their cardiovascular (CV) protective effects. However, evidences from basic to clinical research have contributed to depict a role of HDL in the modulation of immune-inflammatory response thus paving the road to investigate their involvement in other diseases beyond those related to the CV system. HDL-C levels and HDL composition are indeed altered in patients with autoimmune diseases and usually associated to disease severity. At molecular levels, HDL have been shown to modulate the anti-inflammatory potential of endothelial cells and, by controlling the amount of cellular cholesterol, to interfere with the signaling through plasma membrane lipid rafts in immune cells. These findings, coupled to observations acquired from subjects carrying mutations in genes related to HDL system, have helped to elucidate the contribution of HDL beyond cholesterol efflux thus posing HDL-based therapies as a compelling interventional approach to limit the inflammatory burden of immune-inflammatory diseases.
      Citation: Cells
      PubDate: 2021-04-29
      DOI: 10.3390/cells10051061
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1062: Weapons Evolve Faster Than Sperm in Bovids and
           Cervids

    • Authors: Charel Reuland, Leigh W. Simmons, Stefan Lüpold, John L. Fitzpatrick
      First page: 1062
      Abstract: In polyandrous species, males face reproductive competition both before and after mating. Sexual selection thus shapes the evolution of both pre- and postcopulatory traits, creating competing demands on resource allocation to different reproductive episodes. Traits subject to strong selection exhibit accelerated rates of phenotypic divergence, and examining evolutionary rates may inform us about the relative importance and potential fitness consequences of investing in traits under either pre- or postcopulatory sexual selection. Here, we used a comparative approach to assess evolutionary rates of key competitive traits in two artiodactyl families, bovids (family Bovidae) and cervids (family Cervidae), where male–male competition can occur before and after mating. We quantified and compared evolutionary rates of male weaponry (horns and antlers), body size/mass, testes mass, and sperm morphometrics. We found that weapons evolve faster than sperm dimensions. In contrast, testes and body mass evolve at similar rates. These results suggest strong, but differential, selection on both pre- and postcopulatory traits in bovids and cervids. Furthermore, we documented distinct evolutionary rates among different sperm components, with sperm head and midpiece evolving faster than the flagellum. Finally, we demonstrate that, despite considerable differences in weapon development between bovids and cervids, the overall evolutionary patterns between these families were broadly consistent.
      Citation: Cells
      PubDate: 2021-04-29
      DOI: 10.3390/cells10051062
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1063: Metabolite Biomarkers of Leishmania Antimony
           Resistance

    • Authors: Sneider Alexander Gutierrez Guarnizo, Zemfira N. Karamysheva, Elkin Galeano, Carlos E. Muskus
      First page: 1063
      Abstract: Leishmania parasites cause leishmaniasis, one of the most epidemiologically important neglected tropical diseases. Leishmania exhibits a high ability of developing drug resistance, and drug resistance is one of the main threats to public health, as it is associated with increased incidence, mortality, and healthcare costs. The antimonial drug is the main historically implemented drug for leishmaniasis. Nevertheless, even though antimony resistance has been widely documented, the mechanisms involved are not completely understood. In this study, we aimed to identify potential metabolite biomarkers of antimony resistance that could improve leishmaniasis treatment. Here, using L. tropica promastigotes as the biological model, we showed that the level of response to antimony can be potentially predicted using 1H-NMR-based metabolomic profiling. Antimony-resistant parasites exhibited differences in metabolite composition at the intracellular and extracellular levels, suggesting that a metabolic remodeling is required to combat the drug. Simple and time-saving exometabolomic analysis can be efficiently used for the differentiation of sensitive and resistant parasites. Our findings suggest that changes in metabolite composition are associated with an optimized response to the osmotic/oxidative stress and a rearrangement of carbon-energy metabolism. The activation of energy metabolism can be linked to the high energy requirement during the antioxidant stress response. We also found that metabolites such as proline and lactate change linearly with the level of resistance to antimony, showing a close relationship with the parasite’s efficiency of drug resistance. A list of potential metabolite biomarkers is described and discussed.
      Citation: Cells
      PubDate: 2021-04-30
      DOI: 10.3390/cells10051063
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1064: Plant Acyl-CoA-Binding Proteins—Their Lipid
           and Protein Interactors in Abiotic and Biotic Stresses

    • Authors: Sze-Han Lai, Mee-Len Chye
      First page: 1064
      Abstract: Plants are constantly exposed to environmental stresses during their growth and development. Owing to their immobility, plants possess stress-sensing abilities and adaptive responses to cope with the abiotic and biotic stresses caused by extreme temperatures, drought, flooding, salinity, heavy metals and pathogens. Acyl-CoA-binding proteins (ACBPs), a family of conserved proteins among prokaryotes and eukaryotes, bind to a variety of acyl-CoA esters with different affinities and play a role in the transport and maintenance of subcellular acyl-CoA pools. In plants, studies have revealed ACBP functions in development and stress responses through their interactions with lipids and protein partners. This review summarises the roles of plant ACBPs and their lipid and protein interactors in abiotic and biotic stress responses.
      Citation: Cells
      PubDate: 2021-04-30
      DOI: 10.3390/cells10051064
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1065: The MAL Protein, an Integral Component of
           Specialized Membranes, in Normal Cells and Cancer

    • Authors: Armando Rubio-Ramos, Leticia Labat-de-Hoz, Isabel Correas, Miguel A. Alonso
      First page: 1065
      Abstract: The MAL gene encodes a 17-kDa protein containing four putative transmembrane segments whose expression is restricted to human T cells, polarized epithelial cells and myelin-forming cells. The MAL protein has two unusual biochemical features. First, it has lipid-like properties that qualify it as a member of the group of proteolipid proteins. Second, it partitions selectively into detergent-insoluble membranes, which are known to be enriched in condensed cell membranes, consistent with MAL being distributed in highly ordered membranes in the cell. Since its original description more than thirty years ago, a large body of evidence has accumulated supporting a role of MAL in specialized membranes in all the cell types in which it is expressed. Here, we review the structure, expression and biochemical characteristics of MAL, and discuss the association of MAL with raft membranes and the function of MAL in polarized epithelial cells, T lymphocytes, and myelin-forming cells. The evidence that MAL is a putative receptor of the epsilon toxin of Clostridium perfringens, the expression of MAL in lymphomas, the hypermethylation of the MAL gene and subsequent loss of MAL expression in carcinomas are also presented. We propose a model of MAL as the organizer of specialized condensed membranes to make them functional, discuss the role of MAL as a tumor suppressor in carcinomas, consider its potential use as a cancer biomarker, and summarize the directions for future research.
      Citation: Cells
      PubDate: 2021-04-30
      DOI: 10.3390/cells10051065
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1066: Integrated microRNA and mRNA Expression
           Profiling Identifies Novel Targets and Networks Associated with
           Ebstein’s Anomaly

    • Authors: Masood Abu-Halima, Viktoria Wagner, Lea Simone Becker, Basim M. Ayesh, Mohammed Abd El-Rahman, Ulrike Fischer, Eckart Meese, Hashim Abdul-Khaliq
      First page: 1066
      Abstract: Little is known about abundance level changes of circulating microRNAs (miRNAs) and messenger RNAs (mRNA) in patients with Ebstein’s anomaly (EA). Here, we performed an integrated analysis to identify the differentially abundant miRNAs and mRNA targets and to identify the potential therapeutic targets that might be involved in the mechanisms underlying EA. A large panel of human miRNA and mRNA microarrays were conducted to determine the genome-wide expression profiles in the blood of 16 EA patients and 16 age and gender-matched healthy control volunteers (HVs). Differential abundance level of single miRNA and mRNA was validated by Real-Time quantitative PCR (RT-qPCR). Enrichment analyses of altered miRNA and mRNA abundance levels were identified using bioinformatics tools. Altered miRNA and mRNA abundance levels were observed between EA patients and HVs. Among the deregulated miRNAs and mRNAs, 76 miRNAs (49 lower abundance and 27 higher abundance, fold-change of ≥2) and 29 mRNAs (25 higher abundance and 4 lower abundance, fold-change of ≥1.5) were identified in EA patients compared to HVs. Bioinformatics analysis identified 37 pairs of putative miRNA-mRNA interactions. The majority of the correlations were detected between the lower abundance level of miRNA and higher abundance level of mRNA, except for let-7b-5p, which showed a higher abundance level and their target gene, SCRN3, showed a lower abundance level. Pathway enrichment analysis of the deregulated mRNAs identified 35 significant pathways that are mostly involved in signal transduction and cellular interaction pathways. Our findings provide new insights into a potential molecular biomarker(s) for the EA that may guide the development of novel targeting therapies.
      Citation: Cells
      PubDate: 2021-04-30
      DOI: 10.3390/cells10051066
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1067: Metformin Dysregulates the Unfolded Protein
           Response and the WNT/β-Catenin Pathway in Endometrial Cancer Cells
           through an AMPK-Independent Mechanism

    • Authors: Domenico Conza, Paola Mirra, Gaetano Calì, Luigi Insabato, Francesca Fiory, Francesco Beguinot, Luca Ulianich
      First page: 1067
      Abstract: Multiple lines of evidence suggest that metformin, an antidiabetic drug, exerts anti-tumorigenic effects in different types of cancer. Metformin has been reported to affect cancer cells’ metabolism and proliferation mainly through the activation of AMP-activated protein kinase (AMPK). Here, we show that metformin inhibits, indeed, endometrial cancer cells’ growth and induces apoptosis. More importantly, we report that metformin affects two important pro-survival pathways, such as the Unfolded Protein Response (UPR), following endoplasmic reticulum stress, and the WNT/β-catenin pathway. GRP78, a key protein in the pro-survival arm of the UPR, was indeed downregulated, while GADD153/CHOP, a transcription factor that mediates the pro-apoptotic response of the UPR, was upregulated at both the mRNA and protein level. Furthermore, metformin dramatically inhibited β-catenin mRNA and protein expression. This was paralleled by a reduction in β-catenin transcriptional activity, since metformin inhibited the activity of a TCF/LEF-luciferase promoter. Intriguingly, compound C, a well-known inhibitor of AMPK, was unable to prevent all these effects, suggesting that metformin might inhibit endometrial cancer cells’ growth and survival through the modulation of specific branches of the UPR and the inhibition of the Wnt/β-catenin pathway in an AMPK-independent manner. Our findings may provide new insights on the mechanisms of action of metformin and refine the use of this drug in the treatment of endometrial cancer.
      Citation: Cells
      PubDate: 2021-04-30
      DOI: 10.3390/cells10051067
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1068: The Contribution of Lysosomes to DNA
           Replication

    • Authors: Joanna Maria Merchut-Maya, Apolinar Maya-Mendoza
      First page: 1068
      Abstract: Lysosomes, acidic, membrane-bound organelles, are not only the core of the cellular recycling machinery, but they also serve as signaling hubs regulating various metabolic pathways. Lysosomes maintain energy homeostasis and provide pivotal substrates for anabolic processes, such as DNA replication. Every time the cell divides, its genome needs to be correctly duplicated; therefore, DNA replication requires rigorous regulation. Challenges that negatively affect DNA synthesis, such as nucleotide imbalance, result in replication stress with severe consequences for genome integrity. The lysosomal complex mTORC1 is directly involved in the synthesis of purines and pyrimidines to support DNA replication. Numerous drugs have been shown to target lysosomal function, opening an attractive avenue for new treatment strategies against various pathologies, including cancer. In this review, we focus on the interplay between lysosomal function and DNA replication through nucleic acid degradation and nucleotide biosynthesis and how these could be exploited for therapeutic purposes.
      Citation: Cells
      PubDate: 2021-04-30
      DOI: 10.3390/cells10051068
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1069: Cytokine Levels in Human Vitreous in
           Proliferative Diabetic Retinopathy

    • Authors: Dean F. Loporchio, Emily K. Tam, Jane Cho, Jaeyoon Chung, Gyungah R. Jun, Weiming Xia, Marissa G. Fiorello, Nicole H. Siegel, Steven Ness, Thor D. Stein, Manju L. Subramanian
      First page: 1069
      Abstract: In this study, we compare the vitreous cytokine profile in patients with proliferative diabetic retinopathy (PDR) to that of patients without PDR. The identification of novel cytokines involved in the pathogenesis of PDR provides candidate therapeutic targets that may stand alone or work synergistically with current therapies in the management of diabetic retinopathy. Undiluted vitreous humor specimens were collected from 74 patients undergoing vitrectomy for various vitreoretinal disorders. Quantitative immunoassay was performed for a panel of 36 neuroinflammatory cytokines in each specimen and assessed to identify differences between PDR (n = 35) and non-PDR (n = 39) patients. Levels of interleukin-8 (IL-8), IL-15, IL-16, vascular endothelial growth factor (VEGF), VEGF-D, c-reactive protein (CRP), serum amyloid-A (SAA), and intracellular adhesion molecule-1 (ICAM1) were significantly increased in the vitreous of PDR patients compared to non-PDR patients (p < 0.05). We report novel increases in IL-15 and IL-16, in addition to the expected VEGF, in the human vitreous humor of patients with PDR. Additionally, we confirm the elevation of ICAM-1, VCAM-1, SAA, IL-8 and CRP in the vitreous of patients with PDR, which has previously been described.
      Citation: Cells
      PubDate: 2021-04-30
      DOI: 10.3390/cells10051069
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1070: Cancer Stem Cells and Neovascularization

    • Authors: Fengkai Li, Jiahui Xu, Suling Liu
      First page: 1070
      Abstract: Cancer stem cells (CSCs) refer to a subpopulation of cancer cells responsible for tumorigenesis, metastasis, and drug resistance. Increasing evidence suggests that CSC-associated tumor neovascularization partially contributes to the failure of cancer treatment. In this review, we discuss the roles of CSCs on tumor-associated angiogenesis via trans-differentiation or forming the capillary-like vasculogenic mimicry, as well as the roles of CSCs on facilitating endothelial cell-involved angiogenesis to support tumor progression and metastasis. Furthermore, we discuss the underlying regulation mechanisms, including the intrinsic signals of CSCs and the extrinsic signals such as cytokines from the tumor microenvironment. Further research is required to identify and verify some novel targets to develop efficient therapeutic approaches for more efficient cancer treatment through interfering CSC-mediated neovascularization.
      Citation: Cells
      PubDate: 2021-04-30
      DOI: 10.3390/cells10051070
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1071: Endothelial and Vascular Health: A Tale of
           Honey, H2O2 and Calcium

    • Authors: Elia Ranzato, Gregorio Bonsignore, Mauro Patrone, Simona Martinotti
      First page: 1071
      Abstract: Intracellular Ca2+ regulation plays a pivotal role in endothelial biology as well as during endothelial restoration processes. Interest in honey utilization in wound approaches is rising in recent years. In order to evaluate the positive effects of buckwheat honey on endothelial responses, we utilized an immortalized endothelial cell line to evaluate cellular responses upon honey exposure, with particular interest in Ca2+ signaling involvement. The results highlight the positive effects of buckwheat honey on endothelial cells’ responses and the central role played by Ca2+ signaling as an encouraging target for more efficacious clinical treatments.
      Citation: Cells
      PubDate: 2021-04-30
      DOI: 10.3390/cells10051071
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1072: Cartilage Protective and Immunomodulatory
           Features of Osteoarthritis Synovial Fluid-Treated Adipose-Derived
           Mesenchymal Stem Cells Secreted Factors and Extracellular
           Vesicles-Embedded miRNAs

    • Authors: Enrico Ragni, Alessandra Colombini, Marco Viganò, Francesca Libonati, Carlotta Perucca Orfei, Luigi Zagra, Laura de Girolamo
      First page: 1072
      Abstract: Intra-articular administration of adipose-derived mesenchymal stem cells (ASCs), either in vitro expanded or within adipose tissue-based products obtained at point-of-care, has gained popularity as innovative regenerative medicine approach for osteoarthritis (OA) treatment. ASCs can stimulate tissue repair and immunomodulation through paracrine factors, both soluble and extracellular vesicles (EV) embedded, collectively defining the secretome. Interaction with the degenerative/inflamed environment is a crucial factor in understanding the finely tuned molecular message but, to date, the majority of reports have described ASC-secretome features in resting conditions or under chemical stimuli far from the in vivo environment of degenerated OA joints. In this report, the secretory profile of ASCs treated with native synovial fluid from OA patients was evaluated, sifting 200 soluble factors and 754 EV-embedded miRNAs. Fifty-eight factors and 223 EV-miRNAs were identified, and discussed in the frame of cartilage and immune cell homeostasis. Bioinformatics gave a molecular basis for M2 macrophage polarization, T cell proliferation inhibition and T reg expansion enhancement, as well as cartilage protection, further confirmed in an in vitro model of OA chondrocytes. Moreover, a strong influence on immune cell chemotaxis emerged. In conclusion, obtained molecular data support the regenerative and immunomodulatory properties of ASCs when interacting with osteoarthritic joint environment.
      Citation: Cells
      PubDate: 2021-04-30
      DOI: 10.3390/cells10051072
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1073: Myeloid-Derived Suppressor Cells as
           Therapeutic Targets in Uterine Cervical and Endometrial Cancers

    • Authors: Seiji Mabuchi, Tomoyuki Sasano
      First page: 1073
      Abstract: Uterine cervical and endometrial cancers are the two most common gynecological malignancies. As demonstrated in other types of solid malignancies, an increased number of circulating or tumor-infiltrating myeloid-derived suppressor cells (MDSCs) have also been observed in uterine cervical and endometrial cancers, and increased MDSCs are associated with an advanced stage, a short survival, or a poor response to chemotherapy or radiotherapy. In murine models of uterine cervical and endometrial cancers, MDSCs have been shown to play important roles in the progression of cancer. In this review, we have introduced the definition of MDSCs and their functions, discussed the roles of MDSCs in uterine cervical and endometrial cancer progression, and reviewed treatment strategies targeting MDSCs, which may exhibit growth-inhibitory effects and enhance the efficacy of existing anticancer treatments.
      Citation: Cells
      PubDate: 2021-04-30
      DOI: 10.3390/cells10051073
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1074: The Route of Early T Cell Development:
           Crosstalk between Epigenetic and Transcription Factors

    • Authors: Veronica Della Chiara, Lucia Daxinger, Frank J. T. Staal
      First page: 1074
      Abstract: Hematopoietic multipotent progenitors seed the thymus and then follow consecutive developmental stages until the formation of mature T cells. During this process, phenotypic changes of T cells entail stage-specific transcriptional programs that underlie the dynamic progression towards mature lymphocytes. Lineage-specific transcription factors are key drivers of T cell specification and act in conjunction with epigenetic regulators that have also been elucidated as crucial players in the establishment of regulatory networks necessary for proper T cell development. In this review, we summarize the activity of transcription factors and epigenetic regulators that together orchestrate the intricacies of early T cell development with a focus on regulation of T cell lineage commitment.
      Citation: Cells
      PubDate: 2021-04-30
      DOI: 10.3390/cells10051074
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1075: The Type and Source of Reactive Oxygen Species
           Influences the Outcome of Oxidative Stress in Cultured Cells

    • Authors: Goffart, Tikkanen, Michell, Wilson, Pohjoismäki
      First page: 1075
      Abstract: Oxidative stress can be modeled using various different experimental approaches, such as exposing the cells or organisms to oxidative chemicals. However, the actual effects of these chemicals, outside of the immediate measured effect, have attracted relatively little attention. We show here that three commonly used oxidants, menadione, potassium bromate, and hydrogen peroxide, while known to function differently, also elicit different types of responses in HEK293T cells. Menadione and bromate exposure mainly trigger an integrated stress response, whereas hydrogen peroxide affects cellular processes more diversely. Interestingly, acute oxidative stress does not universally cause notable induction of DNA repair or antioxidant defense mechanisms. We also provide evidence that cells with previous experience of oxidative stress show adaptive changes in their responses when the stress is renewed. Our results urge caution when comparing studies where different sources of oxidative stress have been used or when generalizing the findings of these studies to other oxidant types or tissues.
      Citation: Cells
      PubDate: 2021-04-30
      DOI: 10.3390/cells10051075
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1076: An Optimized Preparation Method for Long ssDNA
           Donors to Facilitate Quick Knock-In Mouse Generation

    • Authors: Yukiko U. Inoue, Yuki Morimoto, Mayumi Yamada, Ryosuke Kaneko, Kazumi Shimaoka, Shinji Oki, Mayuko Hotta, Junko Asami, Eriko Koike, Kei Hori, Mikio Hoshino, Itaru Imayoshi, Takayoshi Inoue
      First page: 1076
      Abstract: Fluorescent reporter mouse lines and Cre/Flp recombinase driver lines play essential roles in investigating various molecular functions in vivo. Now that applications of the CRISPR/Cas9 genome-editing system to mouse fertilized eggs have drastically accelerated these knock-in mouse generations, the next need is to establish easier, quicker, and cheaper methods for knock-in donor preparation. Here, we reverify and optimize the phospho-PCR method to obtain highly pure long single-stranded DNAs (ssDNAs) suitable for knock-in mouse generation via genome editing. The sophisticated sequential use of two exonucleases, in which double-stranded DNAs (dsDNAs) amplified by a pair of 5’-phosphorylated primer and normal primer are digested by Lambda exonuclease to yield ssDNA and the following Exonuclease III treatment degrades the remaining dsDNAs, enables much easier long ssDNA productions without laborious gel extraction steps. By microinjecting these donor DNAs along with CRISPR/Cas9 components into mouse zygotes, we have effectively generated fluorescent reporter lines and recombinase drivers. To further broaden the applicability, we have prepared long ssDNA donors in higher concentrations and electroporated them into mouse eggs to successfully obtain knock-in embryos. This classical yet improved method, which is regaining attention on the progress of CRISPR/Cas9 development, shall be the first choice for long donor DNA preparation, and the resulting knock-in lines could accelerate life science research.
      Citation: Cells
      PubDate: 2021-04-30
      DOI: 10.3390/cells10051076
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1077: Combining Mobilizing Agents with Busulfan to
           Reduce Chemotherapy-Based Conditioning for Hematopoietic Stem Cell
           Transplantation

    • Authors: Laura Garcia-Perez, Lieke van van Roon, Marco W. Schilham, Arjan C. Lankester, Karin Pike-Overzet, Frank J.T. Staal
      First page: 1077
      Abstract: In the context of hematopoietic stem cell (HSC) transplantation, conditioning with myelo- and immune-ablative agents is used to eradicate the patient’s diseased cells, generate space in the marrow and suppress immune reactions prior to the infusion of donor HSCs. While conditioning is required for effective and long-lasting HSC engraftment, currently used regimens are also associated with short and long-term side effects on extramedullary tissues and even mortality. Particularly in patients with severe combined immunodeficiency (SCID), who are generally less than 1-year old at the time of transplantation and often suffer from existing comorbidities. There is a pressing need for development of alternative, less toxic conditioning regimens. Hence, we here aimed to improve efficacy of currently used myeloablative protocols by combining busulfan with stem-cell niche-directed therapeutic agents (G-CSF or plerixafor) that are approved for clinical use in stem cell mobilization. T, B and myeloid cell recovery was analyzed in humanized NSG mice after different conditioning regimens. Increasing levels of human leukocyte chimerism were observed in a busulfan dose-dependent manner, showing comparable immune recovery as with total body irradiation in CD34-transplanted NSG mice. Notably, a better T cell reconstitution compared to TBI was observed after busulfan conditioning not only in NSG mice but also in SCID mouse models. Direct effects of reducing the stem cell compartment in the bone marrow were observed after G-CSF and plerixafor administration, as well as in combination with low doses of busulfan. Unfortunately, these direct effects on the stem population in the bone marrow were not reflected in increased human chimerism or immune recovery after CD34 transplantation in NSG mice. These results indicate moderate potential of reduced conditioning regimens for clinical use relevant for all allogeneic transplants.
      Citation: Cells
      PubDate: 2021-04-30
      DOI: 10.3390/cells10051077
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1078: The Role of Lipids, Lipid Metabolism and
           Ectopic Lipid Accumulation in Axon Growth, Regeneration and Repair after
           CNS Injury and Disease

    • Authors: Debasish Roy, Andrea Tedeschi
      First page: 1078
      Abstract: Axons in the adult mammalian nervous system can extend over formidable distances, up to one meter or more in humans. During development, axonal and dendritic growth requires continuous addition of new membrane. Of the three major kinds of membrane lipids, phospholipids are the most abundant in all cell membranes, including neurons. Not only immature axons, but also severed axons in the adult require large amounts of lipids for axon regeneration to occur. Lipids also serve as energy storage, signaling molecules and they contribute to tissue physiology, as demonstrated by a variety of metabolic disorders in which harmful amounts of lipids accumulate in various tissues through the body. Detrimental changes in lipid metabolism and excess accumulation of lipids contribute to a lack of axon regeneration, poor neurological outcome and complications after a variety of central nervous system (CNS) trauma including brain and spinal cord injury. Recent evidence indicates that rewiring lipid metabolism can be manipulated for therapeutic gain, as it favors conditions for axon regeneration and CNS repair. Here, we review the role of lipids, lipid metabolism and ectopic lipid accumulation in axon growth, regeneration and CNS repair. In addition, we outline molecular and pharmacological strategies to fine-tune lipid composition and energy metabolism in neurons and non-neuronal cells that can be exploited to improve neurological recovery after CNS trauma and disease.
      Citation: Cells
      PubDate: 2021-05-01
      DOI: 10.3390/cells10051078
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1079: The Role of Protein Arginine Methylation as
           Post-Translational Modification on Actin Cytoskeletal Components in
           Neuronal Structure and Function

    • Authors: Britta Qualmann, Michael M. Kessels
      First page: 1079
      Abstract: The brain encompasses a complex network of neurons with exceptionally elaborated morphologies of their axonal (signal-sending) and dendritic (signal-receiving) parts. De novo actin filament formation is one of the major driving and steering forces for the development and plasticity of the neuronal arbor. Actin filament assembly and dynamics thus require tight temporal and spatial control. Such control is particularly effective at the level of regulating actin nucleation-promoting factors, as these are key components for filament formation. Arginine methylation represents an important post-translational regulatory mechanism that had previously been mainly associated with controlling nuclear processes. We will review and discuss emerging evidence from inhibitor studies and loss-of-function models for protein arginine methyltransferases (PRMTs), both in cells and whole organisms, that unveil that protein arginine methylation mediated by PRMTs represents an important regulatory mechanism in neuritic arbor formation, as well as in dendritic spine induction, maturation and plasticity. Recent results furthermore demonstrated that arginine methylation regulates actin cytosolic cytoskeletal components not only as indirect targets through additional signaling cascades, but can also directly control an actin nucleation-promoting factor shaping neuronal cells—a key process for the formation of neuronal networks in vertebrate brains.
      Citation: Cells
      PubDate: 2021-05-01
      DOI: 10.3390/cells10051079
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1080: Microtubule-Associated Protein ATIP3, an
           Emerging Target for Personalized Medicine in Breast Cancer

    • Authors: Maria M. Haykal, Sylvie Rodrigues-Ferreira, Clara Nahmias
      First page: 1080
      Abstract: Breast cancer is the leading cause of death by malignancy among women worldwide. Clinical data and molecular characteristics of breast tumors are essential to guide clinician’s therapeutic decisions. In the new era of precision medicine, that aims at personalizing the treatment for each patient, there is urgent need to identify robust companion biomarkers for new targeted therapies. This review focuses on ATIP3, a potent anti-cancer protein encoded by candidate tumor suppressor gene MTUS1, whose expression levels are markedly down-regulated in breast cancer. ATIP3 is a microtubule-associated protein identified both as a prognostic biomarker of patient survival and a predictive biomarker of breast tumors response to taxane-based chemotherapy. We present here recent studies pointing out ATIP3 as an emerging anti-cancer protein and a potential companion biomarker to be combined with future personalized therapy against ATIP3-deficient breast cancer.
      Citation: Cells
      PubDate: 2021-05-01
      DOI: 10.3390/cells10051080
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1081: AGMO Inhibitor Reduces 3T3-L1 Adipogenesis

    • Authors: Caroline Fischer, Annett Wilken-Schmitz, Victor Hernandez-Olmos, Ewgenij Proschak, Holger Stark, Ingrid Fleming, Andreas Weigert, Manuela Thurn, Martine Hofmann, Ernst R. Werner, Gerd Geisslinger, Ellen Niederberger, Katrin Watschinger, Irmgard Tegeder
      First page: 1081
      Abstract: Alkylglycerol monooxygenase (AGMO) is a tetrahydrobiopterin (BH4)-dependent enzyme with major expression in the liver and white adipose tissue that cleaves alkyl ether glycerolipids. The present study describes the disclosure and biological characterization of a candidate compound (Cp6), which inhibits AGMO with an IC50 of 30–100 µM and 5–20-fold preference of AGMO relative to other BH4-dependent enzymes, i.e., phenylalanine-hydroxylase and nitric oxide synthase. The viability and metabolic activity of mouse 3T3-L1 fibroblasts, HepG2 human hepatocytes and mouse RAW264.7 macrophages were not affected up to 10-fold of the IC50. However, Cp6 reversibly inhibited the differentiation of 3T3-L1 cells towards adipocytes, in which AGMO expression was upregulated upon differentiation. Cp6 reduced the accumulation of lipid droplets in adipocytes upon differentiation and in HepG2 cells exposed to free fatty acids. Cp6 also inhibited IL-4-driven differentiation of RAW264.7 macrophages towards M2-like macrophages, which serve as adipocyte progenitors in adipose tissue. Collectively, the data suggest that pharmacologic AGMO inhibition may affect lipid storage.
      Citation: Cells
      PubDate: 2021-05-01
      DOI: 10.3390/cells10051081
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1082: The Genomic Landscape of Thyroid Cancer
           Tumourigenesis and Implications for Immunotherapy

    • Authors: Amandeep Singh, Jeehoon Ham, Joseph William Po, Navin Niles, Tara Roberts, Cheok Soon Lee
      First page: 1082
      Abstract: Thyroid cancer is the most prevalent endocrine malignancy that comprises mostly indolent differentiated cancers (DTCs) and less frequently aggressive poorly differentiated (PDTC) or anaplastic cancers (ATCs) with high mortality. Utilisation of next-generation sequencing (NGS) and advanced sequencing data analysis can aid in understanding the multi-step progression model in the development of thyroid cancers and their metastatic potential at a molecular level, promoting a targeted approach to further research and development of targeted treatment options including immunotherapy, especially for the aggressive variants. Tumour initiation and progression in thyroid cancer occurs through constitutional activation of the mitogen-activated protein kinase (MAPK) pathway through mutations in BRAF, RAS, mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway and/or receptor tyrosine kinase fusions/translocations, and other genetic aberrations acquired in a stepwise manner. This review provides a summary of the recent genetic aberrations implicated in the development and progression of thyroid cancer and implications for immunotherapy.
      Citation: Cells
      PubDate: 2021-05-01
      DOI: 10.3390/cells10051082
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1083: The SOS Error-Prone DNA Polymerase V Mutasome
           and β-Sliding Clamp Acting in Concert on Undamaged DNA and during
           Translesion Synthesis

    • Authors: Adhirath Sikand, Malgorzata Jaszczur, Linda B. Bloom, Roger Woodgate, Michael M. Cox, Myron F. Goodman
      First page: 1083
      Abstract: In the mid 1970s, Miroslav Radman and Evelyn Witkin proposed that Escherichia coli must encode a specialized error-prone DNA polymerase (pol) to account for the 100-fold increase in mutations accompanying induction of the SOS regulon. By the late 1980s, genetic studies showed that SOS mutagenesis required the presence of two “UV mutagenesis” genes, umuC and umuD, along with recA. Guided by the genetics, decades of biochemical studies have defined the predicted error-prone DNA polymerase as an activated complex of these three gene products, assembled as a mutasome, pol V Mut = UmuD’2C-RecA-ATP. Here, we explore the role of the β-sliding processivity clamp on the efficiency of pol V Mut-catalyzed DNA synthesis on undamaged DNA and during translesion DNA synthesis (TLS). Primer elongation efficiencies and TLS were strongly enhanced in the presence of β. The results suggest that β may have two stabilizing roles: its canonical role in tethering the pol at a primer-3’-terminus, and a possible second role in inhibiting pol V Mut’s ATPase to reduce the rate of mutasome-DNA dissociation. The identification of umuC, umuD, and recA homologs in numerous strains of pathogenic bacteria and plasmids will ensure the long and productive continuation of the genetic and biochemical journey initiated by Radman and Witkin.
      Citation: Cells
      PubDate: 2021-05-01
      DOI: 10.3390/cells10051083
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1084: Starch Production in Chlamydomonas reinhardtii
           through Supraoptimal Temperature in a Pilot-Scale Photobioreactor

    • Authors: Ivan N. Ivanov, Vilém Zachleder, Milada Vítová, Maria J. Barbosa, Kateřina Bišová
      First page: 1084
      Abstract: An increase in temperature can have a profound effect on the cell cycle and cell division in green algae, whereas growth and the synthesis of energy storage compounds are less influenced. In Chlamydomonas reinhardtii, laboratory experiments have shown that exposure to a supraoptimal temperature (39 °C) causes a complete block of nuclear and cellular division accompanied by an increased accumulation of starch. In this work we explore the potential of supraoptimal temperature as a method to promote starch production in C. reinhardtii in a pilot-scale photobioreactor. The method was successfully applied and resulted in an almost 3-fold increase in the starch content of C. reinhardtii dry matter. Moreover, a maximum starch content at the supraoptimal temperature was reached within 1–2 days, compared with 5 days for the control culture at the optimal temperature (30 °C). Therefore, supraoptimal temperature treatment promotes rapid starch accumulation and suggests a viable alternative to other starch-inducing methods, such as nutrient depletion. Nevertheless, technical challenges, such as bioreactor design and light availability within the culture, still need to be dealt with.
      Citation: Cells
      PubDate: 2021-05-01
      DOI: 10.3390/cells10051084
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1085: Profiling Non-Coding RNA Changes Associated
           with 16 Different Engineered Nanomaterials in a Mouse Airway Exposure
           Model

    • Authors: Joseph Ndika, Piia Karisola, Pia Kinaret, Marit Ilves, Harri Alenius
      First page: 1085
      Abstract: Perturbations in cellular molecular events and their associated biological processes provide opportunities for hazard assessment based on toxicogenomic profiling. Long non-coding RNAs (lncRNAs) are transcribed from DNA but are typically not translated into full-length proteins. Via epigenetic regulation, they play important roles in organismal response to environmental stress. The effects of nanoparticles on this important part of the epigenome are understudied. In this study, we investigated changes in lncRNA associated with hazardous inhalatory exposure of mice to 16 engineered nanomaterials (ENM)–4 ENM (copper oxide, multi-walled carbon nanotubes, spherical titanium dioxide, and rod-like titanium dioxide particles) with 4 different surface chemistries (pristine, COOH, NH2, and PEG). Mice were exposed to 10 µg of ENM by oropharyngeal aspiration for 4 consecutive days, followed by cytological analyses and transcriptomic characterization of whole lung tissues. The number of significantly altered non-coding RNA transcripts, suggestive of their degrees of toxicity, was different for each ENM type. Particle surface chemistry and shape also had varying effects on lncRNA expression. NH2 and PEG caused the strongest and weakest responses, respectively. Via correlational analyses to mRNA expression from the same samples, we could deduce that significantly altered lncRNAs are potential regulators of genes involved in mitotic cell division and DNA damage response. This study sheds more light on epigenetic mechanisms of ENM toxicity and also emphasizes the importance of the lncRNA superfamily as toxicogenomic markers of adverse ENM exposure.
      Citation: Cells
      PubDate: 2021-05-01
      DOI: 10.3390/cells10051085
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1086: Pathophysiological Significance of
           Neutrophilic Transfer RNA-Derived Small RNAs in Asymptomatic Moyamoya
           Disease

    • Authors: Lingzhi Li, Ping Liu, Rongliang Wang, Yuyou Huang, Jichang Luo, Liqun Jiao, Zhen Tao, Yangmin Zheng, Junfen Fan, Haiping Zhao, Ziping Han, Yumin Luo
      First page: 1086
      Abstract: Understanding asymptomatic moyamoya disease (aMMD), for which treatment options are currently limited, is key to the development of therapeutic strategies that will slow down the progression of this disease, as well as facilitate the discovery of therapeutic targets for symptomatic MMD. Newly found transfer RNA-derived small RNAs (tsRNAs) perform potential regulatory functions in neovascularization, which is a well-known pathological manifestation of MMD. In this study, the neutrophilic tsRNA transcriptome in aMMD was profiled using next-generation RNA sequencing in five patients and five matched healthy subjects. A negative binominal generalized log-linear regression was used to identify differentially expressed (DE)-tsRNAs in aMMD. Gene Ontology and functional pathway analyses were used to identify biological pathways involved with the targeted genes of the DE-tsRNAs. Four tsRNAs were selected and validated using quantitative reverse transcription polymerase chain reaction. In total, 186 tsRNAs were DE between the two groups. Pathophysiological events, including immune response, angiogenesis, axon guidance, and metabolism adjustment, were enriched for the DE-tsRNAs. The expression levels of the four DE-tsRNAs were consistent with those in the neutrophilic transcriptome. These aberrantly expressed tsRNAs and their targeted pathophysiological processes provide a basis for potential future interventions for aMMD.
      Citation: Cells
      PubDate: 2021-05-01
      DOI: 10.3390/cells10051086
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1087: Imaging the Renal Microcirculation in Cell
           Therapy

    • Authors: Katerina Apelt, Roel Bijkerk, Franck Lebrin, Ton J. Rabelink
      First page: 1087
      Abstract: Renal microvascular rarefaction plays a pivotal role in progressive kidney disease. Therefore, modalities to visualize the microcirculation of the kidney will increase our understanding of disease mechanisms and consequently may provide new approaches for evaluating cell-based therapy. At the moment, however, clinical practice is lacking non-invasive, safe, and efficient imaging modalities to monitor renal microvascular changes over time in patients suffering from renal disease. To emphasize the importance, we summarize current knowledge of the renal microcirculation and discussed the involvement in progressive kidney disease. Moreover, an overview of available imaging techniques to uncover renal microvascular morphology, function, and behavior is presented with the associated benefits and limitations. Ultimately, the necessity to assess and investigate renal disease based on in vivo readouts with a resolution up to capillary level may provide a paradigm shift for diagnosis and therapy in the field of nephrology.
      Citation: Cells
      PubDate: 2021-05-02
      DOI: 10.3390/cells10051087
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1088: The Impact of Chlorambucil and Valproic Acid
           on Cell Viability, Apoptosis and Expression of p21, HDM2, BCL2 and MCL1
           Genes in Chronic Lymphocytic Leukemia

    • Authors: Katarzyna Lipska, Agata Filip, Anna Gumieniczek
      First page: 1088
      Abstract: Malignant cells in chronic lymphocytic leukemia (CLL) show resistance to apoptosis, as well as to chemotherapy, which are related to deletions or mutations of TP53, high expression of MCL1 and BCL2 genes and other abnormalities. Thus, the main goal of the present study was to assess the impact of chlorambucil (CLB) combined with valproic acid (VPA), a known antiepileptic drug and histone deacetylation inhibitor, on apoptosis of the cells isolated from 17 patients with CLL. After incubation with CLB (17.5 µM) and VPA (0.5 mM), percentage of apoptosis, as well as expression of two TP53 target genes (p21 and HDM2) and two genes from Bcl-2 family (BCL2 and MCL1), were tested. As a result, an increased percentage of apoptosis was observed for CLL cells treated with CLB and VPA, and with CLB alone. Under the treatment with the drug combination, the expression of p21 gene was visibly higher than under the treatment with CLB alone. At the same time, the cultures under CLB treatment showed visibly higher expression of BCL2 than the cultures with VPA alone. Thus, the present study strongly suggests further investigations on the CLB and VPA combination in CLL treatment.
      Citation: Cells
      PubDate: 2021-05-02
      DOI: 10.3390/cells10051088
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1089: Calcium Signaling in Plant Programmed Cell
           Death

    • Authors: Huimin Ren, Xiaohong Zhao, Wenjie Li, Jamshaid Hussain, Guoning Qi, Shenkui Liu
      First page: 1089
      Abstract: Programmed cell death (PCD) is a process intended for the maintenance of cellular homeostasis by eliminating old, damaged, or unwanted cells. In plants, PCD takes place during developmental processes and in response to biotic and abiotic stresses. In contrast to the field of animal studies, PCD is not well understood in plants. Calcium (Ca2+) is a universal cell signaling entity and regulates numerous physiological activities across all the kingdoms of life. The cytosolic increase in Ca2+ is a prerequisite for the induction of PCD in plants. Although over the past years, we have witnessed significant progress in understanding the role of Ca2+ in the regulation of PCD, it is still unclear how the upstream stress perception leads to the Ca2+ elevation and how the signal is further propagated to result in the onset of PCD. In this review article, we discuss recent advancements in the field, and compare the role of Ca2+ signaling in PCD in biotic and abiotic stresses. Moreover, we discuss the upstream and downstream components of Ca2+ signaling and its crosstalk with other signaling pathways in PCD. The review is expected to provide new insights into the role of Ca2+ signaling in PCD and to identify gaps for future research efforts.
      Citation: Cells
      PubDate: 2021-05-02
      DOI: 10.3390/cells10051089
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1090: Aromatic-Turmerone Analogs Protect
           Dopaminergic Neurons in Midbrain Slice Cultures through Their
           Neuroprotective Activities

    • Authors: Yuria Hori, Reiho Tsutsumi, Kento Nasu, Alex Boateng, Yasuhiko Ashikari, Masaharu Sugiura, Makoto Nakajima, Yuki Kurauchi, Akinori Hisatsune, Hiroshi Katsuki, Takahiro Seki
      First page: 1090
      Abstract: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. The inflammatory activation of microglia participates in dopaminergic neurodegeneration in PD. Therefore, chemicals that inhibit microglial activation are considered to have therapeutic potential for PD. Aromatic (ar)-turmerone is a main component of turmeric oil extracted from Curcuma longa and has anti-inflammatory activity in cultured microglia. The aims of the present study are (1) to investigate whether naturally occurring S-enantiomer of ar-turmerone (S-Tur) protects dopaminergic neurons in midbrain slice cultures and (2) to examine ar-turmerone analogs that have higher activities than S-Tur in inhibiting microglial activation and protecting dopaminergic neurons. R-enantiomer (R-Tur) and two analogs showed slightly higher anti-inflammatory effects in microglial BV2 cells. S- and R-Tur and these two analogs reversed dopaminergic neurodegeneration triggered by microglial activation in midbrain slice cultures. Unexpectedly, this neuroprotection was independent of the inhibition of microglial activation. Additionally, two analogs more potently inhibited dopaminergic neurodegeneration triggered by a neurotoxin, 1-methyl-4-phenylpyridinium, than S-Tur. Taken together, we identified two ar-turmerone analogs that directly and potently protected dopaminergic neurons. An investigation using dopaminergic neuronal precursor cells suggested the possible involvement of nuclear factor erythroid 2-related factor 2 in this neuroprotection.
      Citation: Cells
      PubDate: 2021-05-03
      DOI: 10.3390/cells10051090
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1091: Vascular Calcification Progression Modulates
           the Risk Associated with Vascular Calcification Burden in Incident to
           Dialysis Patients

    • Authors: Antonio Bellasi, Luca Di Lullo, Domenico Russo, Roberto Ciarcia, Michele Magnocavallo, Carlo Lavalle, Carlo Ratti, Mario Cozzolino, Biagio Raffaele Di Iorio
      First page: 1091
      Abstract: Background: It is estimated that chronic kidney disease (CKD) accounts globally for 5 to 10 million deaths annually, mainly due to cardiovascular (CV) diseases. Traditional as well as non-traditional CV risk factors such as vascular calcification are believed to drive this disproportionate risk burden. We aimed to investigate the association of coronary artery calcification (CAC) progression with all-cause mortality in patients new to hemodialysis (HD). Methods: Post hoc analysis of the Independent study (NCT00710788). At study inception and after 12 months of follow-up, 414 patients underwent computed tomography imaging for quantification of CAC via the Agatston methods. The square root method was used to assess CAC progression (CACP), and survival analyses were used to test its association with mortality. Results: Over a median follow-up of 36 months, 106 patients died from all causes. Expired patients were older, more likely to be diabetic or to have experienced an atherosclerotic CV event, and exhibited a significantly greater CAC burden (p = 0.002). Survival analyses confirmed an independent association of CAC burden (hazard ratio: 1.29; 95% confidence interval: 1.17–1.44) and CACP (HR: 5.16; 2.61–10.21) with all-cause mortality. CACP mitigated the risk associated with CAC burden (p = 0.002), and adjustment for calcium-free phosphate binder attenuated the strength of the link between CACP and mortality. Conclusions: CAC burden and CACP predict mortality in incident to dialysis patients. However, CACP reduced the risk associated with baseline CAC, and calcium-free phosphate binders attenuated the association of CACP and outcomes, suggesting that CACP modulation may improve survival in this population. Future endeavors are needed to confirm whether drugs or kidney transplantation may attenuate CACP and improve survival in HD patients.
      Citation: Cells
      PubDate: 2021-05-03
      DOI: 10.3390/cells10051091
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1092: Parametric Imaging of Contrast-Enhanced
           Ultrasound (CEUS) for the Evaluation of Acute Gastrointestinal
           Graft-Versus-Host Disease

    • Authors: Antonia-Maria Pausch, Sylvia Kammerer, Florian Weber, Wolfgang Herr, Christian Stroszczynski, Ernst Holler, Matthias Edinger, Daniel Wolff, Daniela Weber, Ernst-Michael Jung, Tobias Wertheimer
      First page: 1092
      Abstract: In recent years contrast-enhanced ultrasound (CEUS) has been an emerging diagnostic modality for the detection of acute gastrointestinal (GI) graft-versus-host disease (GvHD) in patients after allogeneic stem cell transplantation. However, broad clinical usage has been partially limited by its high dependence on the expertise of an experienced examiner. Thus, the aim of this study was to facilitate detection of acute GI GvHD by implementing false color-coded parametric imaging of CEUS. As such, two inexperienced examiners with basic knowledge in abdominal and vascular ultrasound analyzed parametric images obtained from patients with clinical suspicion for acute GvHD in a blinded fashion. As diagnostic gold standard, histopathological GvHD severity score on intestinal biopsies obtained from lower GI tract endoscopy was performed. The evaluation of parametric images by the two inexperienced ultrasound examiners in patients with histological confirmation of acute GI GvHD was successful in 17 out of 19 patients (89%) as opposed to analysis of combined B-mode ultrasound, strain elastography, and CEUS by an experienced examiner, which was successful in 18 out of 19 of the patients (95%). Therefore, CEUS with parametric imaging of the intestine was technically feasible and has the potential to become a valuable diagnostic tool for rapid and widely accessible detection of acute GvHD in clinical practice.
      Citation: Cells
      PubDate: 2021-05-03
      DOI: 10.3390/cells10051092
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1093: ARCGHR Neurons Regulate Muscle Glucose Uptake

    • Authors: Juliana Bezerra Medeiros de Lima, Lucas Kniess Debarba, Alan C. Rupp, Nathan Qi, Chidera Ubah, Manal Khan, Olesya Didyuk, Iven Ayyar, Madelynn Koch, Darleen A. Sandoval, Marianna Sadagurski
      First page: 1093
      Abstract: The growth hormone receptor (GHR) is expressed in brain regions that are known to participate in the regulation of energy homeostasis and glucose metabolism. We generated a novel transgenic mouse line (GHRcre) to characterize GHR-expressing neurons specifically in the arcuate nucleus of the hypothalamus (ARC). Here, we demonstrate that ARCGHR+ neurons are co-localized with agouti-related peptide (AgRP), growth hormone releasing hormone (GHRH), and somatostatin neurons, which are activated by GH stimulation. Using the designer receptors exclusively activated by designer drugs (DREADD) technique to control the ARCGHR+ neuronal activity, we demonstrate that the activation of ARCGHR+ neurons elevates a respiratory exchange ratio (RER) under both fed and fasted conditions. However, while the activation of ARCGHR+ promotes feeding, under fasting conditions, the activation of ARCGHR+ neurons promotes glucose over fat utilization in the body. This effect was accompanied by significant improvements in glucose tolerance, and was specific to GHR+ versus GHRH+ neurons. The activation of ARCGHR+ neurons increased glucose turnover and whole-body glycolysis, as revealed by hyperinsulinemic-euglycemic clamp studies. Remarkably, the increased insulin sensitivity upon the activation of ARCGHR+ neurons was tissue-specific, as the insulin-stimulated glucose uptake was specifically elevated in the skeletal muscle, in parallel with the increased expression of muscle glycolytic genes. Overall, our results identify the GHR-expressing neuronal population in the ARC as a major regulator of glycolysis and muscle insulin sensitivity in vivo.
      Citation: Cells
      PubDate: 2021-05-03
      DOI: 10.3390/cells10051093
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1094: Mechanisms and Functions of Pexophagy in
           Mammalian Cells

    • Authors: Jing Li, Wei Wang
      First page: 1094
      Abstract: Peroxisomes play essential roles in diverse cellular metabolism functions, and their dynamic homeostasis is maintained through the coordination of peroxisome biogenesis and turnover. Pexophagy, selective autophagic degradation of peroxisomes, is a major mechanism for removing damaged and/or superfluous peroxisomes. Dysregulation of pexophagy impairs the physiological functions of peroxisomes and contributes to the progression of many human diseases. However, the mechanisms and functions of pexophagy in mammalian cells remain largely unknown compared to those in yeast. This review focuses on mammalian pexophagy and aims to advance the understanding of the roles of pexophagy in human health and diseases. Increasing evidence shows that ubiquitination can serve as a signal for pexophagy, and ubiquitin-binding receptors, substrates, and E3 ligases/deubiquitinases involved in pexophagy have been described. Alternatively, pexophagy can be achieved in a ubiquitin-independent manner. We discuss the mechanisms of these ubiquitin-dependent and ubiquitin-independent pexophagy pathways and summarize several inducible conditions currently used to study pexophagy. We highlight several roles of pexophagy in human health and how its dysregulation may contribute to diseases.
      Citation: Cells
      PubDate: 2021-05-03
      DOI: 10.3390/cells10051094
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1095: AICAr, a Widely Used AMPK Activator with
           Important AMPK-Independent Effects: A Systematic Review

    • Authors: Dora Višnjić, Hrvoje Lalić, Vilma Dembitz, Barbara Tomić, Tomislav Smoljo
      First page: 1095
      Abstract: 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAr) has been one of the most commonly used pharmacological modulators of AMPK activity. The majority of early studies on the role of AMPK, both in the physiological regulation of metabolism and in cancer pathogenesis, were based solely on the use of AICAr as an AMPK-activator. Even with more complex models of AMPK downregulation and knockout being introduced, AICAr remained a regular starting point for many studies focusing on AMPK biology. However, there is an increasing number of studies showing that numerous AICAr effects, previously attributed to AMPK activation, are in fact AMPK-independent. This review aims to give an overview of the present knowledge on AMPK-dependent and AMPK-independent effects of AICAr on metabolism, hypoxia, exercise, nucleotide synthesis, and cancer, calling for caution in the interpretation of AICAr-based studies in the context of understanding AMPK signaling pathway.
      Citation: Cells
      PubDate: 2021-05-04
      DOI: 10.3390/cells10051095
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1096: The Role of HSP90 in Preserving the Integrity
           of Genomes Against Transposons Is Evolutionarily Conserved

    • Authors: Valeria Specchia, Maria Pia Bozzetti
      First page: 1096
      Abstract: The HSP90 protein is a molecular chaperone intensively studied for its role in numerous cellular processes both under physiological and stress conditions. This protein acts on a wide range of substrates with a well-established role in cancer and neurological disorders. In this review, we focused on the involvement of HSP90 in the silencing of transposable elements and in the genomic integrity maintenance. The common feature of transposable elements is the potential jumping in new genomic positions, causing chromosome structure rearrangements, gene mutations, and influencing gene expression levels. The role of HSP90 in the control of these elements is evolutionarily conserved and opens new perspectives in the HSP90-related mechanisms underlying human disorders. Here, we discuss the hypothesis that its role in the piRNA pathway regulating transposons may be implicated in the onset of neurological diseases.
      Citation: Cells
      PubDate: 2021-05-04
      DOI: 10.3390/cells10051096
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1097: Pathophysiology and Treatment Options for
           Hepatic Fibrosis: Can It Be Completely Cured'

    • Authors: Arshi Khanam, Paul G. Saleeb, Shyam Kottilil
      First page: 1097
      Abstract: Hepatic fibrosis is a dynamic process that occurs as a wound healing response against liver injury. During fibrosis, crosstalk between parenchymal and non-parenchymal cells, activation of different immune cells and signaling pathways, as well as a release of several inflammatory mediators take place, resulting in inflammation. Excessive inflammation drives hepatic stellate cell (HSC) activation, which then encounters various morphological and functional changes before transforming into proliferative and extracellular matrix (ECM)-producing myofibroblasts. Finally, enormous ECM accumulation interferes with hepatic function and leads to liver failure. To overcome this condition, several therapeutic approaches have been developed to inhibit inflammatory responses, HSC proliferation and activation. Preclinical studies also suggest several targets for the development of anti-fibrotic therapies; however, very few advanced to clinical trials. The pathophysiology of hepatic fibrosis is extremely complex and requires comprehensive understanding to identify effective therapeutic targets; therefore, in this review, we focus on the various cellular and molecular mechanisms associated with the pathophysiology of hepatic fibrosis and discuss potential strategies to control or reverse the fibrosis.
      Citation: Cells
      PubDate: 2021-05-04
      DOI: 10.3390/cells10051097
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1098: Control of Macrophage Inflammation by P2Y
           Purinergic Receptors

    • Authors: Dominik Klaver, Martin Thurnher
      First page: 1098
      Abstract: Macrophages comprise a phenotypically and functionally diverse group of hematopoietic cells. Versatile macrophage subsets engage to ensure maintenance of tissue integrity. To perform tissue stress surveillance, macrophages express many different stress-sensing receptors, including purinergic P2X and P2Y receptors that respond to extracellular nucleotides and their sugar derivatives. Activation of G protein-coupled P2Y receptors can be both pro- and anti-inflammatory. Current examples include the observation that P2Y14 receptor promotes STAT1-mediated inflammation in pro-inflammatory M1 macrophages as well as the demonstration that P2Y11 receptor suppresses the secretion of tumor necrosis factor (TNF)-α and concomitantly promotes the release of soluble TNF receptors from anti-inflammatory M2 macrophages. Here, we review macrophage regulation by P2Y purinergic receptors, both in physiological and disease-associated inflammation. Therapeutic targeting of anti-inflammatory P2Y receptor signaling is desirable to attenuate excessive inflammation in infectious diseases such as COVID-19. Conversely, anti-inflammatory P2Y receptor signaling must be suppressed during cancer therapy to preserve its efficacy.
      Citation: Cells
      PubDate: 2021-05-04
      DOI: 10.3390/cells10051098
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1099: Psoriasis and Liver Damage in HIV-Infected
           Patients

    • Authors: Carmen Busca Arenzana, Lucía Quintana Castanedo, Clara Chiloeches Fernández, Daniel Nieto Rodríguez, Pedro Herranz Pinto, Ana Belén Delgado Hierro, Antonio Olveira Martín, María Luisa Montes Ramírez
      First page: 1099
      Abstract: Background/objectives: Psoriasis is the most frequent skin disease in HIV-infected patients. Nonalcohol fatty liver disease (NAFLD) is more prevalent in patients with psoriasis. We report the prevalence of psoriasis and NAFLD and investigate risk factors of liver damage in HIV-infected patients with psoriasis. Methods: We performed a retrospective observational study. Steatosis was defined as indicative abdominal ultrasound findings, CAP (controlled attenuated parameter by transient elastography) > 238 dB/m, and/or triglyceride and glucose index (TyG) > 8.38. Significant (fibrosis ≥ 2) and advanced liver fibrosis (fibrosis ≤ F3) were studied by transient elastography (TE) and/or FIB-4 using standard cutoff points. FIB-4 (Fibrosis 4 score) results were adjusted for hepatitis C (HCV)-coinfected patients. Results: We identified 80 patients with psoriasis (prevalence, 1.5%; 95% CI, 1.1–1.8). Psoriasis was severe (PASI > 10 and/or psoriatic arthritis) in 27.5% of cases. The prevalence of steatosis was 72.5% (95% CI, 65–85). Severe psoriasis was an independent risk factor for steatosis (OR, 12; 95% CI, 1.2–120; p = 0.03). Significant liver fibrosis (p < 0.05) was associated with HCV coinfection (OR 3.4; 95% CI, 1.1–10.6), total CD4 (OR 0.99; 95% CI, 0.99–1), and time of efavirenz exposure (OR 1.2; 95% CI, 1.0–1.3). Conclusions: The prevalence of psoriasis in HIV-infected patients was similar to that of the general population. Steatosis is highly prevalent, and severe psoriasis is an independent risk factor for steatosis in HIV-infected patients.
      Citation: Cells
      PubDate: 2021-05-04
      DOI: 10.3390/cells10051099
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1100: Glycosylation of Immune Receptors in Cancer

    • Authors: Ruoxuan Sun, Alyssa Min Jung Kim, Seung-Oe Lim
      First page: 1100
      Abstract: Evading host immune surveillance is one of the hallmarks of cancer. Immune checkpoint therapy, which aims to eliminate cancer progression by reprogramming the antitumor immune response, currently occupies a solid position in the rapidly expanding arsenal of cancer therapy. As most immune checkpoints are membrane glycoproteins, mounting attention is drawn to asking how protein glycosylation affects immune function. The answers to this fundamental question will stimulate the rational development of future cancer diagnostics and therapeutic strategies.
      Citation: Cells
      PubDate: 2021-05-04
      DOI: 10.3390/cells10051100
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1101: HDAC8 Activates AKT through Upregulating PLCB1
           and Suppressing DESC1 Expression in MEK1/2 Inhibition-Resistant Cells

    • Authors: Soon-Duck Ha, Naomi Lewin, Shawn S.C. Li, Sung Ouk Kim
      First page: 1101
      Abstract: Inhibition of the RAF-MEK1/2-ERK signaling pathway is an ideal strategy for treating cancers with NRAS or BRAF mutations. However, the development of resistance due to incomplete inhibition of the pathway and activation of compensatory cell proliferation pathways is a major impediment of the targeted therapy. The anthrax lethal toxin (LT), which cleaves and inactivates MEKs, is a modifiable biomolecule that can be delivered selectively to tumor cells and potently kills various tumor cells. However, resistance to LT and the mechanism involved are yet to be explored. Here, we show that LT, through inhibiting MEK1/2-ERK activation, inhibits the proliferation of cancer cells with NRAS/BRAF mutations. Among them, the human colorectal tumor HT-29 and murine melanoma B16-BL6 cells developed resistance to LT in 2 to 3 days of treatment. These resistant cells activated AKT through a histone deacetylase (HDAC) 8-dependent pathway. Using an Affymetrix microarray, followed by qPCR validation, we identified that the differential expression of the phospholipase C-β1 (PLCB1) and squamous cell carcinoma-1 (DESC1) played an important role in HDAC8-mediated AKT activation and resistance to MEK1/2-ERK inhibition. By using inhibitors, small interference RNAs and/or expression vectors, we found that the inhibition of HDAC8 suppressed PLCB1 expression and induced DESC1 expression in the resistant cells, which led to the inhibition of AKT and re-sensitization to LT and MEK1/2 inhibition. These results suggest that targeting PLCB1 and DESC1 is a novel strategy for inhibiting the resistance to MEK1/2 inhibition.
      Citation: Cells
      PubDate: 2021-05-04
      DOI: 10.3390/cells10051101
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1102: Chromothripsis—Explosion in Genetic
           Science

    • Authors: Mariia Shorokhova, Nikolay Nikolsky, Tatiana Grinchuk
      First page: 1102
      Abstract: Chromothripsis has been defined as complex patterns of alternating genes copy number changes (normal, gain or loss) along the length of a chromosome or chromosome segment (International System for Human Cytogenomic Nomenclature 2020). The phenomenon of chromothripsis was discovered in 2011 and changed the concept of genome variability, mechanisms of oncogenic transformation, and hereditary diseases. This review describes the phenomenon of chromothripsis, its prevalence in genomes, the mechanisms underlying this phenomenon, and methods of its detection. Due to the fact that most often the phenomenon of chromothripsis occurs in cancer cells, in this review, we will separately discuss the issue of the contribution of chromothripsis to the process of oncogenesis.
      Citation: Cells
      PubDate: 2021-05-04
      DOI: 10.3390/cells10051102
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1103: Hepatic Failure in COVID-19: Is Iron Overload
           the Dangerous Trigger'

    • Authors: Franca Del Nonno, Roberta Nardacci, Daniele Colombo, Ubaldo Visco-Comandini, Stefania Cicalini, Andrea Antinori, Luisa Marchioni, Gianpiero D’Offizi, Mauro Piacentini, Laura Falasca
      First page: 1103
      Abstract: Liver injury in COVID-19 patients has progressively emerged, even in those without a history of liver disease, yet the mechanism of liver pathogenicity is still controversial. COVID-19 is frequently associated with increased serum ferritin levels, and hyperferritinemia was shown to correlate with illness severity. The liver is the major site for iron storage, and conditions of iron overload have been established to have a pathogenic role in development of liver diseases. We presented here six patients who developed severe COVID-19, with biochemical evidence of liver failure. Three cases were survived patients, who underwent liver biopsy; the other three were deceased patients, who were autopsied. None of the patients suffered underlying liver pathologies. Histopathological and ultrastructural analyses were performed. The most striking finding we demonstrated in all patients was iron accumulation into hepatocytes, associated with degenerative changes. Abundant ferritin particles were found enclosed in siderosomes, and large aggregates of hemosiderin were found, often in close contact with damaged mitochondria. Iron-caused oxidative stress may be responsible for mitochondria metabolic dysfunction. In agreement with this, association between mitochondria and lipid droplets was also found. Overall, our data suggest that hepatic iron overload could be the pathogenic trigger of liver injury associated to COVID-19.
      Citation: Cells
      PubDate: 2021-05-04
      DOI: 10.3390/cells10051103
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1104: Cytokines Involved in the Pathogenesis of SSc
           and Problems in the Development of Anti-Cytokine Therapy

    • Authors: Yoshihito Shima
      First page: 1104
      Abstract: Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology. SSc causes damage to the skin and various organs including the lungs, heart, and digestive tract, but the extent of the damage varies from patient to patient. The pathology of SSc includes ischemia, inflammation, and fibrosis, but the degree of progression varies from case to case. Many cytokines have been reported to be involved in the pathogenesis of SSc: interleukin-6 is associated with inflammation and transforming growth factor-β and interleukin-13 are associated with fibrosis. Therapeutic methods to control these cytokines have been proposed; however, which cytokines have a dominant role in SSc might differ depending on the extent of visceral lesions and the stage of disease progression. Therefore, it is necessary to consider the disease state of the patient to be targeted and the type of evaluation method when an anti-cytokine therapy is conducted. Here, we review the pathology of SSc and potential cytokine targets, especially interleukin-6, as well as the use of anti-cytokine therapy for SSc.
      Citation: Cells
      PubDate: 2021-05-04
      DOI: 10.3390/cells10051104
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1105: The Anti-Infectious Role of Sphingosine in
           Microbial Diseases

    • Authors: Yuqing Wu, Yongjie Liu, Erich Gulbins, Heike Grassmé
      First page: 1105
      Abstract: Sphingolipids are important structural membrane components and, together with cholesterol, are often organized in lipid rafts, where they act as signaling molecules in many cellular functions. They play crucial roles in regulating pathobiological processes, such as cancer, inflammation, and infectious diseases. The bioactive metabolites ceramide, sphingosine-1-phosphate, and sphingosine have been shown to be involved in the pathogenesis of several microbes. In contrast to ceramide, which often promotes bacterial and viral infections (for instance, by mediating adhesion and internalization), sphingosine, which is released from ceramide by the activity of ceramidases, kills many bacterial, viral, and fungal pathogens. In particular, sphingosine is an important natural component of the defense against bacterial pathogens in the respiratory tract. Pathologically reduced sphingosine levels in cystic fibrosis airway epithelial cells are normalized by inhalation of sphingosine, and coating plastic implants with sphingosine prevents bacterial infections. Pretreatment of cells with exogenous sphingosine also prevents the viral spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) from interacting with host cell receptors and inhibits the propagation of herpes simplex virus type 1 (HSV-1) in macrophages. Recent examinations reveal that the bactericidal effect of sphingosine might be due to bacterial membrane permeabilization and the subsequent death of the bacteria.
      Citation: Cells
      PubDate: 2021-05-04
      DOI: 10.3390/cells10051105
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1106: Beiging Modulates Inflammatory Adipogenesis in
           Salt-Treated and MEK6–Transfected Adipocytes

    • Authors: Songjoo Kang, Myoungsook Lee
      First page: 1106
      Abstract: To investigate whether the beiging process changes the interactive effects of salt and MEK6 gene on inflammatory adipogenesis, the salt treatment (NaCl 50 mM) and MEK6 transfection of Tg(+/+) cells were performed with white adipocytes (WAT) and beige-like-adipocytes (BLA). BLA induced by T3 were confirmed by UCP-1 expression and the MEK6 protein was 3.5 times higher in MEK6 transfected WAT than the control. The adipogenic genes, PPAR-γ and C/EBP-α, were 1.5 times more highly expressed in the salt-treated groups than the non-salt-treated groups, and adipogenesis was greatly increased in Tg(+/+) WAT compared to non-transfected Tg(−/−). The adipogenesis induced by salt treatment and MEK6 transfection was significantly reduced in BLA. The inflammatory adipocytokines, TNF-α, IL-1β, and IL-6, were increased in the salt-treated Tg(+/+) WAT, but an anti-inflammation biomarker, the adiponectin/leptin ratio, was reduced in Tg(+/+), to tenth of that in Tg(−/−). However, the production of adipocytokines in WAT was strongly weakened in BLA, although a combination of salt and MEK6 transfection had the most significant effects on inflammation in both WAT and BLA. Oxygen consumption in mitochondria was maximized in salt-treated and MEK6 transfected WAT, but it was decreased by 50% in BLA. In conclusion, beiging controls the synergistic effects of salt and MEK6 on adipogenesis, inflammation, and energy expenditure.
      Citation: Cells
      PubDate: 2021-05-04
      DOI: 10.3390/cells10051106
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1107: Fibrotic Events in the Progression of
           Cholestatic Liver Disease

    • Authors: Wu, Chen, Ziani, Nelson, Ávila, Nevzorova, Cubero
      First page: 1107
      Abstract: Cholestatic liver diseases including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with active hepatic fibrogenesis, which can ultimately lead to the development of cirrhosis. However, the exact relationship between the development of liver fibrosis and the progression of cholestatic liver disease remains elusive. Periductular fibroblasts located around the bile ducts seem biologically different from hepatic stellate cells (HSCs). The fibrotic events in these clinical conditions appear to be related to complex crosstalk between immune/inflammatory mechanisms, cytokine signalling, and perturbed homeostasis between cholangiocytes and mesenchymal cells. Several animal models including bile duct ligation (BDL) and the Mdr2-knockout mice have improved our understanding of mechanisms underlying chronic cholestasis. In the present review, we aim to elucidate the mechanisms of fibrosis in order to help to identify potential diagnostic and therapeutic targets.
      Citation: Cells
      PubDate: 2021-05-05
      DOI: 10.3390/cells10051107
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1108: Differential Effects of Angiotensin-II
           Compared to Phenylephrine on Arterial Stiffness and Hemodynamics: A
           Placebo-Controlled Study in Healthy Humans

    • Authors: Klaas F. Franzen, Moritz Meusel, Julia Engel, Tamara Röcker, Daniel Drömann, Friedhelm Sayk
      First page: 1108
      Abstract: The α1-adrenoceptor agonist phenylephrine (PE) and Angiotensin II (Ang II) are both potent vasoconstrictors at peripheral resistance arteries. PE has pure vasoconstrictive properties. Ang II, additionally, modulates central nervous blood pressure (BP) control via sympathetic baroreflex resetting. However, it is unknown whether Ang II vs. PE mediated vasoconstriction at equipressor dose uniformly or specifically modifies arterial stiffness. We conducted a three-arm randomized placebo-controlled cross-over trial in 30 healthy volunteers (15 female) investigating the effects of Ang II compared to PE at equal systolic pressor dose on pulse wave velocity (PWV), pulse wave reflection (augmentation index normalized to heart rate 75/min, AIx) and non-invasive hemodynamics by Mobil-O-Graph™ and circulating core markers of endothelial (dys-)function. PE but not Ang II-mediated hypertension induced a strong reflex-decrease in cardiac output. Increases in PWV, AIx, total peripheral resistance and pulse pressure, in contrast, were stronger during PE compared to Ang II at equal mean aortic BP. This was accompanied by minute changes in circulating markers of endothelial function. Moreover, we observed differential hemodynamic changes after stopping either vasoactive infusion. Ang II- and PE-mediated BP increase specifically modifies arterial stiffness and hemodynamics with aftereffects lasting beyond mere vasoconstriction. This appears attributable in part to different interactions with central nervous BP control including modified baroreflex function.
      Citation: Cells
      PubDate: 2021-05-05
      DOI: 10.3390/cells10051108
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1109: The Systemic Immune Response in COVID-19 Is
           Associated with a Shift to Formyl-Peptide Unresponsive Eosinophils

    • Authors: Leo Koenderman, Maarten J. Siemers, Corneli van Aalst, Suzanne H. Bongers, Roy Spijkerman, Bas J. J. Bindels, Giulio Giustarini, Harriët M. R. van Goor, Karin A. H. Kaasjager, Nienke Vrisekoop
      First page: 1109
      Abstract: A malfunction of the innate immune response in COVID-19 is associated with eosinopenia, particularly in more severe cases. This study tested the hypothesis that this eosinopenia is COVID-19 specific and is associated with systemic activation of eosinophils. Blood of 15 healthy controls and 75 adult patients with suspected COVID-19 at the ER were included before PCR testing and analyzed by point-of-care automated flow cytometry (CD10, CD11b, CD16, and CD62L) in the absence or presence of a formyl peptide (fNLF). Forty-five SARS-CoV-2 PCR positive patients were grouped based on disease severity. PCR negative patients with proven bacterial (n = 20) or other viral (n = 10) infections were used as disease controls. Eosinophils were identified with the use of the FlowSOM algorithm. Low blood eosinophil numbers (<100 cells/μL; p < 0.005) were found both in patients with COVID-19 and with other infectious diseases, albeit less pronounced. Two discrete eosinophil populations were identified in healthy controls both before and after activation with fNLF based on the expression of CD11b. Before activation, the CD11bbright population consisted of 5.4% (CI95% = 3.8, 13.4) of total eosinophils. After activation, this population of CD11bbright cells comprised nearly half the population (42.21%, CI95% = 35.9, 54.1). Eosinophils in COVID-19 had a similar percentage of CD11bbright cells before activation (7.6%, CI95% = 4.5, 13.6), but were clearly refractory to activation with fNLF as a much lower percentage of cells end up in the CD11bbright fraction after activation (23.7%, CI95% = 18.5, 27.6; p < 0.001). Low eosinophil numbers in COVID-19 are associated with refractoriness in responsiveness to fNLF. This might be caused by migration of fully functional cells to the tissue.
      Citation: Cells
      PubDate: 2021-05-05
      DOI: 10.3390/cells10051109
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1110: Apigenin and Structurally Related Flavonoids
           Allosterically Potentiate the Function of Human α7-Nicotinic
           Acetylcholine Receptors Expressed in SH-EP1 Cells

    • Authors: Waheed Shabbir, Keun-Hang Susan Yang, Bassem Sadek, Murat Oz
      First page: 1110
      Abstract: Phytochemicals, such as monoterpenes, polyphenols, curcuminoids, and flavonoids, are known to have anti-inflammatory, antioxidant, neuroprotective, and procognitive effects. In this study, the effects of several polyhydroxy flavonoids, as derivatives of differently substituted 5,7-dihydroxy-4H-chromen-4-one including apigenin, genistein, luteolin, kaempferol, quercetin, gossypetin, and phloretin with different lipophilicities (cLogP), as well as topological polar surface area (TPSA), were tested for induction of Ca2+ transients by α7 human nicotinic acetylcholine (α7 nACh) receptors expressed in SH-EP1 cells. Apigenin (10 μM) caused a significant potentiation of ACh (30 μM)-induced Ca2+ transients, but did not affect Ca2+ transients induced by high K+ (60 mM) containing solutions. Co-application of apigenin with ACh was equally effective as apigenin preincubation. However, the effect of apigenin significantly diminished by increasing ACh concentrations. The flavonoids tested also potentiated α7 nACh mediated Ca2+ transients with descending potency (highest to lowest) by genistein, gossypetin, kaempferol, luteolin, phloretin, quercetin, and apigenin. The specific binding of α7 nACh receptor antagonist [125I]-bungarotoxin remained unchanged in the presence of any of the tested polyhydroxy flavonoids, suggesting that these compounds act as positive allosteric modulators of the α7-nACh receptor in SH-EP1 cells. These findings suggest a clinical potential for these phytochemicals in the treatment of various human diseases from pain to inflammation and neural disease.
      Citation: Cells
      PubDate: 2021-05-05
      DOI: 10.3390/cells10051110
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1111: Cross-Reactivity and Sequence Homology between
           Al-Pha-Synuclein and Food Products: A Step Further for Parkinson’s
           Disease Synucleinopathy

    • Authors: Aristo Vojdani, Aaron Lerner, Elroy Vojdani
      First page: 1111
      Abstract: Introduction: Parkinson’s disease is characterized by non-motor/motor dysfunction midbrain neuronal death and α-synuclein deposits. The accepted hypothesis is that unknown environmental factors induce α-synuclein accumulation in the brain via the enteric nervous system. Material and Methods: Monoclonal antibodies made against recombinant α-synuclein protein or α-synuclein epitope 118–123 were applied to the antigens of 180 frequently consumed food products. The specificity of those antibody-antigen reactions was confirmed by serial dilution and inhibition studies. The Basic Local Alignment Search Tool sequence matching program was used for sequence homologies. Results: While the antibody made against recombinant α-synuclein reacted significantly with 86/180 specific food antigens, the antibody made against α-synuclein epitope 118–123 reacted with only 32/180 tested food antigens. The food proteins with the greatest number of peptides that matched with α-synuclein were yeast, soybean, latex hevein, wheat germ agglutinin, potato, peanut, bean agglutinin, pea lectin, shrimp, bromelain, and lentil lectin. Conclusions: The cross-reactivity and sequence homology between α-synuclein and frequently consumed foods, reinforces the autoimmune aspect of Parkinson’s disease. It is hypothesized that luminal food peptides that share cross-reactive epitopes with human α-synuclein and have molecular similarity with brain antigens are involved in the synucleinopathy. The findings deserve further confirmation by extensive research.
      Citation: Cells
      PubDate: 2021-05-05
      DOI: 10.3390/cells10051111
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1112: New Treatment Strategy Targeting Galectin-1
           against Thyroid Cancer

    • Authors: Laetitia Gheysen, Laura Soumoy, Anne Trelcat, Laurine Verset, Fabrice Journe, Sven Saussez
      First page: 1112
      Abstract: Although the overall survival rate of papillary or follicular thyroid cancers is good, anaplastic carcinomas and radio iodine refractory cancers remain a significant therapeutic challenge. Galectin-1 (Gal-1) is overexpressed in tumor cells and tumor-associated endothelial cells, and is broadly implicated in angiogenesis, cancer cell motility and invasion, and immune system escape. Our team has previously demonstrated a higher serum level of Gal-1 in patients with differentiated thyroid cancers versus healthy patients, and explored, by a knockdown strategy, the effect of Gal-1 silencing on cell proliferation and invasion in vitro, and on tumor and metastasis development in vivo. OTX008 is a calixarene derivative designed to bind the Gal-1 amphipathic β-sheet conformation and has previously demonstrated anti-proliferative and anti-invasive properties in several cancer cell lines including colon, breast, head and neck, and prostate cancer lines. In the current work, the impacts of OTX008 were evaluated in six thyroid cancer cell lines, and significant inhibitions of proliferation, migration, and invasion were observed in all lines expressing high Gal-1 levels. In addition, the signaling pathways affected by this drug were examined using RPPA (reverse phase protein array) and phosphoprotein expression assays, and opposite regulation of eNos, PYK2, and HSP27 by OTX008 was detected by comparing the two anaplastic lines 8505c and CAL 62. Finally, the sensitive 8505c line was xenografted in nude mice, and 3 weeks of OTX008 treatment (5 mg/kg/day) demonstrated a significant reduction in tumor and lung metastasize sizes without side effects. Overall, OXT008 showed significant anti-cancer effects both in vitro and in vivo in thyroid cancer lines expressing Gal-1, supporting further investigation of the molecular mechanisms of the drug and future clinical trials in patients with anaplastic thyroid cancer.
      Citation: Cells
      PubDate: 2021-05-05
      DOI: 10.3390/cells10051112
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1113: Adipose Tissue-Derived Stem Cell Yield Depends
           on Isolation Protocol and Cell Counting Method

    • Authors: Lukas Prantl, Andreas Eigenberger, Eva Brix, Sally Kempa, Magnus Baringer, Oliver Felthaus
      First page: 1113
      Abstract: In plastic surgery, lipofilling is a frequent procedure. Unsatisfactory vascularization and impaired cell vitality can lead to unpredictable take rates in the fat graft. The proliferation and neovascularization inducing properties of adipose tissue-derived stem cells may contribute to solve this problem. Therefore, the enrichment of fat grafts with stem cells is studied intensively. However, it is difficult to compare these studies because many factors—often not precisely described—are influencing the results. Our study summarizes some factors which influence the cell yield like harvesting, isolation procedure and quantification. Stem cells were isolated after liposuction. Quantification was done using a cell chamber, colony counting, or flow cytometry with changes to one parameter, only, for each comparison. Quantification of cells isolated after liposuction at the same harvesting site from the same patient can vary greatly depending on the details of the isolation protocol and the method of quantification. Cell yield can be influenced strongly by many factors. Therefore, a comparison of different studies should be handled with care.
      Citation: Cells
      PubDate: 2021-05-05
      DOI: 10.3390/cells10051113
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1114: CD4+ T Cells in Chronic Hepatitis B and T
           Cell-Directed Immunotherapy

    • Authors: Sonja I. Buschow, Diahann T. S. L. Jansen
      First page: 1114
      Abstract: The impaired T cell responses observed in chronic hepatitis B (HBV) patients are considered to contribute to the chronicity of the infection. Research on this impairment has been focused on CD8+ T cells because of their cytotoxic effector function; however, CD4+ T cells are crucial in the proper development of these long-lasting effector CD8+ T cells. In this review, we summarize what is known about CD4+ T cells in chronic HBV infection and discuss the importance and opportunities of including CD4+ T cells in T cell-directed immunotherapeutic strategies to cure chronic HBV.
      Citation: Cells
      PubDate: 2021-05-06
      DOI: 10.3390/cells10051114
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1115: Elevated Free Phosphatidylcholine Levels in
           Cerebrospinal Fluid Distinguish Bacterial from Viral CNS Infections

    • Authors: Amani Al-Mekhlafi, Kurt-Wolfram Sühs, Sven Schuchardt, Maike Kuhn, Kirsten Müller-Vahl, Corinna Trebst, Thomas Skripuletz, Frank Klawonn, Martin Stangel, Frank Pessler
      First page: 1115
      Abstract: The identification of CSF biomarkers for bacterial meningitis can potentially improve diagnosis and understanding of pathogenesis, and the differentiation from viral CNS infections is of particular clinical importance. Considering that substantial changes in CSF metabolites in CNS infections have recently been demonstrated, we compared concentrations of 188 metabolites in CSF samples from patients with bacterial meningitis (n = 32), viral meningitis/encephalitis (n = 34), and noninflamed controls (n = 66). Metabolite reprogramming in bacterial meningitis was greatest among phosphatidylcholines, and concentrations of all 54 phosphatidylcholines were significantly (p = 1.2 × 10−25–1.5 × 10−4) higher than in controls. Indeed, all biomarkers for bacterial meningitis vs. viral meningitis/encephalitis with an AUC ≥ 0.86 (ROC curve analysis) were phosphatidylcholines. Four of the five most accurate (AUC ≥ 0.9) phosphatidylcholine biomarkers had higher sensitivity and negative predictive values than CSF lactate or cell count. Concentrations of the 10 most accurate phosphatidylcholine biomarkers were lower in meningitis due to opportunistic pathogens than in meningitis due to typical meningitis pathogens, and they correlated most strongly with parameters reflecting blood–CSF barrier dysfunction and CSF lactate (r = 0.73–0.82), less so with CSF cell count, and not with blood CRP. In contrast to the elevated phosphatidylcholine concentrations in CSF, serum concentrations remained relatively unchanged. Taken together, these results suggest that increased free CSF phosphatidylcholines are sensitive biomarkers for bacterial meningitis and do not merely reflect inflammation but are associated with local disease and a shift in CNS metabolism.
      Citation: Cells
      PubDate: 2021-05-06
      DOI: 10.3390/cells10051115
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1116: Calcium and Redox Liaison: A Key Role of
           Selenoprotein N in Skeletal Muscle

    • Authors: Ester Zito, Ana Ferreiro
      First page: 1116
      Abstract: Selenoprotein N (SEPN1) is a type II glycoprotein of the endoplasmic reticulum (ER) that senses calcium levels to tune the activity of the sarcoplasmic reticulum calcium pump (SERCA pump) through a redox-mediated mechanism, modulating ER calcium homeostasis. In SEPN1-depleted muscles, altered ER calcium homeostasis triggers ER stress, which induces CHOP-mediated malfunction, altering excitation–contraction coupling. SEPN1 is localized in a region of the ER where the latter is in close contact with mitochondria, i.e., the mitochondria-associated membranes (MAM), which are important for calcium mobilization from the ER to mitochondria. Accordingly, SEPN1-depleted models have impairment of both ER and mitochondria calcium regulation and ATP production. SEPN1-related myopathy (SEPN1-RM) is an inherited congenital muscle disease due to SEPN1 loss of function, whose main histopathological features are minicores, i.e., areas of mitochondria depletion and sarcomere disorganization in muscle fibers. SEPN1-RM presents with weakness involving predominantly axial and diaphragmatic muscles. Since there is currently no disease-modifying drug to treat this myopathy, analysis of SEPN1 function in parallel with that of the muscle phenotype in SEPN1 loss of function models should help in understanding the pathogenic basis of the disease and possibly point to novel drugs for therapy. The present essay recapitulates the novel biological findings on SEPN1 and how these reconcile with the muscle and bioenergetics phenotype of SEPN1-related myopathy.
      Citation: Cells
      PubDate: 2021-05-06
      DOI: 10.3390/cells10051116
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1117: PEDF-Mediated Mitophagy Triggers the Visual
           Cycle by Enhancing Mitochondrial Functions in a H2O2-Injured Rat Model

    • Authors: Jae-Yeon Kim, Sohae Park, Hee-Jung Park, Se-Ho Kim, Helen Lew, Gi-Jin Kim
      First page: 1117
      Abstract: Retinal degenerative diseases result from oxidative stress and mitochondrial dysfunction, leading to the loss of visual acuity. Damaged retinal pigment epithelial (RPE) and photoreceptor cells undergo mitophagy. Pigment epithelium-derived factor (PEDF) protects from oxidative stress in RPE and improves mitochondrial functions. Overexpression of PEDF in placenta-derived mesenchymal stem cells (PD-MSCs; PD-MSCsPEDF) provides therapeutic effects in retinal degenerative diseases. Here, we investigated whether PD-MSCsPEDF restored the visual cycle through a mitophagic mechanism in RPE cells in hydrogen peroxide (H2O2)-injured rat retinas. Compared with naïve PD-MSCs, PD-MSCsPEDF augmented mitochondrial biogenesis and translation markers as well as mitochondrial respiratory states. In the H2O2-injured rat model, intravitreal administration of PD-MSCsPEDF restored total retinal layer thickness compared to that of naïve PD-MSCs. In particular, PTEN-induced kinase 1 (PINK1), which is the major mitophagy marker, exhibited increased expression in retinal layers and RPE cells after PD-MSCPEDF transplantation. Similarly, expression of the visual cycle enzyme retinol dehydrogenase 11 (RDH11) showed the same patterns as PINK1 levels, resulting in improved visual activity. Taken together, these findings suggest that PD-MSCsPEDF facilitate mitophagy and restore the loss of visual cycles in H2O2-injured rat retinas and RPE cells. These data indicate a new strategy for next-generation MSC-based treatment of retinal degenerative diseases.
      Citation: Cells
      PubDate: 2021-05-06
      DOI: 10.3390/cells10051117
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1118: Multifaceted Role of AMPK in Viral Infections

    • Authors: Maimoona Bhutta, Elisa Gallo, Ronen Borenstein
      First page: 1118
      Abstract: Viral pathogens often exploit host cell regulatory and signaling pathways to ensure an optimal environment for growth and survival. Several studies have suggested that 5′-adenosine monophosphate-activated protein kinase (AMPK), an intracellular serine/threonine kinase, plays a significant role in the modulation of infection. Traditionally, AMPK is a key energy regulator of cell growth and proliferation, host autophagy, stress responses, metabolic reprogramming, mitochondrial homeostasis, fatty acid β-oxidation and host immune function. In this review, we highlight the modulation of host AMPK by various viruses under physiological conditions. These intracellular pathogens trigger metabolic changes altering AMPK signaling activity that then facilitates or inhibits viral replication. Considering the COVID-19 pandemic, understanding the regulation of AMPK signaling following infection can shed light on the development of more effective therapeutic strategies against viral infectious diseases.
      Citation: Cells
      PubDate: 2021-05-06
      DOI: 10.3390/cells10051118
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1119: Mixing Cells for Vascularized Kidney
           Regeneration

    • Authors: Michael Namestnikov, Oren Pleniceanu, Benjamin Dekel
      First page: 1119
      Abstract: The worldwide rise in prevalence of chronic kidney disease (CKD) demands innovative bio-medical solutions for millions of kidney patients. Kidney regenerative medicine aims to replenish tissue which is lost due to a common pathological pathway of fibrosis/inflammation and rejuvenate remaining tissue to maintain sufficient kidney function. To this end, cellular therapy strategies devised so far utilize kidney tissue-forming cells (KTFCs) from various cell sources, fetal, adult, and pluripotent stem-cells (PSCs). However, to increase engraftment and potency of the transplanted cells in a harsh hypoxic diseased environment, it is of importance to co-transplant KTFCs with vessel forming cells (VFCs). VFCs, consisting of endothelial cells (ECs) and mesenchymal stem-cells (MSCs), synergize to generate stable blood vessels, facilitating the vascularization of self-organizing KTFCs into renovascular units. In this paper, we review the different sources of KTFCs and VFCs which can be mixed, and report recent advances made in the field of kidney regeneration with emphasis on generation of vascularized kidney tissue by cell transplantation.
      Citation: Cells
      PubDate: 2021-05-06
      DOI: 10.3390/cells10051119
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1120: Chronic Alcohol Exposure of Cells Using
           Controlled Alcohol-Releasing Capillaries

    • Authors: Wanil Kim, Hye-Seon Jeong, Sang-Chan Kim, Chang-Hyung Choi, Kyung-Ha Lee
      First page: 1120
      Abstract: Alcohol is one of the main causes of liver diseases such as fatty liver, alcoholic hepatitis, and chronic hepatitis with liver fibrosis or cirrhosis. To reproduce the conditions of alcohol-induced liver diseases and to identify the disease-causing mechanisms at the cellular level, several methods have been used to expose the cells to ethanol. As ethanol evaporates easily, it is difficult to mimic chronic alcohol exposure conditions at the cellular level. In this study, we developed a glass capillary system containing ethanol, which could steadily release ethanol from the polyethylene tubing and hydrogel portion at both sides of the capillary. The ethanol-containing capillary could release ethanol in the cell culture medium for up to 144 h, and the concentration of ethanol in the cell culture medium could be adjusted by controlling the number of capillaries. A long-term exposure to ethanol by the capillary system led to an increased toxicity of cells and altered the cellular physiologies, such as increasing the lipid accumulation and hepatic transaminase release in cells, as compared to the traditional direct ethanol addition method. Ethanol capillaries showed different gene expression patterns of lipid accumulation- or chronic alcoholism-related genes. Our results suggest that our ethanol-containing capillary system can be used as a valuable tool for studying the mechanism of chronic alcohol-mediated hepatic diseases at the cellular level.
      Citation: Cells
      PubDate: 2021-05-06
      DOI: 10.3390/cells10051120
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1121: A Histological and Morphometric Assessment of
           the Adult and Juvenile Rat Livers after Mild Traumatic Brain Injury

    • Authors: Ruslan Prus, Olena Appelhans, Maksim Logash, Petro Pokotylo, Grzegorz Józef Nowicki, Barbara Ślusarska
      First page: 1121
      Abstract: Traumatic brain injury (TBI) is one of the most severe problems of modern medicine that plays a dominant role in morbidity and mortality in economically developed countries. Our experimental study aimed to evaluate the histological and morphological changes occurring in the liver of adult and juvenile mildly traumatized rats (mTBI) in a time-dependent model. The experiment was performed on 70 adult white rats at three months of age and 70 juvenile rats aged 20 days. The mTBI was modelled by the Impact-Acceleration Model-free fall of weight in the parieto-occipital area. For histopathological comparison, the samples were taken on the 1st, 3rd, 5th, 7th, 14th, and 21st days after TBI. In adult rats, dominated changes in the microcirculatory bed in the form of blood stasis in sinusoidal capillaries and veins, RBC sludge, and adherence to the vessel wall with the subsequent appearance of perivascular and focal leukocytic infiltrates. In juvenile rats, changes in the parenchyma in the form of hepatocyte dystrophy prevailed. In both groups, the highest manifestation of the changes was observed on 5–7 days of the study. On 14–21 days, compensatory phenomena prevailed in both groups. Mild TBI causes changes in the liver of both adult and juvenile rats. The morphological pattern and dynamics of liver changes, due to mild TBI, are different in adult and juvenile rats.
      Citation: Cells
      PubDate: 2021-05-06
      DOI: 10.3390/cells10051121
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1122: The Role of AMPK Signaling in Brown Adipose
           Tissue Activation

    • Authors: Jamie I. van der van der Vaart, Mariëtte R. Boon, Riekelt H. Houtkooper
      First page: 1122
      Abstract: Obesity is becoming a pandemic, and its prevalence is still increasing. Considering that obesity increases the risk of developing cardiometabolic diseases, research efforts are focusing on new ways to combat obesity. Brown adipose tissue (BAT) has emerged as a possible target to achieve this for its functional role in energy expenditure by means of increasing thermogenesis. An important metabolic sensor and regulator of whole-body energy balance is AMP-activated protein kinase (AMPK), and its role in energy metabolism is evident. This review highlights the mechanisms of BAT activation and investigates how AMPK can be used as a target for BAT activation. We review compounds and other factors that are able to activate AMPK and further discuss the therapeutic use of AMPK in BAT activation. Extensive research shows that AMPK can be activated by a number of different kinases, such as LKB1, CaMKK, but also small molecules, hormones, and metabolic stresses. AMPK is able to activate BAT by inducing adipogenesis, maintaining mitochondrial homeostasis and inducing browning in white adipose tissue. We conclude that, despite encouraging results, many uncertainties should be clarified before AMPK can be posed as a target for anti-obesity treatment via BAT activation.
      Citation: Cells
      PubDate: 2021-05-06
      DOI: 10.3390/cells10051122
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1123: YY2 in Mouse Preimplantation Embryos and in
           Embryonic Stem Cells

    • Authors: Raquel Pérez-Palacios, María Climent, Javier Santiago-Arcos, Sofía Macías-Redondo, Martin Klar, Pedro Muniesa, Jon Schoorlemmer
      First page: 1123
      Abstract: Yin Yang 2 encodes a mammalian-specific transcription factor (YY2) that shares high homology in the zinc finger region with both YY1 and REX1/ZFP42, encoded by the Yin Yang 1 and Reduced Expression Protein 1/Zinc Finger Protein 42 gene, respectively. In contrast to the well-established roles of the latter two in gene regulation, X chromosome inactivation and binding to specific transposable elements (TEs), much less is known about YY2, and its presence during mouse preimplantation development has not been described. As it has been reported that mouse embryonic stem cells (mESC) cannot be propagated in the absence of Yy2, the mechanistic understanding of how Yy2 contributes to mESC maintenance remains only very partially characterized. We describe Yy2 expression studies using RT-PCR and staining with a high-affinity polyclonal serum in mouse embryos and mESC. Although YY2 is expressed during preimplantation development, its presence appears dispensable for developmental progress in vitro until formation of the blastocyst. Attenuation of Yy2 levels failed to alter either Zscan4 levels in two-cell embryos or IAP and MERVL levels at later preimplantation stages. In contrast to previous claims that constitutively expressed shRNA against Yy2 in mESC prohibited the propagation of mESC in culture, we obtained colonies generated from mESC with attenuated Yy2 levels. Concomitant with a decreased number of undifferentiated colonies, Yy2-depleted mESC expressed higher levels of Zscan4 but no differences in the expression of TEs or other pluripotency markers including Sox2, Oct4, Nanog and Esrrb were observed. These results confirm the contribution of Yy2 to the maintenance of mouse embryonic stem cells and show the preimplantation expression of YY2. These functions are discussed in relation to mammalian-specific functions of YY1 and REX1.
      Citation: Cells
      PubDate: 2021-05-07
      DOI: 10.3390/cells10051123
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1124: Microglial Adenosine Receptors: From
           Preconditioning to Modulating the M1/M2 Balance in Activated Cells

    • Authors: Rafael Franco, Alejandro Lillo, Rafael Rivas-Santisteban, Irene Reyes-Resina, Gemma Navarro
      First page: 1124
      Abstract: Neuronal survival depends on the glia, that is, on the astroglial and microglial support. Neurons die and microglia are activated not only in neurodegenerative diseases but also in physiological aging. Activated microglia, once considered harmful, express two main phenotypes: the pro-inflammatory or M1, and the neuroprotective or M2. When neuroinflammation, i.e., microglial activation occurs, it is important to achieve a good M1/M2 balance, i.e., at some point M1 microglia must be skewed into M2 cells to impede chronic inflammation and to afford neuronal survival. G protein-coupled receptors in general and adenosine receptors in particular are potential targets for increasing the number of M2 cells. This article describes the mechanisms underlying microglial activation and analyzes whether these cells exposed to a first damaging event may be ready to be preconditioned to better react to exposure to more damaging events. Adenosine receptors are relevant due to their participation in preconditioning. They can also be overexpressed in activated microglial cells. The potential of adenosine receptors and complexes formed by adenosine receptors and cannabinoids as therapeutic targets to provide microglia-mediated neuroprotection is here discussed.
      Citation: Cells
      PubDate: 2021-05-07
      DOI: 10.3390/cells10051124
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1125: Non-Random Genome Editing and Natural Cellular
           Engineering in Cognition-Based Evolution

    • Authors: William B. Miller, Francisco J. Enguita, Ana Lúcia Leitão
      First page: 1125
      Abstract: Neo-Darwinism presumes that biological variation is a product of random genetic replication errors and natural selection. Cognition-Based Evolution (CBE) asserts a comprehensive alternative approach to phenotypic variation and the generation of biological novelty. In CBE, evolutionary variation is the product of natural cellular engineering that permits purposive genetic adjustments as cellular problem-solving. CBE upholds that the cornerstone of biology is the intelligent measuring cell. Since all biological information that is available to cells is ambiguous, multicellularity arises from the cellular requirement to maximize the validity of available environmental information. This is best accomplished through collective measurement purposed towards maintaining and optimizing individual cellular states of homeorhesis as dynamic flux that sustains cellular equipoise. The collective action of the multicellular measurement and assessment of information and its collaborative communication is natural cellular engineering. Its yield is linked cellular ecologies and mutualized niche constructions that comprise biofilms and holobionts. In this context, biological variation is the product of collective differential assessment of ambiguous environmental cues by networking intelligent cells. Such concerted action is enabled by non-random natural genomic editing in response to epigenetic impacts and environmental stresses. Random genetic activity can be either constrained or deployed as a ‘harnessing of stochasticity’. Therefore, genes are cellular tools. Selection filters cellular solutions to environmental stresses to assure continuous cellular-organismal-environmental complementarity. Since all multicellular eukaryotes are holobionts as vast assemblages of participants of each of the three cellular domains (Prokaryota, Archaea, Eukaryota) and the virome, multicellular variation is necessarily a product of co-engineering among them.
      Citation: Cells
      PubDate: 2021-05-07
      DOI: 10.3390/cells10051125
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1126: SIRT5 Inhibition Induces Brown Fat-Like
           Phenotype in 3T3-L1 Preadipocytes

    • Authors: Francesca Molinari, Alessandra Feraco, Simone Mirabilii, Serena Saladini, Luigi Sansone, Enza Vernucci, Giada Tomaselli, Vincenzo Marzolla, Dante Rotili, Matteo A. Russo, Maria Rosaria Ricciardi, Agostino Tafuri, Antonello Mai, Massimiliano Caprio, Marco Tafani, Andrea Armani
      First page: 1126
      Abstract: Brown adipose tissue (BAT) activity plays a key role in regulating systemic energy. The activation of BAT results in increased energy expenditure, making this tissue an attractive pharmacological target for therapies against obesity and type 2 diabetes. Sirtuin 5 (SIRT5) affects BAT function by regulating adipogenic transcription factor expression and mitochondrial respiration. We analyzed the expression of SIRT5 in the different adipose depots of mice. We treated 3T3-L1 preadipocytes and mouse primary preadipocyte cultures with the SIRT5 inhibitor MC3482 and investigated the effects of this compound on adipose differentiation and function. The administration of MC3482 during the early stages of differentiation promoted the expression of brown adipocyte and mitochondrial biogenesis markers. Upon treatment with MC3482, 3T3-L1 adipocytes showed an increased activation of the AMP-activated protein kinase (AMPK), which is known to stimulate brown adipocyte differentiation. This effect was paralleled by an increase in autophagic/mitophagic flux and a reduction in lipid droplet size, mediated by a higher lipolytic rate. Of note, MC3482 increased the expression and the activity of adipose triglyceride lipase, without modulating hormone-sensitive lipase. Our findings reveal that SIRT5 inhibition stimulates brown adipogenesis in vitro, supporting this approach as a strategy to stimulate BAT and counteract obesity.
      Citation: Cells
      PubDate: 2021-05-07
      DOI: 10.3390/cells10051126
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1127: A Monolayer System for the Efficient
           Generation of Motor Neuron Progenitors and Functional Motor Neurons from
           Human Pluripotent Stem Cells

    • Authors: Alessandro Cutarelli, Vladimir A. Martínez-Rojas, Alice Tata, Ingrid Battistella, Daniela Rossi, Daniele Arosio, Carlo Musio, Luciano Conti
      First page: 1127
      Abstract: Methods for the conversion of human induced pluripotent stem cells (hiPSCs) into motor neurons (MNs) have opened to the generation of patient-derived in vitro systems that can be exploited for MN disease modelling. However, the lack of simplified and consistent protocols and the fact that hiPSC-derived MNs are often functionally immature yet limit the opportunity to fully take advantage of this technology, especially in research aimed at revealing the disease phenotypes that are manifested in functionally mature cells. In this study, we present a robust, optimized monolayer procedure to rapidly convert hiPSCs into enriched populations of motor neuron progenitor cells (MNPCs) that can be further amplified to produce a large number of cells to cover many experimental needs. These MNPCs can be efficiently differentiated towards mature MNs exhibiting functional electrical and pharmacological neuronal properties. Finally, we report that MN cultures can be long-term maintained, thus offering the opportunity to study degenerative phenomena associated with pathologies involving MNs and their functional, networked activity. These results indicate that our optimized procedure enables the efficient and robust generation of large quantities of MNPCs and functional MNs, providing a valid tool for MNs disease modelling and for drug discovery applications.
      Citation: Cells
      PubDate: 2021-05-07
      DOI: 10.3390/cells10051127
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1128: Codon Bias Can Determine Sorting of a
           Potassium Channel Protein

    • Authors: Anja J. Engel, Marina Kithil, Markus Langhans, Oliver Rauh, Matea Cartolano, James L. Van Etten, Anna Moroni, Gerhard Thiel
      First page: 1128
      Abstract: Due to the redundancy of the genetic code most amino acids are encoded by multiple synonymous codons. It has been proposed that a biased frequency of synonymous codons can affect the function of proteins by modulating distinct steps in transcription, translation and folding. Here, we use two similar prototype K+ channels as model systems to examine whether codon choice has an impact on protein sorting. By monitoring transient expression of GFP-tagged channels in mammalian cells, we find that one of the two channels is sorted in a codon and cell cycle-dependent manner either to mitochondria or the secretory pathway. The data establish that a gene with either rare or frequent codons serves, together with a cell-state-dependent decoding mechanism, as a secondary code for sorting intracellular membrane proteins.
      Citation: Cells
      PubDate: 2021-05-07
      DOI: 10.3390/cells10051128
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1129: Post-Transcriptional Regulation of Viral RNA
           through Epitranscriptional Modification

    • Authors: David G. Courtney
      First page: 1129
      Abstract: The field of mRNA modifications has been steadily growing in recent years as technologies have improved and the importance of these residues became clear. However, a subfield has also arisen, specifically focused on how these modifications affect viral RNA, with the possibility that viruses can also be used as a model to best determine the role that these modifications play on cellular mRNAs. First, virologists focused on the most abundant internal mRNA modification, m6A, mapping this modification and elucidating its effects on the RNA of a wide range of RNA and DNA viruses. Next, less common RNA modifications including m5C, Nm and ac4C were investigated and also found to be present on viral RNA. It now appears that viral RNA is littered with a multitude of RNA modifications. In biological systems that are under constant evolutionary pressure to out compete both the host as well as newly arising viral mutants, it poses an interesting question about what evolutionary benefit these modifications provide as it seems evident, at least to this author, that these modifications have been selected for. In this review, I discuss how RNA modifications are identified on viral RNA and the roles that have now been uncovered for these modifications in regard to viral replication. Finally, I propose some interesting avenues of research that may shed further light on the exact role that these modifications play in viral replication.
      Citation: Cells
      PubDate: 2021-05-07
      DOI: 10.3390/cells10051129
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1130: The Discovery of Naringenin as Endolysosomal
           Two-Pore Channel Inhibitor and Its Emerging Role in SARS-CoV-2 Infection

    • Authors: Antonella D’Amore, Antonella Gradogna, Fioretta Palombi, Velia Minicozzi, Matteo Ceccarelli, Armando Carpaneto, Antonio Filippini
      First page: 1130
      Abstract: The flavonoid naringenin (Nar), present in citrus fruits and tomatoes, has been identified as a blocker of an emerging class of human intracellular channels, namely the two-pore channel (TPC) family, whose role has been established in several diseases. Indeed, Nar was shown to be effective against neoangiogenesis, a process essential for solid tumor progression, by specifically impairing TPC activity. The goal of the present review is to illustrate the rationale that links TPC channels to the mechanism of coronavirus infection, and how their inhibition by Nar could be an efficient pharmacological strategy to fight the current pandemic plague COVID-19.
      Citation: Cells
      PubDate: 2021-05-07
      DOI: 10.3390/cells10051130
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1131: Impact of the Uncoupling Protein 1 on
           Cardiovascular Risk in Patients with Rheumatoid Arthritis

    • Authors: Lovisa I. Lyngfelt, Malin C. Erlandsson, Mitra Nadali, Shahram Hedjazifar, Rille Pullerits, Karin M. Andersson, Petra Brembeck, Sofia Töyrä Silfverswärd, Ulf Smith, Maria I. Bokarewa
      First page: 1131
      Abstract: Adiposity is strongly associated with cardiovascular (CV) morbidity. Uncoupling protein 1 (UCP1) increases energy expenditure in adipocytes and may counteract adiposity. Our objective was to investigate a connection between UCP1 expression and cardiovascular health in patients with rheumatoid arthritis (RA) in a longitudinal observational study. Transcription of UCP1 was measured by qPCR in the subcutaneous adipose tissue of 125 female RA patients and analyzed with respect to clinical parameters and the estimated CV risk. Development of new CV events and diabetes mellitus was followed for five years. Transcription of UCP1 was identified in 89 (71%) patients. UCP1 positive patients had often active RA disease (p = 0.017), high serum levels of IL6 (p = 0.0025) and were frequently overweight (p = 0.015). IL-6hiBMIhi patients and patients treated with IL6 receptor inhibitor tocilizumab had significantly higher levels of UCP1 compared to other RA patients (p < 0.0001, p = 0.032, respectively). Both UCP1hi groups displayed unfavorable metabolic profiles with high plasma glucose levels and high triglyceride-to-HDL ratios, which indicated insulin resistance. Prospective follow-up revealed no significant difference in the incidence of new CV and metabolic events in the UCP1hi groups and remaining RA patients. The study shows that high transcription of UCP1 in adipose tissue is related to IL6-driven processes and reflects primarily metabolic CV risk in female RA patients.
      Citation: Cells
      PubDate: 2021-05-07
      DOI: 10.3390/cells10051131
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1132: Xmrks the Spot: Fish Models for Investigating
           Epidermal Growth Factor Receptor Signaling in Cancer Research

    • Authors: Jerry D. Monroe, Faiza Basheer, Yann Gibert
      First page: 1132
      Abstract: Studies conducted in several fish species, e.g., Xiphophorus hellerii (green swordtail) and Xiphophorus maculatus (southern platyfish) crosses, Oryzias latipes (medaka), and Danio rerio (zebrafish), have identified an oncogenic role for the receptor tyrosine kinase, Xmrk, a gene product closely related to the human epidermal growth factor receptor (EGFR), which is associated with a wide variety of pathological conditions, including cancer. Comparative analyses of Xmrk and EGFR signal transduction in melanoma have shown that both utilize STAT5 signaling to regulate apoptosis and cell proliferation, PI3K to modulate apoptosis, FAK to control migration, and the Ras/Raf/MEK/MAPK pathway to regulate cell survival, proliferation, and differentiation. Further, Xmrk and EGFR may also modulate similar chemokine, extracellular matrix, oxidative stress, and microRNA signaling pathways in melanoma. In hepatocellular carcinoma (HCC), Xmrk and EGFR signaling utilize STAT5 to regulate cell proliferation, and Xmrk may signal through PI3K and FasR to modulate apoptosis. At the same time, both activate the Ras/Raf/MEK/MAPK pathway to regulate cell proliferation and E-cadherin signaling. Xmrk models of melanoma have shown that inhibitors of PI3K and MEK have an anti-cancer effect, and in HCC, that the steroidal drug, adrenosterone, can prevent metastasis and recover E-cadherin expression, suggesting that fish Xmrk models can exploit similarities with EGFR signal transduction to identify and study new chemotherapeutic drugs.
      Citation: Cells
      PubDate: 2021-05-07
      DOI: 10.3390/cells10051132
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1133: Dissecting the Hormonal Signaling Landscape in
           Castration-Resistant Prostate Cancer

    • Authors: Fabrizio Fontana, Patrizia Limonta
      First page: 1133
      Abstract: Understanding the molecular mechanisms underlying prostate cancer (PCa) progression towards its most aggressive, castration-resistant (CRPC) stage is urgently needed to improve the therapeutic options for this almost incurable pathology. Interestingly, CRPC is known to be characterized by a peculiar hormonal landscape. It is now well established that the androgen/androgen receptor (AR) axis is still active in CRPC cells. The persistent activity of this axis in PCa progression has been shown to be related to different mechanisms, such as intratumoral androgen synthesis, AR amplification and mutations, AR mRNA alternative splicing, increased expression/activity of AR-related transcription factors and coregulators. The hypothalamic gonadotropin-releasing hormone (GnRH), by binding to its specific receptors (GnRH-Rs) at the pituitary level, plays a pivotal role in the regulation of the reproductive functions. GnRH and GnRH-R are also expressed in different types of tumors, including PCa. Specifically, it has been demonstrated that, in CRPC cells, the activation of GnRH-Rs is associated with a significant antiproliferative/proapoptotic, antimetastatic and antiangiogenic activity. This antitumor activity is mainly mediated by the GnRH-R-associated Gαi/cAMP signaling pathway. In this review, we dissect the molecular mechanisms underlying the role of the androgen/AR and GnRH/GnRH-R axes in CRPC progression and the possible therapeutic implications.
      Citation: Cells
      PubDate: 2021-05-07
      DOI: 10.3390/cells10051133
      Issue No: Vol. 10, No. 5 (2021)
       
  • Cells, Vol. 10, Pages 1134: Crosstalk between Interleukin-1β and Type I
           Interferons Signaling in Autoinflammatory Diseases

    • Authors: Philippe Georgel
      First page: 1134
      Abstract: Interleukin-1β (IL-1β) and type I interferons (IFNs) are major cytokines involved in autoinflammatory/autoimmune diseases. Separately, the overproduction of each of these cytokines is well described and constitutes the hallmark of inflammasomopathies and interferonopathies, respectively. While their interaction and the crosstalk between their downstream signaling pathways has been mostly investigated in the frame of infectious diseases, little information on their interconnection is still available in the context of autoinflammation promoted by sterile triggers. In this review, we will examine the respective roles of IL-1β and type I IFNs in autoinflammatory/rheumatic diseases and analyze their potential connections in the pathophysiology of some of these diseases, which could reveal novel therapeutic opportunities.
      Citation: Cells
      PubDate: 2021-05-08
      DOI: 10.3390/cells10051134
      Issue No: Vol. 10, No. 5 (2021)
       
 
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