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Showing 1 - 200 of 231 Journals sorted alphabetically
Acoustics     Open Access   (Followers: 2)
Actuators     Open Access   (Followers: 4)
Administrative Sciences     Open Access   (Followers: 4)
Aerospace     Open Access   (Followers: 56, SJR: 0.305, CiteScore: 1)
Agriculture     Open Access   (Followers: 8, SJR: 0.33, CiteScore: 2)
AgriEngineering     Open Access   (Followers: 1)
Agronomy     Open Access   (Followers: 14, SJR: 0.695, CiteScore: 2)
Algorithms     Open Access   (Followers: 12, 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: 8)
Atmosphere     Open Access   (Followers: 24)
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: 3)
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: 4)
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: 3)
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Chemistry     Open Access  
Chemosensors     Open Access   (Followers: 1)
Children     Open Access   (Followers: 2)
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Condensed Matter     Open Access   (Followers: 3)
Corrosion and Materials Degradation     Open Access   (Followers: 1)
Cosmetics     Open Access   (Followers: 5)
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Crystals     Open Access   (Followers: 3, SJR: 0.566, CiteScore: 2)
Cyber     Open Access   (Followers: 2)
Dairy     Open Access   (Followers: 1)
Data     Open Access   (Followers: 4)
Dentistry J.     Open Access   (Followers: 6)
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Diagnostics     Open Access   (Followers: 1, SJR: 0.669, CiteScore: 2)
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Electronics     Open Access   (Followers: 111, SJR: 0.548, CiteScore: 3)
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Entropy     Open Access   (Followers: 7, 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)
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Fluids     Open Access   (Followers: 1)
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Forecasting     Open Access   (Followers: 1)
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Fractal and Fractional     Open Access  
Future Internet     Open Access   (Followers: 180, SJR: 0.219, CiteScore: 1)
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Information     Open Access   (Followers: 48, SJR: 0.222, CiteScore: 1)
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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: 25, 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: 3)
Intl. J. of Turbomachinery, Propulsion and Power     Open Access   (Followers: 10)
Inventions     Open Access  
IoT     Open Access   (Followers: 2)
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 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)
Land     Open Access   (Followers: 4)
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Life     Open Access   (Followers: 2, SJR: 1.625, CiteScore: 3)
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Logistics     Open Access   (Followers: 3)
Lubricants     Open Access   (Followers: 2)
Machine Learning and Knowledge Extraction     Open Access   (Followers: 5)
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: 4, 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: 5)
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: 5)
Neuroglia     Open Access   (Followers: 1)
Nitrogen     Open Access   (Followers: 2)
Non-Coding RNA     Open Access  
Nursing Reports     Open Access   (Followers: 2)
Nutrients     Open Access   (Followers: 11, SJR: 1.557, CiteScore: 4)
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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)
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Photonics     Open Access   (Followers: 5, SJR: 0.709, CiteScore: 2)
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Plants     Open Access   (SJR: 1.39, CiteScore: 3)
Plasma     Open Access   (Followers: 3)
Polymers     Open Access   (Followers: 20, SJR: 0.852, CiteScore: 3)
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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: 53, SJR: 1.386, CiteScore: 4)
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Resources     Open Access   (SJR: 0.688, CiteScore: 3)
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Robotics     Open Access   (Followers: 9)
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Sci     Open Access  
Scientia Pharmaceutica     Open Access   (SJR: 0.268, CiteScore: 1)
Sensors     Open Access   (Followers: 25, SJR: 0.584, CiteScore: 3)

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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  [231 journals]
  • Cells, Vol. 9, Pages 2081: Metabolic Constrains Rule Metastasis

    • Authors: Niccolo’ Roda, Valentina Gambino, Marco Giorgio
      First page: 2081
      Abstract: Metastasis formation accounts for the majority of tumor-associated deaths and consists of different steps, each of them being characterized by a distinctive adaptive phenotype of the cancer cells. Metabolic reprogramming represents one of the main adaptive phenotypes exploited by cancer cells during all the main steps of tumor and metastatic progression. In particular, the metabolism of cancer cells evolves profoundly through all the main phases of metastasis formation, namely the metastatic dissemination, the metastatic colonization of distant organs, the metastatic dormancy, and ultimately the outgrowth into macroscopic lesions. However, the metabolic reprogramming of metastasizing cancer cells has only recently become the subject of intense study. From a clinical point of view, the latter steps of the metastatic process are very important, because patients often undergo surgical removal of the primary tumor when cancer cells have already left the primary tumor site, even though distant metastases are not clinically detectable yet. In this scenario, to precisely elucidate if and how metabolic reprogramming drives acquisition of cancer-specific adaptive phenotypes might pave the way to new therapeutic strategies by combining chemotherapy with metabolic drugs for better cancer eradication. In this review we discuss the latest evidence that claim the importance of metabolic adaptation for cancer progression.
      Citation: Cells
      PubDate: 2020-09-11
      DOI: 10.3390/cells9092081
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2083: FAM64A: A Novel Oncogenic Target of Lung
           Adenocarcinoma Regulated by Both Strands of miR-99a (miR-99a-5p and

    • Authors: Keiko Mizuno, Kengo Tanigawa, Nijiro Nohata, Shunsuke Misono, Reona Okada, Shunichi Asai, Shogo Moriya, Takayuki Suetsugu, Hiromasa Inoue, Naohiko Seki
      First page: 2083
      Abstract: Lung adenocarcinoma (LUAD) is the most aggressive cancer and the prognosis of these patients is unfavorable. We revealed that the expression levels of both strands of miR-99a (miR-99a-5p and miR-99a-3p) were significantly suppressed in several cancer tissues. Analyses of large The Cancer Genome Atlas (TCGA) datasets showed that reduced miR-99a-5p or miR-99a-3p expression is associated with worse prognoses in LUAD patients (disease-free survival (DFS): p = 0.1264 and 0.0316; overall survival (OS): p = 0.0176 and 0.0756, respectively). Ectopic expression of these miRNAs attenuated LUAD cell proliferation, suggesting their tumor-suppressive roles. Our in silico analysis revealed 23 putative target genes of pre-miR-99a in LUAD cells. Among these targets, high expressions of 19 genes were associated with worse prognoses in LUAD patients (OS: p < 0.05). Notably, FAM64A was regulated by both miR-99a-5p and miR-99a-3p in LUAD cells, and its aberrant expression was significantly associated with poor prognosis in LUAD patients (OS: p = 0.0175; DFS: p = 0.0276). FAM64A knockdown using siRNAs suggested that elevated FAM64A expression contributes to cancer progression. Aberrant FAM64A expression was detected in LUAD tissues by immunostaining. Taken together, our miRNA-based analysis might be effective for identifying prognostic and therapeutic molecules in LUAD.
      Citation: Cells
      PubDate: 2020-09-11
      DOI: 10.3390/cells9092083
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2084: Quantification of Boron Compound Concentration
           for BNCT Using Positron Emission Tomography

    • Authors: Marcin Balcerzyk, Manuel De-Miguel, Carlos Guerrero, Begoña Fernandez
      First page: 2084
      Abstract: Background: Boron neutron capture therapy requires a 2 mM 10B concentration in the tumor. The well-known BNCT patient treatment method using boronophenylalanine (BPA) as a boron-carrying agent utilizes [18F]fluoroBPA ([18F]FBPA) as an agent to qualify for treatment. Precisely, [18F]FBPA must have at least a 3:1 tumor to background tissue ratio to qualify the patient for BNCT treatment. Normal, hyperplasia, and cancer thyroids capture iodine and several other large ions, including BF4−, through a sodium-iodine symporter (NIS) expressed on the cell surface in normal conditions. In cancer, NIS is also expressed within the thyroid cell and is not functional. Methods: To visualize the thyroids and NIS, we have used a [18F]NaBF4 positron emission tomography (PET) tracer. It was injected into the tail veins of rats. The [18F]NaBF4 PET tracer was produced from NaBF4 by the isotopic exchange of natural 19F with radioactive 18F. Rats were subject to hyperplasia and tumor-inducing treatment. The NIS in thyroids was visualized by immunofluorescence staining. The boron concentration was calculated from Standard Uptake Values (SUV) in the PET/CT images and from the production data. Results: 41 MBq, 0.64 pmol of [18F]NaBF4 PET tracer that contained 0.351 mM, 53 nmol of NaBF4 was injected into the tail vein. After 17 min, the peak activity in the thyroid reached 2.3 MBq/mL (9 SUVmax). The natB concentration in the thyroid with hyperplasia reached 381 nM. Conclusions: Such an incorporation would require an additional 110 mg/kg dose of [10B]NaBF4 to reach the necessary 2 mM 10B concentration in the tumor. For future BNCT treatments of thyroid cancer, contrary to the 131I used now, there is no post-treatment radioactive decay, the patient can be immediately discharged from hospital, and there is no six-month moratorium for pregnancy. This method can be used for BNCT treatment compounds of the type R-BFn, where 1 <= n <= 3, labeled with 18F relatively easily, as in our example. A patient may undergo injection of a mixture of nonradioactive R-BFn to reach the necessary 10B concentration for BNCT treatment in the tumor together, with [18F]R-BFn for boron mapping.
      Citation: Cells
      PubDate: 2020-09-12
      DOI: 10.3390/cells9092084
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2085: Development of Feline Ileum- and Colon-Derived

    • Authors: Gergely Tekes, Rosina Ehmann, Steeve Boulant, Megan L. Stanifer
      First page: 2085
      Abstract: Feline coronaviruses (FCoVs) infect both wild and domestic cat populations world-wide. FCoVs present as two main biotypes: the mild feline enteric coronavirus (FECV) and the fatal feline infectious peritonitis virus (FIPV). FIPV develops through mutations from FECV during a persistence infection. So far, the molecular mechanism of FECV-persistence and contributing factors for FIPV development may not be studied, since field FECV isolates do not grow in available cell culture models. In this work, we aimed at establishing feline ileum and colon organoids that allow the propagation of field FECVs. We have determined the best methods to isolate, culture and passage feline ileum and colon organoids. Importantly, we have demonstrated using GFP-expressing recombinant field FECV that colon organoids are able to support infection of FECV, which were unable to infect traditional feline cell culture models. These organoids in combination with recombinant FECVs can now open the door to unravel the molecular mechanisms by which FECV can persist in the gut for a longer period of time and how transition to FIPV is achieved.
      Citation: Cells
      PubDate: 2020-09-12
      DOI: 10.3390/cells9092085
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2086: Sexual Dimorphism in Osteoclasts

    • Authors: Joseph Lorenzo
      First page: 2086
      Abstract: Osteoclasts are the principal mediators of bone resorption. They form through the fusion of mononuclear precursor cells under the principal influence of the cytokines macrophage colony stimulating factor (M-CSF, aka CSF-1) and receptor activator of NF-κB ligand (RANKL, aka TNFSF11). Sexual dimorphism in the development of the skeleton and in the incidence of skeletal diseases is well described. In general, females, at any given age, have a lower bone mass than males. The reasons for the differences in the bone mass of the skeleton between women and men at various ages, and the incidence of certain metabolic bone diseases, are multitude, and include the actions of sex steroids, genetics, age, environment and behavior. All of these influence the rate that osteoclasts form, resorb and die, and frequently produce different effects in females and males. Hence, a variety of factors are responsible for the sexual dimorphism of the skeleton and the activity of osteoclasts in bone. This review will provide an overview of what is currently known about these factors and their effects on osteoclasts.
      Citation: Cells
      PubDate: 2020-09-12
      DOI: 10.3390/cells9092086
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2087: Multivalency Beats Complexity: A Study on the
           Cell Uptake of Carbohydrate Functionalized Nanocarriers to Dendritic Cells

    • Authors: Matthias Krumb, Marie-Luise Frey, Jens Langhanki, Robert Forster, Danuta Kowalczyk, Volker Mailänder, Katharina Landfester, Till Opatz
      First page: 2087
      Abstract: Herein, we report the synthesis of carbohydrate and glycodendron structures for dendritic cell targeting, which were subsequently bound to hydroxyethyl starch (HES) nanocapsules prepared by the inverse miniemulsion technique. The uptake of the carbohydrate-functionalized HES nanocapsules into immature human dendritic cells (hDCs) revealed a strong dependence on the used carbohydrate. A multivalent mannose-terminated dendron was found to be far superior in uptake compared to the structurally more complex oligosaccharides used.
      Citation: Cells
      PubDate: 2020-09-12
      DOI: 10.3390/cells9092087
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2088: The Amazonian Red Side-Necked Turtle Rhinemys
           rufipes (Spix, 1824) (Testudines, Chelidae) Has a GSD Sex-Determining
           Mechanism with an Ancient XY Sex Microchromosome System

    • Authors: Patrik F. Viana, Eliana Feldberg, Marcelo B. Cioffi, Vinicius Tadeu de Carvalho, Sabrina Menezes, Richard C. Vogt, Thomas Liehr, Tariq Ezaz
      First page: 2088
      Abstract: The Amazonian red side-necked turtle Rhynemis rufipes is an endemic Amazonian Chelidae species that occurs in small streams throughout Colombia and Brazil river basins. Little is known about various biological aspects of this species, including its sex determination strategies. Among chelids, the greatest karyotype diversity is found in the Neotropical species, with several 2n configurations, including cases of triploidy. Here, we investigate the karyotype of Rhinemys rufipes by applying combined conventional and molecular cytogenetic procedures. This allowed us to discover a genetic sex-determining mechanism that shares an ancestral micro XY sex chromosome system. This ancient micro XY system recruited distinct repeat motifs before it diverged from several South America and Australasian species. We propose that such a system dates back to the earliest lineages of the chelid species before the split of South America and Australasian lineages.
      Citation: Cells
      PubDate: 2020-09-12
      DOI: 10.3390/cells9092088
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2089: Activation of Cdc42 GTPase upon CRY2-Induced
           Cortical Recruitment is Antagonized by GAPs in Fission Yeast

    • Authors: Lamas, Weber, Martin
      First page: 2089
      Abstract: The small GTPase Cdc42 is critical for cell polarization in eukaryotic cells. In rod-shaped fission yeast Schizosaccharomyces pombe cells, active GTP-bound Cdc42 promotes polarized growth at cell poles, while inactive Cdc42-GDP localizes ubiquitously also along cell sides. Zones of Cdc42 activity are maintained by positive feedback amplification involving the formation of a complex between Cdc42-GTP, the scaffold Scd2, and the guanine nucleotide exchange factor (GEF) Scd1, which promotes the activation of more Cdc42. Here, we use the CRY2-CIB1 optogenetic system to recruit and cluster a cytosolic Cdc42 variant at the plasma membrane and show that this leads to its moderate activation also on cell sides. Surprisingly, Scd2, which binds Cdc42-GTP, is still recruited to CRY2-Cdc42 clusters at cell sides in individual deletion of the GEFs Scd1 or Gef1. We show that activated Cdc42 clusters at cell sides are able to recruit Scd1, dependent on the scaffold Scd2. However, Cdc42 activity is not amplified by positive feedback and does not lead to morphogenetic changes, due to antagonistic activity of the GTPase activating protein Rga4. Thus, the cell architecture is robust to moderate activation of Cdc42 at cell sides.
      Citation: Cells
      PubDate: 2020-09-12
      DOI: 10.3390/cells9092089
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2090: Ionocytes and CFTR Chloride Channel Expression
           in Normal and Cystic Fibrosis Nasal and Bronchial Epithelial Cells

    • Authors: Paolo Scudieri, Ilaria Musante, Arianna Venturini, Daniela Guidone, Michele Genovese, Federico Cresta, Emanuela Caci, Alessandro Palleschi, Marco Poeta, Francesca Santamaria, Fabiana Ciciriello, Vincenzina Lucidi, Luis J. V. Galietta
      First page: 2090
      Abstract: The airway epithelium contains ionocytes, a rare cell type with high expression of Forkhead Box I1 (FOXI1) transcription factor and Cystic Fibrosis Transmembrane conductance Regulator (CFTR), a chloride channel that is defective in cystic fibrosis (CF). Our aim was to verify if ionocyte development is altered in CF and to investigate the relationship between ionocytes and CFTR-dependent chloride secretion. We collected nasal cells by brushing to determine ionocyte abundance. Nasal and bronchial cells were also expanded in vitro and reprogrammed to differentiated epithelia for morphological and functional studies. We found a relatively high (~3%) ionocyte abundance in ex vivo nasal samples, with no difference between CF and control individuals. In bronchi, ionocytes instead appeared very rarely as previously reported, thus suggesting a possible proximal–distal gradient in human airways. The difference between nasal and bronchial epithelial cells was maintained in culture, which suggests an epigenetic control of ionocyte development. In the differentiation phase of the culture procedure, we used two media that resulted in a different pattern of CFTR expression: confined to ionocytes or more broadly expressed. CFTR function was similar in both conditions, thus indicating that chloride secretion equally occurs irrespective of CFTR expression pattern.
      Citation: Cells
      PubDate: 2020-09-13
      DOI: 10.3390/cells9092090
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2091: BV-2 Microglial Cells Respond to Rotenone Toxic
           Insult by Modifying Pregnenolone, 5α-Dihydroprogesterone and Pregnanolone

    • Authors: Rossella Avallone, Chiara Lucchi, Giulia Puja, Alessandro Codeluppi, Monica Filaferro, Giovanni Vitale, Cecilia Rustichelli, Giuseppe Biagini
      First page: 2091
      Abstract: Neuroinflammation, whose distinctive sign is the activation of microglia, is supposed to play a key role in the development and progression of neurodegenerative diseases. The aim of this investigation was to determine levels of neurosteroids produced by resting and injured BV-2 microglial cells. BV-2 cells were exposed to increasing concentrations of rotenone to progressively reduce their viability by increasing reactive oxygen species (ROS) production. BV-2 cell viability was significantly reduced 24, 48 and 72 h after rotenone (50–1000 nM) exposure. Concomitantly, rotenone (50–100 nM) determined a dose-independent augmentation of ROS production. Then, BV-2 cells were exposed to a single, threshold dose of rotenone (75 nM) to evaluate the overtime release of neurosteroids. In particular, pregnenolone, pregnenolone sulfate, progesterone, 5α-dihydroprogesterone (5α-DHP), allopregnanolone, and pregnanolone, were quantified in the culture medium by liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis. BV-2 cells synthesized all the investigated neurosteroids and, after exposure to rotenone, 5αDHP and pregnanolone production was remarkably increased. In conclusion, we found that BV-2 cells not only synthesize several neurosteroids, but further increase this production following oxidative damage. Pregnanolone and 5α-DHP may play a role in modifying the progression of neuroinflammation in neurodegenerative diseases.
      Citation: Cells
      PubDate: 2020-09-13
      DOI: 10.3390/cells9092091
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2092: An Evolutionary Cancer Epigenetic Approach
           Revealed DNA Hypermethylation of Ultra-Conserved Non-Coding Elements in
           Squamous Cell Carcinoma of Different Mammalian Species

    • Authors: Luca Morandi, Silvia Sabattini, Andrea Renzi, Antonella Rigillo, Giuliano Bettini, Eva Dervas, Alexandria Schauer, Marco Morandi, Davide B. Gissi, Achille Tarsitano, Stefania Evangelisti, Caterina Tonon
      First page: 2092
      Abstract: Background: Ultra-conserved non-coding elements (UCNEs) are genomic sequences that exhibit > 95% sequence identity between humans, mammals, birds, reptiles, and fish. Recent findings reported their functional role in cancer. The aim of this study was to evaluate the DNA methylation modifications of UNCEs in squamous cell carcinoma (SCC) from different mammal species. Methods: Fifty SCCs from 26 humans, 17 cats, 3 dogs, 1 horse, 1 bovine, 1 badger, and 1 porcupine were investigated. Fourteen feline stomatitis and normal samples from 36 healthy human donors, 7 cats, 5 dogs, 5 horses, 2 bovines and 1 badger were collected as normal controls. Bisulfite next generation sequencing evaluated the DNA methylation level from seven UCNEs (uc.160, uc.283, uc.416, uc.339, uc.270, uc.299, and uc.328). Results: 57/59 CpGs were significantly different according to the Kruskal–Wallis test (p < 0.05) comparing normal samples with SCC. A common DNA hypermethylation pattern was observed in SCCs from all the species evaluated in this study, with an increasing trend of hypermethylation starting from normal mucosa, through stomatitis to SCC. Conclusions: Our findings indicate that UCNEs are hypermethylated in human SCC, and this behavior is also conserved among different species of mammals.
      Citation: Cells
      PubDate: 2020-09-13
      DOI: 10.3390/cells9092092
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2093: Dim Light at Night Induced Neurodegeneration
           and Ameliorative Effect of Curcumin

    • Authors: Namgyal, Chandan, Sultan, Aftab, Ali, Mehta, El-Serehy, Al-Misned, Sarwat
      First page: 2093
      Abstract: It is a well-known fact that following a proper routine light/dark or diurnal rhythm controls almost all biological processes. With the introduction of modern lighting and artificial illumination systems, continuous exposure to light at night may lead to the disruption of diurnal rhythm. However, the effect of light during the night on brain anatomy, physiology, and human body functions is less explored and poorly understood. In this study, we have evaluated the effect of exposure to dim light (5 lux) at night (dLAN) on Swiss Albino mice over a duration of three consecutive weeks. Results have revealed that exposure to dLAN led to an impairment of cognitive and non-cognitive behaviour, oxidative stress–mediated elevation of lipid peroxidation, and reduction of superoxide dismutase and catalase activity. It also led to the downregulation of hippocampal proteins (BDNF, Synapsin II and DCX) at both protein and mRNA level. Additionally, there was downregulation of CREB and SIRT1 mRNAs and neurodegeneration-associated miRNA21a-5p and miRNA34a-5p. The pyramidal and cortical neurons started showing pyknotic and chromatolysis characteristics. However, a dose of curcumin administered to the mice positively modulated these parameters in our experimental animals. We proposed the modulatory role of curcumin in addressing the deleterious effects of dLAN.
      Citation: Cells
      PubDate: 2020-09-13
      DOI: 10.3390/cells9092093
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2094: Cell Biological Techniques and Cell-Biomaterial

    • Authors: Yunqing Kang
      First page: 2094
      Abstract: Biomaterials play a key role in modern tissue engineering and regenerative medicine. They are expected to take over the function of a damaged tissue in the long term, trigger the self-healing potential of the body, and biodegrade at an appropriate rate. To meet these requirements, it is imperative to understand the cell-biomaterial interactions and develop new cell biotechnologies. The collection of this Special Issue brings together a number of studies portraying the underlying mechanisms of cell-biomaterial interactions.
      Citation: Cells
      PubDate: 2020-09-14
      DOI: 10.3390/cells9092094
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2095: Breaking Bottlenecks for the TCR Therapy of

    • Authors: Lena Gaissmaier, Mariam Elshiaty, Petros Christopoulos
      First page: 2095
      Abstract: Immune checkpoint inhibitors have redefined the treatment of cancer, but their efficacy depends critically on the presence of sufficient tumor-specific lymphocytes, and cellular immunotherapies develop rapidly to fill this gap. The paucity of suitable extracellular and tumor-associated antigens in solid cancers necessitates the use of neoantigen-directed T-cell-receptor (TCR)-engineered cells, while prevention of tumor evasion requires combined targeting of multiple neoepitopes. These can be currently identified within 2 weeks by combining cutting-edge next-generation sequencing with bioinformatic pipelines and used to select tumor-reactive TCRs in a high-throughput manner for expeditious scalable non-viral gene editing of autologous or allogeneic lymphocytes. “Young” cells with a naive, memory stem or central memory phenotype can be additionally armored with “next-generation” features against exhaustion and the immunosuppressive tumor microenvironment, where they wander after reinfusion to attack heavily pretreated and hitherto hopeless neoplasms. Facilitated by major technological breakthroughs in critical manufacturing steps, based on a solid preclinical rationale, and backed by rapidly accumulating evidence, TCR therapies break one bottleneck after the other and hold the promise to become the next immuno-oncological revolution.
      Citation: Cells
      PubDate: 2020-09-14
      DOI: 10.3390/cells9092095
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2096: Treatment of Grade 3 and 4 Osteoarthritis with
           Intraoperatively Separated Adipose Tissue-Derived Stromal Vascular
           Fraction: A Comparative Case Series

    • Authors: Denis Simunec, Honey Salari, Juliane Meyer
      First page: 2096
      Abstract: Osteoarthritis (OA) is the most common form of arthritis of the joints. The stromal vascular fraction (SVF) is a regenerative cell population that can be isolated from adipose tissue. It is the immunomodulatory properties of the stromal vascular fraction that make it a promising candidate for the regenerative treatment of OA. Patients with grade 3 and 4 osteoarthritis were treated with the stromal vascular fraction with and without platelet-rich plasma (PRP) and followed up on their Knee Injury and Osteoarthritis Outcome Score (KOOS) score for 12 months, with MRI and subjective evaluation of the procedure. Magnetic resonance imaging (MRI) revealed a widening of the joint space, a restructuring of the cartilage, and an alleviation of effusions in the treated joints. In three of the four treatment groups, a substantial improvement of the KOOS scores was documented at the 12-month follow-up time point. According to the subjective evaluation, 67% of the patients were satisfied or very satisfied with the procedure and would recommend it to others. No serious adverse events or unwanted side effects related to the SVF treatment were observed or reported. Prior to an invasive artificial joint replacement, the treatment of arthritic knee joints with the intraarticular injection of autologous adipose tissue-derived SVF should be considered a regenerative treatment option.
      Citation: Cells
      PubDate: 2020-09-14
      DOI: 10.3390/cells9092096
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2097: Spirulina-in Silico-Mutations and Their
           Comparative Analyses in the Metabolomics Scale by Using Proteome-Based
           Flux Balance Analysis

    • Authors: Supatcha Lertampaiporn, Jittisak Senachak, Wassana Taenkaew, Chiraphan Khannapho, Apiradee Hongsthong
      First page: 2097
      Abstract: This study used an in silico metabolic engineering strategy for modifying the metabolic capabilities of Spirulina under specific conditions as an approach to modifying culture conditions in order to generate the intended outputs. In metabolic models, the basic metabolic fluxes in steady-state metabolic networks have generally been controlled by stoichiometric reactions; however, this approach does not consider the regulatory mechanism of the proteins responsible for the metabolic reactions. The protein regulatory network plays a critical role in the response to stresses, including environmental stress, encountered by an organism. Thus, the integration of the response mechanism of Spirulina to growth temperature stresses was investigated via simulation of a proteome-based GSMM, in which the boundaries were established by using protein expression levels obtained from quantitative proteomic analysis. The proteome-based flux balance analysis (FBA) under an optimal growth temperature (35 °C), a low growth temperature (22 °C) and a high growth temperature (40 °C) showed biomass yields that closely fit the experimental data obtained in previous research. Moreover, the response mechanism was analyzed by the integration of the proteome and protein–protein interaction (PPI) network, and those data were used to support in silico knockout/overexpression of selected proteins involved in the PPI network. The Spirulina, wild-type, proteome fluxes under different growth temperatures and those of mutants were compared, and the proteins/enzymes catalyzing the different flux levels were mapped onto their designated pathways for biological interpretation.
      Citation: Cells
      PubDate: 2020-09-15
      DOI: 10.3390/cells9092097
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2098: Identification and Comparison of
           Hyperglycemia-Induced Extracellular Vesicle Transcriptome in Different
           Mouse Stem Cells

    • Authors: Grace Huang, Venkata Naga Srikanth Garikipati, Yan Zhou, Cynthia Benedict, Steven R. Houser, Walter J. Koch, Raj Kishore
      First page: 2098
      Abstract: Extracellular vesicles (EVs) derived from stem /progenitor cells harbor immense potential to promote cardiomyocyte survival and neovascularization, and to mitigate ischemic injury. However, EVs’ parental stem/progenitor cells showed modest benefits in clinical trials, suggesting autologous stem cell/EV quality might have been altered by stimuli associated with the co-morbidities such as hyperglycemia associated with diabetes. Hyperglycemia is a characteristic of diabetes and a major driving factor in cardiovascular disease. The functional role of stem/progenitor cell-derived EVs and the molecular signature of their secreted EV cargo under hyperglycemic conditions remain elusive. Therefore, we hypothesized that hyperglycemic stress causes transcriptome changes in stem/progenitor cell-derived EVs that may compromise their reparative function. In this study, we performed an unbiased analysis of EV transcriptome signatures from 3 different stem/progenitor cell types by RNA sequencing. The analysis revealed differential expression of a variety of RNA species in EVs. Specifically, we identified 241 common-dysregulated mRNAs, 21 ncRNAs, and 16 miRNAs in three stem cell-derived EVs. Gene Ontology revealed that potential function of common mRNAs mostly involved in metabolism and transcriptional regulation. This study provides potential candidates for preventing the adverse effects of hyperglycemia-induced stem/progenitor cell-derived EV dysfunction, and reference data for future biological studies and application of stem/progenitor cell-derived EVs.
      Citation: Cells
      PubDate: 2020-09-15
      DOI: 10.3390/cells9092098
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2099: Increased Uptake of Silica Nanoparticles in
           Inflamed Macrophages but Not upon Co-Exposure to Micron-Sized Particles

    • Authors: Eva Susnik, Patricia Taladriz-Blanco, Barbara Drasler, Sandor Balog, Alke Petri-Fink, Barbara Rothen-Rutishauser
      First page: 2099
      Abstract: Silica nanoparticles (NPs) are widely used in various industrial and biomedical applications. Little is known about the cellular uptake of co-exposed silica particles, as can be expected in our daily life. In addition, an inflamed microenvironment might affect a NP’s uptake and a cell’s physiological response. Herein, prestimulated mouse J774A.1 macrophages with bacterial lipopolysaccharide were post-exposed to micron- and nanosized silica particles, either alone or together, i.e., simultaneously or sequentially, for different time points. The results indicated a morphological change and increased expression of tumor necrosis factor alpha in lipopolysaccharide prestimulated cells, suggesting a M1-polarization phenotype. Confocal laser scanning microscopy revealed the intracellular accumulation and uptake of both particle types for all exposure conditions. A flow cytometry analysis showed an increased particle uptake in lipopolysaccharide prestimulated macrophages. However, no differences were observed in particle uptakes between single- and co-exposure conditions. We did not observe any colocalization between the two silica (SiO2) particles. However, there was a positive colocalization between lysosomes and nanosized silica but only a few colocalized events with micro-sized silica particles. This suggests differential intracellular localizations of silica particles in macrophages and a possible activation of distinct endocytic pathways. The results demonstrate that the cellular uptake of NPs is modulated in inflamed macrophages but not in the presence of micron-sized particles.
      Citation: Cells
      PubDate: 2020-09-15
      DOI: 10.3390/cells9092099
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2100: Ivermectin as a Broad-Spectrum Host-Directed
           Antiviral: The Real Deal'

    • Authors: David A. Jans, Kylie M. Wagstaff
      First page: 2100
      Abstract: The small molecule macrocyclic lactone ivermectin, approved by the US Food and Drug Administration for parasitic infections, has received renewed attention in the last eight years due to its apparent exciting potential as an antiviral. It was identified in a high-throughput chemical screen as inhibiting recognition of the nuclear localizing Human Immunodeficiency Virus-1 (HIV-1) integrase protein by the host heterodimeric importin (IMP) α/β1 complex, and has since been shown to bind directly to IMPα to induce conformational changes that prevent its normal function in mediating nuclear import of key viral and host proteins. Excitingly, cell culture experiments show robust antiviral action towards HIV-1, dengue virus (DENV), Zika virus, West Nile virus, Venezuelan equine encephalitis virus, Chikungunya virus, Pseudorabies virus, adenovirus, and SARS-CoV-2 (COVID-19). Phase III human clinical trials have been completed for DENV, with >50 trials currently in progress worldwide for SARS-CoV-2. This mini-review discusses the case for ivermectin as a host-directed broad-spectrum antiviral agent for a range of viruses, including SARS-CoV-2.
      Citation: Cells
      PubDate: 2020-09-15
      DOI: 10.3390/cells9092100
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2101: Interplay between Cellular Autophagy and
           Hepatitis B Virus Replication: A Systematic Review

    • Authors: Yong Lin, Zhenyu Zhao, Ailong Huang, Mengji Lu
      First page: 2101
      Abstract: Autophagy, a conserved process in which cells break down and destroy old, damaged, or abnormal proteins and other substances in the cytoplasm through lysosomal degradation, occurs via autophagosome formation and aids in the maintenance of intracellular homeostasis. Autophagy is closely associated with hepatitis B virus (HBV) replication and assembly. Currently, HBV infection is still one of the most serious public health issues worldwide. The unavailability of satisfactory therapeutic strategies for chronic HBV infection indicates an urgent need to elucidate the mechanisms underlying the pathogenesis of HBV infection. Increasing evidence has shown that HBV not only possesses the ability to induce incomplete autophagy but also evades autophagic degradation, indicating that HBV utilizes or hijacks the autophagy machinery for its own replication. Therefore, autophagy might be a crucial target pathway for controlling HBV infection. The definite molecular mechanisms underlying the association between cellular autophagy and HBV replication require further clarification. In this review, we have summarized and discussed the latest findings on the interplay between autophagy and HBV replication.
      Citation: Cells
      PubDate: 2020-09-15
      DOI: 10.3390/cells9092101
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2102: Nano-Enhanced Cancer Immunotherapy: Immunology
           Encounters Nanotechnology

    • Authors: Ernesto Bockamp, Sebastian Rosigkeit, Dominik Siegl, Detlef Schuppan
      First page: 2102
      Abstract: Cancer immunotherapy utilizes the immune system to fight cancer and has already moved from the laboratory to clinical application. However, and despite excellent therapeutic outcomes in some hematological and solid cancers, the regular clinical use of cancer immunotherapies reveals major limitations. These include the lack of effective immune therapy options for some cancer types, unresponsiveness to treatment by many patients, evolving therapy resistance, the inaccessible and immunosuppressive nature of the tumor microenvironment (TME), and the risk of potentially life-threatening immune toxicities. Given the potential of nanotechnology to deliver, enhance, and fine-tune cancer immunotherapeutic agents, the combination of cancer immunotherapy with nanotechnology can overcome some of these limitations. In this review, we summarize innovative reports and novel strategies that successfully combine nanotechnology and cancer immunotherapy. We also provide insight into how nanoparticular combination therapies can be used to improve therapy responsiveness, to reduce unwanted toxicity, and to overcome adverse effects of the TME.
      Citation: Cells
      PubDate: 2020-09-15
      DOI: 10.3390/cells9092102
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2103: HNSCC: Tumour Antigens and Their Targeting by

    • Authors: Adrian von Witzleben, Chuan Wang, Simon Laban, Natalia Savelyeva, Christian H. Ottensmeier
      First page: 2103
      Abstract: Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of malignant tumours typically caused by alcohol and tobacco consumption, although an increasing number of HNSCC arise due to persistent infection with high-risk human papilloma virus (HPV). The treatment of HNSCC remains challenging, and the first-line setting is focused on surgery and chemoradiotherapy. A substantial proportion of HNSCC patients die from their disease, especially those with recurrent and metastatic disease. Among factors linked with good outcome, immune cell infiltration appears to have a major role. HPV-driven HNSCC are often T-cell rich, reflecting the presence of HPV antigens that are immunogenic. Tumour-associated antigens that are shared between patients or that are unique to an individual person may also induce varying degrees of immune response; studying these is important for the understanding of the interaction between the host immune system and the cancer. The resulting knowledge is critical for the design of better immunotherapies. Key questions are: Which antigens lead to an adaptive immune response in the tumour' Which of these are exploitable for immunotherapy' Here, we review the current thinking regarding tumour antigens in HNSCC and what has been learned from early phase clinical trials.
      Citation: Cells
      PubDate: 2020-09-15
      DOI: 10.3390/cells9092103
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2104: In Vitro Characterization of Gut
           Microbiota-Derived Commensal Strains: Selection of Parabacteroides
           distasonis Strains Alleviating TNBS-Induced Colitis in Mice

    • Authors: Bernardo Cuffaro, Aka L. W. Assohoun, Denise Boutillier, Lenka Súkeníková, Jérémy Desramaut, Samira Boudebbouze, Sophie Salomé-Desnoulez, Jiří Hrdý, Anne-Judith Waligora-Dupriet, Emmanuelle Maguin, Corinne Grangette
      First page: 2104
      Abstract: Alterations in the gut microbiota composition and diversity seem to play a role in the development of chronic diseases, including inflammatory bowel disease (IBD), leading to gut barrier disruption and induction of proinflammatory immune responses. This opens the door for the use of novel health-promoting bacteria. We selected five Parabacteroides distasonis strains isolated from human adult and neonates gut microbiota. We evaluated in vitro their immunomodulation capacities and their ability to reinforce the gut barrier and characterized in vivo their protective effects in an acute murine model of colitis. The in vitro beneficial activities were highly strain dependent: two strains exhibited a potent anti-inflammatory potential and restored the gut barrier while a third strain reinstated the epithelial barrier. While their survival to in vitro gastric conditions was variable, the levels of P. distasonis DNA were higher in the stools of bacteria-treated animals. The strains that were positively scored in vitro displayed a strong ability to rescue mice from colitis. We further showed that two strains primed dendritic cells to induce regulatory T lymphocytes from naïve CD4+ T cells. This study provides better insights on the functionality of commensal bacteria and crucial clues to design live biotherapeutics able to target inflammatory chronic diseases such as IBD.
      Citation: Cells
      PubDate: 2020-09-16
      DOI: 10.3390/cells9092104
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2105: Evaluating Serum Heat Shock Protein Levels as
           Novel Biomarkers for Atrial Fibrillation

    • Authors: Denise M. S. van Marion, Eva A. H. Lanters, Kennedy S. Ramos, Jin Li, Marit Wiersma, Luciënne Baks-te Bulte, Agnes J. Q. M. Muskens, Eric Boersma, Natasja M. S. de Groot, Bianca J. J. M. Brundel
      First page: 2105
      Abstract: Background: Staging of atrial fibrillation (AF) is essential to understanding disease progression and the accompanied increase in therapy failure. Blood-based heat shock protein (HSP) levels may enable staging of AF and the identification of patients with higher risk for AF recurrence after treatment. Objective: This study evaluates the relationship between serum HSP levels, presence of AF, AF stage and AF recurrence following electrocardioversion (ECV) or pulmonary vein isolation (PVI). Methods: To determine HSP27, HSP70, cardiovascular (cv)HSP and HSP60 levels, serum samples were collected from control patients without AF and patients with paroxysmal atrial fibrillation (PAF), persistent (PeAF) and longstanding persistent (LSPeAF) AF, presenting for ECV or PVI, prior to intervention and at 3-, 6- and 12-months post-PVI. Results: The study population (n = 297) consisted of 98 control and 199 AF patients admitted for ECV (n = 98) or PVI (n = 101). HSP27, HSP70, cvHSP and HSP60 serum levels did not differ between patients without or with PAF, PeAF or LSPeAF. Additionally, baseline HSP levels did not correlate with AF recurrence after ECV or PVI. However, in AF patients with AF recurrence, HSP27 levels were significantly elevated post-PVI relative to baseline, compared to patients without recurrence. Conclusions: No association was observed between baseline HSP levels and the presence of AF, AF stage or AF recurrence. However, HSP27 levels were increased in serum samples of patients with AF recurrence within one year after PVI, suggesting that HSP27 levels may predict recurrence of AF after ablative therapy.
      Citation: Cells
      PubDate: 2020-09-16
      DOI: 10.3390/cells9092105
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2106: Gastric Juice Expression of Th-17 and T-Reg
           Related Cytokines in Scleroderma Esophageal Involvement

    • Authors: Stefania Nicola, Giovanni Rolla, Caterina Bucca, Giada Geronazzo, Irene Ridolfi, Andrea Ferraris, Enrico Fusaro, Clara Lisa Peroni, Luca Dughera, Luisa Brussino
      First page: 2106
      Abstract: Background: Systemic sclerosis (SSc) is a connective tissue disorder which key feature is a fibrotic process. The role of Endothelin-1 (ET-1) and T-helper (Th)-1 cells in lung and skin fibrosis is well known, although Th17- and Treg-cells were found to be involved. However, no studies analyzed cytokines expression in gastric-juice of SSc patients. Our study aimed to evaluate proinflammatory and profibrotic cytokines in gastric-juice of SSc patients and to investigate their correlations with esophageal dysmotility. Methods: Patients performed upper-gastrointestinal-endoscopy with gastric-juice collection, esophageal manometry and thoracic CT-scan. GM-CSF, ET-1, Th-1 (IFN-γ, IL-1β, TNF-α, IL-2, IL-6, IL-9), Th-17 (IL-17, IL-21, IL-22, IL-23) and T-reg (IL-10, TGF-β) related cytokines were measured in 29 SSc-patients and 20 healthy-controls. Results: Patients showed significant lower levels of IL-6, IL-17, IL-22 and ET-1 (p < 0.005) compared with controls. Patients with atrophic gastritis presented significant lower levels of IL-2, IL-9, IL-6, TGF-β, GM-CSF, IL-17 and ET-1 (p < 0.005) compared to patients without gastritis. Increased values of IL-2, IL-9, IL-1β, IL-17, ET-1 and GM-CSF (p < 0.005) were observed in patients with esophageal impairment. This is the first report of cytokines measurement in gastric juice of patients with SSc. The high IL-17 concentrations in gastric-juice of scleroderma patients with esophageal dysmotility support the signature of Th-17 cells in scleroderma esophageal fibrosis.
      Citation: Cells
      PubDate: 2020-09-16
      DOI: 10.3390/cells9092106
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2107: RBM10, a New Regulator of p53

    • Authors: Ji Hoon Jung, Hyemin Lee, Shelya X Zeng, Hua Lu
      First page: 2107
      Abstract: The tumor suppressor p53 acts as a transcription factor that regulates the expression of a number of genes responsible for DNA repair, cell cycle arrest, metabolism, cell migration, angiogenesis, ferroptosis, senescence, and apoptosis. It is the most commonly silenced or mutated gene in cancer, as approximately 50% of all types of human cancers harbor TP53 mutations. Activation of p53 is detrimental to normal cells, thus it is tightly regulated via multiple mechanisms. One of the recently identified regulators of p53 is RNA-binding motif protein 10 (RBM10). RBM10 is an RNA-binding protein frequently deleted or mutated in cancer cells. Its loss of function results in various deformities, such as cleft palate and malformation of the heart, and diseases such as lung adenocarcinoma. In addition, RBM10 mutations are frequently observed in lung adenocarcinomas, colorectal carcinomas, and pancreatic ductal adenocarcinomas. RBM10 plays a regulatory role in alternative splicing. Several recent studies not only linked this splicing regulation of RBM10 to cancer development, but also bridged RBM10′s anticancer function to the p53 pathway. This review will focus on the current progress in our understanding of RBM10 regulation of p53, and its role in p53-dependent cancer prevention.
      Citation: Cells
      PubDate: 2020-09-16
      DOI: 10.3390/cells9092107
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2108: Raloxifene and n-Acetylcysteine Ameliorate
           TGF-Signalling in Fibroblasts from Patients with Recessive Dominant
           Epidermolysis Bullosa

    • Authors: Tania Aguado, Marta García, Adela García, Gemma Ferrer-Mayorga, Lucía Martínez-Santamaría, Marcela del Río, Luisa-María Botella, José-María Sánchez-Puelles
      First page: 2108
      Abstract: Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disease caused by mutation of the COL7A1 gene. RDEB is associated with high levels of TGF-β1, which is likely to be involved in the fibrosis that develops in this disease. Endoglin (CD105) is a type III coreceptor for TGF-β1 and its overexpression in fibroblasts deregulates physiological Smad/Alk1/Alk5 signalling, repressing the synthesis of TGF-β1 and extracellular matrix (ECM) proteins. Raloxifene is a specific estrogen receptor modulator designated as an orphan drug for hereditary hemorrhagic telangiectasia, a rare vascular disease. Raloxifene stimulates endoglin synthesis, which could attenuate fibrosis. By contrast, the antioxidant N-acetylcysteine may have therapeutic value to rectify inflammation, fibrosis and endothelial dysfunction. Thus, we present here a repurposing strategy based on the molecular and functional screening of fibroblasts from RDEB patients with these drugs, leading us to propose the repositioning of these two well-known drugs currently in clinical use, raloxifene and N-acetylcysteine, to counteract fibrosis and inflammation in RDEB. Both compounds modulate the profibrotic events that may ultimately be responsible for the clinical manifestations in RDEB, suggesting that these findings may also be relevant for other diseases in which fibrosis is an important pathophysiological event.
      Citation: Cells
      PubDate: 2020-09-16
      DOI: 10.3390/cells9092108
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2109: Lessons from Bacillus Calmette-Guérin:
           Harnessing Trained Immunity for Vaccine Development

    • Authors: Samuel T. Pasco, Juan Anguita
      First page: 2109
      Abstract: Vaccine design traditionally focuses on inducing adaptive immune responses against a sole target pathogen. Considering that many microbes evade innate immune mechanisms to initiate infection, and in light of the discovery of epigenetically mediated innate immune training, the paradigm of vaccine design has the potential to change. The Bacillus Calmette-Guérin (BCG) vaccine induces some level of protection against Mycobacterium tuberculosis (Mtb) while stimulating trained immunity that correlates with lower mortality and increased protection against unrelated pathogens. This review will explore BCG-induced trained immunity, including the required pathways to establish this phenotype. Additionally, potential methods to improve or expand BCG trained immunity effects through alternative vaccine delivery and formulation methods will be discussed. Finally, advances in new anti-Mtb vaccines, other antimicrobial uses for BCG, and “innate memory-based vaccines” will be examined.
      Citation: Cells
      PubDate: 2020-09-16
      DOI: 10.3390/cells9092109
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2110: Maintenance Therapy for ATM-Deficient
           Pancreatic Cancer by Multiple DNA Damage Response Interferences after
           Platinum-Based Chemotherapy

    • Authors: Elodie Roger, Johann Gout, Frank Arnold, Alica K. Beutel, Martin Müller, Alireza Abaei, Thomas F. E. Barth, Volker Rasche, Thomas Seufferlein, Lukas Perkhofer, Alexander Kleger
      First page: 2110
      Abstract: Personalized medicine in treating pancreatic ductal adenocarcinoma (PDAC) is still in its infancy, albeit PDAC-related deaths are projected to rise over the next decade. Only recently, maintenance therapy with the PARP inhibitor olaparib showed improved progression-free survival in germline BRCA1/2-mutated PDAC patients after platinum-based induction for the first time. Transferability of such a concept to other DNA damage response (DDR) genes remains unclear. Here, we conducted a placebo-controlled, three-armed preclinical trial to evaluate the efficacy of multi-DDR interference (mDDRi) as maintenance therapy vs. continuous FOLFIRINOX treatment, implemented with orthotopically transplanted ATM-deficient PDAC cell lines. Kaplan–Meier analysis, cross-sectional imaging, histology, and in vitro analysis served as analytical readouts. Median overall survival was significantly longer in the mDDRi maintenance arm compared to the maintained FOLFIRINOX treatment. This survival benefit was mirrored in the highest DNA-damage load, accompanied by superior disease control and reduced metastatic burden. In vitro analysis suggests FOLFIRINOX-driven selection of invasive subclones, erased by subsequent mDDRi treatment. Collectively, this preclinical trial substantiates mDDRi in a maintenance setting as a novel therapeutic option and extends the concept to non-germline BRCA1/2-mutant PDAC.
      Citation: Cells
      PubDate: 2020-09-16
      DOI: 10.3390/cells9092110
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2111: Exercise-Induced Changes in Bioactive Lipids
           Might Serve as Potential Predictors of Post-Exercise Hypotension. A Pilot
           Study in Healthy Volunteers

    • Authors: Miriam C. Wolters, Julia Schmetzer, Christine V. Möser, Lisa Hahnefeld, Carlo Angioni, Dominique Thomas, Nerea Ferreirós, Gerd Geisslinger, Ellen Niederberger
      First page: 2111
      Abstract: Post-exercise hypotension (PEH) is the phenomenon of lowered blood pressure after a single bout of exercise. Only a fraction of people develops PEH but its occurrence correlates well with long-term effects of sports on blood pressure. Therefore, PEH has been suggested as a suitable predictor for the effectivity of exercise as therapy in hypertension. Local vascular bioactive lipids might play a potential role in this context. We performed a cross-over clinical pilot study with 18 healthy volunteers to investigate the occurrence of PEH after a single short-term endurance exercise. Furthermore, we investigated the plasma lipid profile with focus on arachidonic acid (AA)-derived metabolites as potential biomarkers of PEH. A single bout of ergometer cycling induced a significant PEH in healthy volunteers with the expected high inter-individual variability. Targeted lipid spectrum analysis revealed significant upregulation of several lipids in the direct post-exercise phase. Among these changes, only 15- hydroxyeicosatetranoic acid (HETE) correlated significantly with the extent of PEH but in an AA-independent manner, suggesting that 15-HETE might act as specific PEH-marker. Our data indicate that specific lipid modulation might facilitate the identification of patients who will benefit from exercise activity in hypertension therapy. However, larger trials including hypertonic patients are necessary to verify the clinical value of this hypothesis.
      Citation: Cells
      PubDate: 2020-09-16
      DOI: 10.3390/cells9092111
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2112: Visualizing Cell Cycle Phase Organization and
           Control During Neural Lineage Elaboration

    • Authors: Fatma Rabia Urun, Adrian W Moore
      First page: 2112
      Abstract: In neural precursors, cell cycle regulators simultaneously control both progression through the cell cycle and the probability of a cell fate switch. Precursors act in lineages, where they transition through a series of cell types, each of which has a unique molecular identity and cellular behavior. Thus, investigating links between cell cycle and cell fate control requires simultaneous identification of precursor type and cell cycle phase, as well as an ability to read out additional regulatory factor expression or activity. We use a combined FUCCI-EdU labelling protocol to do this, and then applied it to the embryonic olfactory neural lineage, in which the spatial position of a cell correlates with its precursor identity. Using this integrated model, we find the CDKi p27KIP1 has different regulation relative to cell cycle phase in neural stem cells versus intermediate precursors. In addition, Hes1, which is the principle transcriptional driver of neural stem cell self-renewal, surprisingly does not regulate p27KIP1 in this cell type. Rather, Hes1 indirectly represses p27KIP1 levels in the intermediate precursor cells downstream in the lineage. Overall, the experimental model described here enables investigation of cell cycle and cell fate control linkage from a single precursor through to a lineage systems level.
      Citation: Cells
      PubDate: 2020-09-17
      DOI: 10.3390/cells9092112
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2113: Hyaluronic Acid Biomaterials for Central
           Nervous System Regenerative Medicine

    • Authors: Gregory Jensen, Julianne L. Holloway, Sarah E. Stabenfeldt
      First page: 2113
      Abstract: Hyaluronic acid (HA) is a primary component of the brain extracellular matrix and functions through cellular receptors to regulate cell behavior within the central nervous system (CNS). These behaviors, such as migration, proliferation, differentiation, and inflammation contribute to maintenance and homeostasis of the CNS. However, such equilibrium is disrupted following injury or disease leading to significantly altered extracellular matrix milieu and cell functions. This imbalance thereby inhibits inherent homeostatic processes that support critical tissue health and functionality in the CNS. To mitigate the damage sustained by injury/disease, HA-based tissue engineering constructs have been investigated for CNS regenerative medicine applications. HA’s effectiveness in tissue healing and regeneration is primarily attributed to its impact on cell signaling and the ease of customizing chemical and mechanical properties. This review focuses on recent findings to highlight the applications of HA-based materials in CNS regenerative medicine.
      Citation: Cells
      PubDate: 2020-09-17
      DOI: 10.3390/cells9092113
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2114: Hedgehog Signaling and Truncated GLI1 in Cancer

    • Authors: Daniel Doheny, Sara G. Manore, Grace L. Wong, Hui-Wen Lo
      First page: 2114
      Abstract: The hedgehog (HH) signaling pathway regulates normal cell growth and differentiation. As a consequence of improper control, aberrant HH signaling results in tumorigenesis and supports aggressive phenotypes of human cancers, such as neoplastic transformation, tumor progression, metastasis, and drug resistance. Canonical activation of HH signaling occurs through binding of HH ligands to the transmembrane receptor Patched 1 (PTCH1), which derepresses the transmembrane G protein-coupled receptor Smoothened (SMO). Consequently, the glioma-associated oncogene homolog 1 (GLI1) zinc-finger transcription factors, the terminal effectors of the HH pathway, are released from suppressor of fused (SUFU)-mediated cytoplasmic sequestration, permitting nuclear translocation and activation of target genes. Aberrant activation of this pathway has been implicated in several cancer types, including medulloblastoma, rhabdomyosarcoma, basal cell carcinoma, glioblastoma, and cancers of lung, colon, stomach, pancreas, ovarian, and breast. Therefore, several components of the HH pathway are under investigation for targeted cancer therapy, particularly GLI1 and SMO. GLI1 transcripts are reported to undergo alternative splicing to produce truncated variants: loss-of-function GLI1ΔN and gain-of-function truncated GLI1 (tGLI1). This review covers the biochemical steps necessary for propagation of the HH activating signal and the involvement of aberrant HH signaling in human cancers, with a highlight on the tumor-specific gain-of-function tGLI1 isoform.
      Citation: Cells
      PubDate: 2020-09-17
      DOI: 10.3390/cells9092114
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2115: Role of GPER-Mediated Signaling in Testicular
           Functions and Tumorigenesis

    • Authors: Adele Chimento, Arianna De Luca, Marta Claudia Nocito, Paola Avena, Davide La Padula, Lucia Zavaglia, Vincenzo Pezzi
      First page: 2115
      Abstract: Estrogen signaling plays important roles in testicular functions and tumorigenesis. Fifteen years ago, it was discovered that a member of the G protein-coupled receptor family, GPR30, which binds also with high affinity to estradiol and is responsible, in part, for the rapid non-genomic actions of estrogens. GPR30, renamed as GPER, was detected in several tissues including germ cells (spermatogonia, spermatocytes, spermatids) and somatic cells (Sertoli and Leydig cells). In our previous review published in 2014, we summarized studies that evidenced a role of GPER signaling in mediating estrogen action during spermatogenesis and testis development. In addition, we evidenced that GPER seems to be involved in modulating estrogen-dependent testicular cancer cell growth; however, the effects on cell survival and proliferation depend on specific cell type. In this review, we update the knowledge obtained in the last years on GPER roles in regulating physiological functions of testicular cells and its involvement in neoplastic transformation of both germ and somatic cells. In particular, we will focus our attention on crosstalk among GPER signaling, classical estrogen receptors and other nuclear receptors involved in testis physiology regulation.
      Citation: Cells
      PubDate: 2020-09-17
      DOI: 10.3390/cells9092115
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2116: Incorporating Prognostic Biomarkers into Risk
           Assessment Models and TNM Staging for Prostate Cancer

    • Authors: Ragheed Saoud, Nassib Abou Heidar, Alessia Cimadamore, Gladell P. Paner
      First page: 2116
      Abstract: In current practice, prostate cancer staging alone is not sufficient to adequately assess the patient’s prognosis and plan the management strategies. Multiple clinicopathological parameters and risk tools for prostate cancer have been developed over the past decades to better characterize the disease and provide an enhanced assessment of prognosis. Herein, we review novel prognostic biomarkers and their integration into risk assessment models for prostate cancer focusing on their capability to help avoid unnecessary imaging studies, biopsies and diagnosis of low risk prostate cancers, to help in the decision-making process between active surveillance and treatment intervention, and to predict recurrence after radical prostatectomy. There is an imperative need of reliable biomarkers to stratify prostate cancer patients that may benefit from different management approaches. The integration of biomarkers panel with risk assessment models appears to improve prostate cancer diagnosis and management. However, integration of novel genomic biomarkers in future prognostic models requires further validation in their clinical efficacy, standardization, and cost-effectiveness in routine application.
      Citation: Cells
      PubDate: 2020-09-17
      DOI: 10.3390/cells9092116
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2117: Seeking and Exploring Efficient Ways to Target

    • Authors: Tuula Kallunki
      First page: 2117
      Abstract: Anti-cancer treatments have never been so numerous and so efficient [...]
      Citation: Cells
      PubDate: 2020-09-17
      DOI: 10.3390/cells9092117
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2118: How Relevant Are Bone Marrow-Derived Mast Cells
           (BMMCs) as Models for Tissue Mast Cells' A Comparative Transcriptome
           Analysis of BMMCs and Peritoneal Mast Cells

    • Authors: Srinivas Akula, Aida Paivandy, Zhirong Fu, Michael Thorpe, Gunnar Pejler, Lars Hellman
      First page: 2118
      Abstract: Bone marrow-derived mast cells (BMMCs) are often used as a model system for studies of the role of MCs in health and disease. These cells are relatively easy to obtain from total bone marrow cells by culturing under the influence of IL-3 or stem cell factor (SCF). After 3 to 4 weeks in culture, a nearly homogenous cell population of toluidine blue-positive cells are often obtained. However, the question is how relevant equivalents these cells are to normal tissue MCs. By comparing the total transcriptome of purified peritoneal MCs with BMMCs, here we obtained a comparative view of these cells. We found several important transcripts that were expressed at very high levels in peritoneal MCs, but were almost totally absent from the BMMCs, including the major chymotryptic granule protease Mcpt4, the neurotrophin receptor Gfra2, the substance P receptor Mrgprb2, the metalloprotease Adamts9 and the complement factor 2 (C2). In addition, there were a number of other molecules that were expressed at much higher levels in peritoneal MCs than in BMMCs, including the transcription factors Myb and Meis2, the MilR1 (Allergin), Hdc (Histidine decarboxylase), Tarm1 and the IL-3 receptor alpha chain. We also found many transcripts that were highly expressed in BMMCs but were absent or expressed at low levels in the peritoneal MCs. However, there were also numerous MC-related transcripts that were expressed at similar levels in the two populations of cells, but almost absent in peritoneal macrophages and B cells. These results reveal that the transcriptome of BMMCs shows many similarities, but also many differences to that of tissue MCs. BMMCs can thereby serve as suitable models in many settings concerning the biology of MCs, but our findings also emphasize that great care should be taken when extrapolating findings from BMMCs to the in vivo function of tissue-resident MCs.
      Citation: Cells
      PubDate: 2020-09-17
      DOI: 10.3390/cells9092118
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2119: Genetic Variation in CNS Myelination and
           Functional Brain Connectivity in Recombinant Inbred Mice

    • Authors: Andrea Goudriaan, Maarten Loos, Sabine Spijker, August B. Smit, Mark H. G. Verheijen
      First page: 2119
      Abstract: Myelination greatly increases the speed of action potential propagation of neurons, thereby enhancing the efficacy of inter-neuronal communication and hence, potentially, optimizing the brain’s signal processing capability. The impact of genetic variation on the extent of axonal myelination and its consequences for brain functioning remain to be determined. Here we investigated this question using a genetic reference panel (GRP) of mouse BXD recombinant inbred (RI) strains, which partly model genetic diversity as observed in human populations, and which show substantial genetic differences in a variety of behaviors, including learning, memory and anxiety. We found coherent differences in the expression of myelin genes in brain tissue of RI strains of the BXD panel, with the largest differences in the hippocampus. The parental C57BL/6J (C57) and DBA/2J (DBA) strains were on opposite ends of the expression spectrum, with C57 showing higher myelin transcript expression compared with DBA. Our experiments showed accompanying differences between C57 and DBA in myelin protein composition, total myelin content, and white matter conduction velocity. Finally, the hippocampal myelin gene expression of the BXD strains correlated significantly with behavioral traits involving anxiety and/or activity. Taken together, our data indicate that genetic variation in myelin gene expression translates to differences observed in myelination, axonal conduction speed, and possibly in anxiety/activity related behaviors.
      Citation: Cells
      PubDate: 2020-09-18
      DOI: 10.3390/cells9092119
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2120: Therapeutic Benefit of the Association of
           Lodenafil with Mesenchymal Stem Cells on Hypoxia-induced Pulmonary
           Hypertension in Rats

    • Authors: Marina de Moraes Carvalho da Silva, Allan Kardec Nogueira de Alencar, Jaqueline Soares da Silva, Tadeu Lima Montagnoli, Grazielle Fernandes da Silva, Bruna de Souza Rocha, Guilherme Carneiro Montes, Rosália Mendez-Otero, Pedro Moreno Pimentel-Coelho, Juliana F. Vasques, Margarete Manhães Trahez, Roberto Takashi Sudo, Gisele Zapata-Sudo
      First page: 2120
      Abstract: Pulmonary arterial hypertension (PAH) is characterized by the remodeling of pulmonary arteries, with an increased pulmonary arterial pressure and right ventricle (RV) overload. This work investigated the benefit of the association of human umbilical cord mesenchymal stem cells (hMSCs) with lodenafil, a phosphodiesterase-5 inhibitor, in an animal model of PAH. Male Wistar rats were exposed to hypoxia (10% O2) for three weeks plus a weekly i.p. injection of a vascular endothelial growth factor receptor inhibitor (SU5416, 20 mg/kg, SuHx). After confirmation of PAH, animals received intravenous injection of 5.105 hMSCs or vehicle, followed by oral treatment with lodenafil carbonate (10 mg/kg/day) for 14 days. The ratio between pulmonary artery acceleration time and RV ejection time reduced from 0.42 ± 0.01 (control) to 0.24 ± 0.01 in the SuHx group, which was not altered by lodenafil alone but was recovered to 0.31 ± 0.01 when administered in association with hMSCs. RV afterload was confirmed in the SuHx group with an increased RV systolic pressure (mmHg) of 52.1 ± 8.8 normalized to 29.6 ± 2.2 after treatment with the association. Treatment with hMSCs + lodenafil reversed RV hypertrophy, fibrosis and interstitial cell infiltration in the SuHx group. Combined therapy of lodenafil and hMSCs may be a strategy for PAH treatment.
      Citation: Cells
      PubDate: 2020-09-18
      DOI: 10.3390/cells9092120
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2121: Regulation of Apoptosis by the Bcl-2 Family of
           Proteins: Field on a Brink

    • Authors: Alexey S. Ladokhin
      First page: 2121
      Abstract: Apoptosis, a form of programmed cell death, is a highly regulated process critical for tissue development, homeostasis, and pathogenesis of various diseases [...]
      Citation: Cells
      PubDate: 2020-09-18
      DOI: 10.3390/cells9092121
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2122: NIR-Triggered Hyperthermal Effect of
           Polythiophene Nanoparticles Synthesized by Surfactant-Free Oxidative
           Polymerization Method on Colorectal Carcinoma Cells

    • Authors: Deval Prasad Bhattarai, Beom Su Kim
      First page: 2122
      Abstract: In this work, polythiophene nanoparticles (PTh–NPs) were synthesized by a surfactant-free oxidative chemical polymerization method at 60 °C, using ammonium persulphate as an oxidant. Various physicochemical properties were studied in terms of field emission scanning electron microscopy (FESEM), X-ray diffraction (XRD), Fourier transform infra-red (FT-IR) spectroscopy, and differential scanning calorimetry (DSC)/thermogravimetric analysis (TGA). Photothermal performance of the as-synthesized PTh–NPs was studied by irradiating near infra-red of 808 nm under different concentration of the substrate and power supply. The photothermal stability of PTh–NPs was also studied. Photothermal effects of the as-synthesized PTh–NPs on colorectal cancer cells (CT-26) were studied at 100 µg/mL concentration and 808 nm NIR irradiation of 2.0 W/cm2 power. Our in vitro results showed remarkable NIR laser-triggered photothermal apoptotic cell death by PTh–NPs. Based on the experimental findings, it is revealed that PTh–NPs can act as a heat mediator and can be an alternative material for photothermal therapy in cancer treatment.
      Citation: Cells
      PubDate: 2020-09-18
      DOI: 10.3390/cells9092122
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2123: Human Amnion Epithelial Cells Impair T Cell
           Proliferation: The Role of HLA-G and HLA-E Molecules

    • Authors: Fabio Morandi, Danilo Marimpietri, Andre Görgens, Alessia Gallo, Raghuraman Chittor Srinivasan, Samir El-Andaloussi, Roberto Gramignoli
      First page: 2123
      Abstract: The immunoprivilege status characteristic of human amnion epithelial cells (hAECs) has been recently highlighted in the context of xenogenic transplantation. However, the mechanism(s) involved in such regulatory functions have been so far only partially been clarified. Here, we have analyzed the expression of HLA-Ib molecules in isolated hAEC obtained from full term placentae. Moreover, we asked whether these molecules are involved in the immunoregulatory functions of hAEC. Human amnion-derived cells expressed surface HLA-G and HLA-F at high levels, whereas the commonly expressed HLA-E molecule has been measured at a very low level or null on freshly isolated cells. HLA-Ib molecules can be expressed as membrane-bound and soluble forms, and in all hAEC batches analyzed we measured high levels of sHLA-G and sHLA-E when hAEC were maintained in culture, and such a release was time-dependent. Moreover, HLA-G was present in extracellular vesicles (EVs) released by hAEC. hAEC suppressed T cell proliferation in vitro at different hAEC:T cell ratios, as previously reported. Moreover, inhibition of T cell proliferation was partially reverted by pretreating hAEC with anti-HLA-G, anti-HLA-E and anti-β2 microglobulin, thus suggesting that HLA-G and -E molecules are involved in hAEC-mediated suppression of T cell proliferation. Finally, either large-size EV (lsEV) or small-size EV (ssEV) derived from hAEC significantly modulated T-cell proliferation. In conclusion, we have here characterized one of the mechanism(s) underlying immunomodulatory functions of hAEC, related to the expression and release of HLA-Ib molecules.
      Citation: Cells
      PubDate: 2020-09-19
      DOI: 10.3390/cells9092123
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2124: Attempts at the Characterization of In-Cell
           Biophysical Processes Non-Invasively—Quantitative NMR Diffusometry of a
           Model Cellular System

    • Authors: Weronika Mazur, Artur T. Krzyżak
      First page: 2124
      Abstract: In the literature, diffusion studies of cell systems are usually limited to two water pools that are associated with the extracellular space and the entire interior of the cell. Therefore, the time-dependent diffusion coefficient contains information about the geometry of these two water regions and the water exchange through their boundary. This approach is due to the fact that most of these studies use pulse techniques and relatively low gradients, which prevents the achievement of high b-values. As a consequence, it is not possible to register the signal coming from proton populations with a very low bulk or apparent self-diffusion coefficient, such as cell organelles. The purpose of this work was to obtain information on the geometry and dynamics of water at a level lower than the cell size, i.e., in cellular structures, using the time-dependent diffusion coefficient method. The model of the cell system was made of baker’s yeast (Saccharomyces cerevisiae) since that is commonly available and well-characterized. We measured characteristic fresh yeast properties with the application of a compact Nuclear Magnetic Resonance (NMR)-Magritek Mobile Universal Surface Explorer (MoUSE) device with a very high, constant gradient (~24 T/m), which enabled us to obtain a sufficient stimulated echo attenuation even for very short diffusion times (0.2–40 ms) and to apply very short diffusion encoding times. In this work, due to a very large diffusion weighting (b-values), splitting the signal into three components was possible, among which one was associated only with cellular structures. Time-dependent diffusion coefficient analysis allowed us to determine the self-diffusion coefficients of extracellular fluid, cytoplasm and cellular organelles, as well as compartment sizes. Cellular organelles contributing to each compartment were identified based on the random walk simulations and approximate volumes of water pools calculated using theoretical sizes or molar fractions. Information about different cell structures is contained in different compartments depending on the diffusion regime, which is inherent in studies applying extremely high gradients.
      Citation: Cells
      PubDate: 2020-09-19
      DOI: 10.3390/cells9092124
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2125: Transcriptional Regulation of Wnt/β-Catenin
           Pathway in Colorectal Cancer

    • Authors: Bian, Dannappel, Wan, Firestein
      First page: 2125
      Abstract: The Wnt/β-catenin signaling pathway exerts integral roles in embryogenesis and adult homeostasis. Aberrant activation of the pathway is implicated in growth-associated diseases and cancers, especially as a key driver in the initiation and progression of colorectal cancer (CRC). Loss or inactivation of Adenomatous polyposis coli (APC) results in constitutive activation of Wnt/β-catenin signaling, which is considered as an initiating event in the development of CRC. Increased Wnt/β-catenin signaling is observed in virtually all CRC patients, underscoring the importance of this pathway for therapeutic intervention. Prior studies have deciphered the regulatory networks required for the cytoplasmic stabilisation or degradation of the Wnt pathway effector, β-catenin. However, the mechanism whereby nuclear β-catenin drives or inhibits expression of Wnt target genes is more diverse and less well characterised. Here, we describe a brief synopsis of the core canonical Wnt pathway components, set the spotlight on nuclear mediators and highlight the emerging role of chromatin regulators as modulators of β-catenin-dependent transcription activity and oncogenic output.
      Citation: Cells
      PubDate: 2020-09-19
      DOI: 10.3390/cells9092125
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2126: FRET-Based Sorting of Live Cells Reveals
           Shifted Balance between PLK1 and CDK1 Activities During Checkpoint

    • Authors: Lorenzo Lafranchi, Erik Müllers, Dorothea Rutishauser, Arne Lindqvist
      First page: 2126
      Abstract: Cells recovering from the G2/M DNA damage checkpoint rely more on Aurora A-PLK1 signaling than cells progressing through an unperturbed G2 phase, but the reason for this discrepancy is not known. Here, we devised a method based on a FRET reporter for PLK1 activity to sort cells in distinct populations within G2 phase. We employed mass spectroscopy to characterize changes in protein levels through an unperturbed G2 phase and validated that ATAD2 levels decrease in a proteasome-dependent manner. Comparing unperturbed cells with cells recovering from DNA damage, we note that at similar PLK1 activities, recovering cells contain higher levels of Cyclin B1 and increased phosphorylation of CDK1 targets. The increased Cyclin B1 levels are due to continuous Cyclin B1 production during a DNA damage response and are sustained until mitosis. Whereas partial inhibition of PLK1 suppresses mitotic entry more efficiently when cells recover from a checkpoint, partial inhibition of CDK1 suppresses mitotic entry more efficiently in unperturbed cells. Our findings provide a resource for proteome changes during G2 phase, show that the mitotic entry network is rewired during a DNA damage response, and suggest that the bottleneck for mitotic entry shifts from CDK1 to PLK1 after DNA damage.
      Citation: Cells
      PubDate: 2020-09-19
      DOI: 10.3390/cells9092126
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2127: Juniperonic Acid Biosynthesis is Essential in
           Caenorhabditis Elegans Lacking Δ6 Desaturase (fat-3) and Generates New
           ω-3 Endocannabinoids

    • Authors: Sujay Guha, Serafina Calarco, M. Salomé Gachet, Jürg Gertsch
      First page: 2127
      Abstract: In eukaryotes, the C20:4 polyunsaturated fatty acid arachidonic acid (AA) plays important roles as a phospholipid component, signaling molecule and precursor of the endocannabinoid-prostanoid axis. Accordingly, the absence of AA causes detrimental effects. Here, compensatory mechanisms involved in AA deficiency in Caenorhabditis elegans were investigated. We show that the ω-3 C20:4 polyunsaturated fatty acid juniperonic acid (JuA) is generated in the C. elegansfat-3(wa22) mutant, which lacks Δ6 desaturase activity and cannot generate AA and ω-3 AA. JuA partially rescued the loss of function of AA in growth and development. Additionally, we observed that supplementation of AA and ω-3 AA modulates lifespan of fat-3(wa22) mutants. We described a feasible biosynthetic pathway that leads to the generation of JuA from α-linoleic acid (ALA) via elongases ELO-1/2 and Δ5 desaturase which is rate-limiting. Employing liquid chromatography mass spectrometry (LC-MS/MS), we identified endocannabinoid-like ethanolamine and glycerol derivatives of JuA and ω-3 AA. Like classical endocannabinoids, these lipids exhibited binding interactions with NPR-32, a G protein coupled receptor (GPCR) shown to act as endocannabinoid receptor in C. elegans. Our study suggests that the eicosatetraenoic acids AA, ω-3 AA and JuA share similar biological functions. This biosynthetic plasticity of eicosatetraenoic acids observed in C. elegans uncovers a possible biological role of JuA and associated ω-3 endocannabinoids in Δ6 desaturase deficiencies, highlighting the importance of ALA.
      Citation: Cells
      PubDate: 2020-09-19
      DOI: 10.3390/cells9092127
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2128: EpCAM as Modulator of Tissue Plasticity

    • Authors: François Fagotto
      First page: 2128
      Abstract: The Epithelial Cell Adhesion Molecule or EpCAM is a well-known marker highly expressed in carcinomas and showing a strong correlation with poor cancer prognosis. While its name relates to its proposed function as a cell adhesion molecule, EpCAM has been shown to have various signalling functions. In particular, it has been identified as an important positive regulator of cell adhesion and migration, playing an essential role in embryonic morphogenesis as well as intestinal homeostasis. This activity is not due to its putative adhesive function, but rather to its ability to repress myosin contractility by impinging on a PKC signalling cascade. This mechanism confers EpCAM the unique property of favouring tissue plasticity. I review here the currently available data, comment on possible connections with other properties of EpCAM, and discuss the potential significance in the context of cancer invasion.
      Citation: Cells
      PubDate: 2020-09-19
      DOI: 10.3390/cells9092128
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2129: High Sensitivity of Circulating Tumor Cells
           Derived from a Colorectal Cancer Patient for Dual Inhibition with AKT and
           mTOR Inhibitors

    • Authors: Daniel J. Smit, Laure Cayrefourcq, Marie-Therese Haider, Nico Hinz, Klaus Pantel, Catherine Alix-Panabières, Manfred Jücker
      First page: 2129
      Abstract: Circulating tumor cells (CTCs) are cells shed from the primary tumor into the bloodstream. While many studies on solid tumor cells exist, data on CTCs are scarce. The mortality of cancer is mostly associated with metastasis and recent research identified CTCs as initiators of metastasis. The PI3K/AKT/mTOR signaling pathway is an intracellular pathway that regulates essential functions including protein biosynthesis, cell growth, cell cycle control, survival and migration. Importantly, activating oncogenic mutations and amplifications in this pathway are frequently observed in a wide variety of cancer entities, underlining the significance of this signaling pathway. In this study, we analyzed the functional role of the PI3K/AKT/mTOR signaling pathway in the CTC-MCC-41 line, derived from a patient with metastatic colorectal cancer. One striking finding in our study was the strong sensitivity of this CTC line against AKT inhibition using MK2206 and mTOR inhibition using RAD001 within the nanomolar range. This suggests that therapies targeting AKT and mTOR could have been beneficial for the patient from which the CTC line was isolated. Additionally, a dual targeting approach of AKT/mTOR inside the PI3K/AKT/mTOR signaling pathway in the colorectal CTCs showed synergistic effects in vitro. Depending on the phenotypical behavior of CTC-MCC-41 in cell culture (adherent vs. suspension), we identified altered phosphorylation levels inside the PI3K/AKT/mTOR pathway. We observed a downregulation of the PI3K/AKT/mTOR signaling pathway, but not of the RAS/RAF/MAPK pathway, in CTCs growing in suspension in comparison to adherent CTCs. Our results highlight distinct functions of AKT isoforms in CTC-MCC-41 cells with respect to cell proliferation. Knockdown of AKT1 and AKT2 leads to significantly impaired proliferation of CTC-MCC-41 cells in vitro. Therefore, our data demonstrate that the PI3K/AKT/mTOR signaling pathway plays a key role in the proliferation of CTC-MCC-41.
      Citation: Cells
      PubDate: 2020-09-20
      DOI: 10.3390/cells9092129
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2130: Neutrophils and Neutrophil Extracellular Traps
           Regulate Immune Responses in Health and Disease

    • Authors: Shrikant R. Mulay, Hans-Joachim Anders
      First page: 2130
      Abstract: Neutrophils are first responders of antimicrobial host defense and sterile inflammation, and therefore, play important roles during health and disease [...]
      Citation: Cells
      PubDate: 2020-09-20
      DOI: 10.3390/cells9092130
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2131: Schwann Cell Role in Selectivity of Nerve

    • Authors: Sara Bolívar, Xavier Navarro, Esther Udina
      First page: 2131
      Abstract: Peripheral nerve injuries result in the loss of the motor, sensory and autonomic functions of the denervated segments of the body. Neurons can regenerate after peripheral axotomy, but inaccuracy in reinnervation causes a permanent loss of function that impairs complete recovery. Thus, understanding how regenerating axons respond to their environment and direct their growth is essential to improve the functional outcome of patients with nerve lesions. Schwann cells (SCs) play a crucial role in the regeneration process, but little is known about their contribution to specific reinnervation. Here, we review the mechanisms by which SCs can differentially influence the regeneration of motor and sensory axons. Mature SCs express modality-specific phenotypes that have been associated with the promotion of selective regeneration. These include molecular markers, such as L2/HNK-1 carbohydrate, which is differentially expressed in motor and sensory SCs, or the neurotrophic profile after denervation, which differs remarkably between SC modalities. Other important factors include several molecules implicated in axon-SC interaction. This cell–cell communication through adhesion (e.g., polysialic acid) and inhibitory molecules (e.g., MAG) contributes to guiding growing axons to their targets. As many of these factors can be modulated, further research will allow the design of new strategies to improve functional recovery after peripheral nerve injuries.
      Citation: Cells
      PubDate: 2020-09-20
      DOI: 10.3390/cells9092131
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2132: Microglia and Macrophages in the Pathological
           Central and Peripheral Nervous Systems

    • Authors: Naoki Abe, Tasuku Nishihara, Toshihiro Yorozuya, Junya Tanaka
      First page: 2132
      Abstract: Microglia, the immunocompetent cells in the central nervous system (CNS), have long been studied as pathologically deteriorating players in various CNS diseases. However, microglia exert ameliorating neuroprotective effects, which prompted us to reconsider their roles in CNS and peripheral nervous system (PNS) pathophysiology. Moreover, recent findings showed that microglia play critical roles even in the healthy CNS. The microglial functions that normally contribute to the maintenance of homeostasis in the CNS are modified by other cells, such as astrocytes and infiltrated myeloid cells; thus, the microglial actions on neurons are extremely complex. For a deeper understanding of the pathophysiology of various diseases, including those of the PNS, it is important to understand microglial functioning. In this review, we discuss both the favorable and unfavorable roles of microglia in neuronal survival in various CNS and PNS disorders. We also discuss the roles of blood-borne macrophages in the pathogenesis of CNS and PNS injuries because they cooperatively modify the pathological processes of resident microglia. Finally, metabolic changes in glycolysis and oxidative phosphorylation, with special reference to the pro-/anti-inflammatory activation of microglia, are intensively addressed, because they are profoundly correlated with the generation of reactive oxygen species and changes in pro-/anti-inflammatory phenotypes.
      Citation: Cells
      PubDate: 2020-09-21
      DOI: 10.3390/cells9092132
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2133: NRF2 is an Upstream Regulator of MYC-Mediated
           Osteoclastogenesis and Pathological Bone Erosion

    • Authors: Peter Sang Uk Park, Se Hwan Mun, Steven L. Zeng, Haemin Kim, Seyeon Bae, Kyung-Hyun Park-Min
      First page: 2133
      Abstract: Osteoclasts are the sole bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathogenic bone destruction such as inflammatory arthritis. Pharmacologically targeting osteoclasts has been a promising approach to alleviating bone disease, but there remains room for improvement in mitigating drug side effects and enhancing cell specificity. Recently, we demonstrated the crucial role of MYC and its downstream effectors in driving osteoclast differentiation. Despite these advances, upstream regulators of MYC have not been well defined. In this study, we identify nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor known to regulate the expression of phase II antioxidant enzymes, as a novel upstream regulator of MYC. NRF2 negatively regulates receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis through the ERK and p38 signaling-mediated suppression of MYC transcription. Furthermore, the ablation of MYC in osteoclasts reverses the enhanced osteoclast differentiation and activity in NRF2 deficiency in vivo and in vitro in addition to protecting NRF2-deficient mice from pathological bone loss in a murine model of inflammatory arthritis. Our findings indicate that this novel NRF2-MYC axis could be instrumental for the fine-tuning of osteoclast formation and provides additional ways in which osteoclasts could be therapeutically targeted to prevent pathological bone erosion.
      Citation: Cells
      PubDate: 2020-09-21
      DOI: 10.3390/cells9092133
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2134: The Rationale of Neprilysin Inhibition in
           Prevention of Myocardial Ischemia-Reperfusion Injury during ST-Elevation
           Myocardial Infarction

    • Authors: Alessandro Bellis, Ciro Mauro, Emanuele Barbato, Giuseppe Di Gioia, Daniela Sorriento, Bruno Trimarco, Carmine Morisco
      First page: 2134
      Abstract: During the last three decades, timely myocardial reperfusion using either thrombolytic therapy or primary percutaneous intervention (pPCI) has allowed amazing improvements in outcomes with a more than halving in 1-year ST-elevation myocardial infarction (STEMI) mortality. However, mortality and left ventricle (LV) remodeling remain substantial in these patients. As such, novel therapeutic interventions are required to reduce myocardial infarction size, preserve LV systolic function, and improve survival in reperfused-STEMI patients. Myocardial ischemia-reperfusion injury (MIRI) prevention represents the main goal to reach in order to reduce STEMI mortality. There is currently no effective therapy for MIRI prevention in STEMI patients. A significant reason for the weak and inconsistent results obtained in this field may be the presence of multiple, partially redundant, mechanisms of cell death during ischemia-reperfusion, whose relative importance may depend on the conditions. Therefore, it is always more recognized that it is important to consider a “multi-targeted cardioprotective therapy”, defined as an additive or synergistic cardioprotective agents or interventions directed to distinct targets with different timing of application (before, during, or after pPCI). Given that some neprilysin (NEP) substrates (natriuretic peptides, angiotensin II, bradykinin, apelins, substance P, and adrenomedullin) exert a cardioprotective effect against ischemia-reperfusion injury, it is conceivable that antagonism of proteolytic activity by this enzyme may be considered in a multi-targeted strategy for MIRI prevention. In this review, by starting from main pathophysiological mechanisms promoting MIRI, we discuss cardioprotective effects of NEP substrates and the potential benefit of NEP pharmacological inhibition in MIRI prevention.
      Citation: Cells
      PubDate: 2020-09-21
      DOI: 10.3390/cells9092134
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2135: Mitochondrial Calcium Deregulation in the
           Mechanism of Beta-Amyloid and Tau Pathology

    • Authors: Noemi Esteras, Andrey Y. Abramov
      First page: 2135
      Abstract: Aggregation and deposition of β-amyloid and/or tau protein are the key neuropathological features in neurodegenerative disorders such as Alzheimer’s disease (AD) and other tauopathies including frontotemporal dementia (FTD). The interaction between oxidative stress, mitochondrial dysfunction and the impairment of calcium ions (Ca2+) homeostasis induced by­ misfolded tau and β-amyloid plays an important role in the progressive neuronal loss occurring in specific areas of the brain. In addition to the control of bioenergetics and ROS production, mitochondria are fine regulators of the cytosolic Ca2+ homeostasis that induce vital signalling mechanisms in excitable cells such as neurons. Impairment in the mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) or release through the Na+/Ca2+ exchanger may lead to mitochondrial Ca2+ overload and opening of the permeability transition pore inducing neuronal death. Recent evidence suggests an important role for these mechanisms as the underlying causes for neuronal death in β-amyloid and tau pathology. The present review will focus on the mechanisms that lead to cytosolic and especially mitochondrial Ca2+ disturbances occurring in AD and tau-induced FTD, and propose possible therapeutic interventions for these disorders.
      Citation: Cells
      PubDate: 2020-09-21
      DOI: 10.3390/cells9092135
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2136: Cytokine Profiling in Myeloproliferative
           Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role
           of Genetic Variants

    • Authors: Elena Masselli, Giulia Pozzi, Giuliana Gobbi, Stefania Merighi, Stefania Gessi, Marco Vitale, Cecilia Carubbi
      First page: 2136
      Abstract: Among hematologic malignancies, the classic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are considered a model of inflammation-related cancer development. In this context, the use of immune-modulating agents has recently expanded the MPN therapeutic scenario. Cytokines are key mediators of an auto-amplifying, detrimental cross-talk between the MPN clone and the tumor microenvironment represented by immune, stromal, and endothelial cells. This review focuses on recent advances in cytokine-profiling of MPN patients, analyzing different expression patterns among the three main Philadelphia-negative (Ph-negative) MPNs, as well as correlations with disease molecular profile, phenotype, progression, and outcome. The role of the megakaryocytic clone as the main source of cytokines, particularly in myelofibrosis, is also reviewed. Finally, we report emerging intriguing evidence on the contribution of host genetic variants to the chronic pro-inflammatory state that typifies MPNs.
      Citation: Cells
      PubDate: 2020-09-21
      DOI: 10.3390/cells9092136
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2137: Choice of Differentiation Media Significantly
           Impacts Cell Lineage and Response to CFTR Modulators in Fully
           Differentiated Primary Cultures of Cystic Fibrosis Human Airway Epithelial

    • Authors: Vinciane Saint-Criq, Livia Delpiano, John Casement, Jennifer C. Onuora, JinHeng Lin, Michael A. Gray
      First page: 2137
      Abstract: In vitro cultures of primary human airway epithelial cells (hAECs) grown at air–liquid interface have become a valuable tool to study airway biology under normal and pathologic conditions, and for drug discovery in lung diseases such as cystic fibrosis (CF). An increasing number of different differentiation media, are now available, making comparison of data between studies difficult. Here, we investigated the impact of two common differentiation media on phenotypic, transcriptomic, and physiological features of CF and non-CF epithelia. Cellular architecture and density were strongly impacted by the choice of medium. RNA-sequencing revealed a shift in airway cell lineage; one medium promoting differentiation into club and goblet cells whilst the other enriched the growth of ionocytes and multiciliated cells. Pathway analysis identified differential expression of genes involved in ion and fluid transport. Physiological assays (intracellular/extracellular pH, Ussing chamber) specifically showed that ATP12A and CFTR function were altered, impacting pH and transepithelial ion transport in CF hAECs. Importantly, the two media differentially affected functional responses to CFTR modulators. We argue that the effect of growth conditions should be appropriately determined depending on the scientific question and that our study can act as a guide for choosing the optimal growth medium for specific applications.
      Citation: Cells
      PubDate: 2020-09-21
      DOI: 10.3390/cells9092137
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2138: Oxidoreductases in Glycoprotein Glycosylation,
           Folding, and ERAD

    • Authors: Chaitanya Patel, Haddas Saad, Marina Shenkman, Gerardo Z. Lederkremer
      First page: 2138
      Abstract: N-linked glycosylation and sugar chain processing, as well as disulfide bond formation, are among the most common post-translational protein modifications taking place in the endoplasmic reticulum (ER). They are essential modifications that are required for membrane and secretory proteins to achieve their correct folding and native structure. Several oxidoreductases responsible for disulfide bond formation, isomerization, and reduction have been shown to form stable, functional complexes with enzymes and chaperones that are involved in the initial addition of an N-glycan and in folding and quality control of the glycoproteins. Some of these oxidoreductases are selenoproteins. Recent studies also implicate glycan machinery–oxidoreductase complexes in the recognition and processing of misfolded glycoproteins and their reduction and targeting to ER-associated degradation. This review focuses on the intriguing cooperation between the glycoprotein-specific cell machineries and ER oxidoreductases, and highlights open questions regarding the functions of many members of this large family.
      Citation: Cells
      PubDate: 2020-09-22
      DOI: 10.3390/cells9092138
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2139: Neutrophil Extracellular Traps Promote the
           Development and Growth of Human Salivary Stones

    • Authors: Mirco Schapher, Michael Koch, Daniela Weidner, Michael Scholz, Stefan Wirtz, Aparna Mahajan, Irmgard Herrmann, Jeeshan Singh, Jasmin Knopf, Moritz Leppkes, Christine Schauer, Anika Grüneboom, Christoph Alexiou, Georg Schett, Heinrich Iro, Luis E. Muñoz, Martin Herrmann
      First page: 2139
      Abstract: Salivary gland stones, or sialoliths, are the most common cause of the obstruction of salivary glands. The mechanism behind the formation of sialoliths has been elusive. Symptomatic sialolithiasis has a prevalence of 0.45% in the general population, is characterized by recurrent painful periprandial swelling of the affected gland, and often results in sialadenitis with the need for surgical intervention. Here, we show by the use of immunohistochemistry, immunofluorescence, computed tomography (CT) scans and reconstructions, special dye techniques, bacterial genotyping, and enzyme activity analyses that neutrophil extracellular traps (NETs) initiate the formation and growth of sialoliths in humans. The deposition of neutrophil granulocyte extracellular DNA around small crystals results in the dense aggregation of the latter, and the subsequent mineralization creates alternating layers of dense mineral, which are predominantly calcium salt deposits and DNA. The further agglomeration and appositional growth of these structures promotes the development of macroscopic sialoliths that finally occlude the efferent ducts of the salivary glands, causing clinical symptoms and salivary gland dysfunction. These findings provide an entirely novel insight into the mechanism of sialolithogenesis, in which an immune system-mediated response essentially participates in the physicochemical process of concrement formation and growth.
      Citation: Cells
      PubDate: 2020-09-22
      DOI: 10.3390/cells9092139
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2140: The Role of Chaperone-Mediated Autophagy in
           Cell Cycle Control and Its Implications in Cancer

    • Authors: Marina Andrade-Tomaz, Izadora de Souza, Clarissa Ribeiro Reily Rocha, Luciana Rodrigues Gomes
      First page: 2140
      Abstract: The cell cycle involves a network of proteins that modulate the sequence and timing of proliferation events. Unregulated proliferation is the most fundamental hallmark of cancer; thus, changes in cell cycle control are at the heart of malignant transformation processes. Several cellular processes can interfere with the cell cycle, including autophagy, the catabolic pathway involved in degradation of intracellular constituents in lysosomes. According to the mechanism used to deliver cargo to the lysosome, autophagy can be classified as macroautophagy (MA), microautophagy (MI), or chaperone-mediated autophagy (CMA). Distinct from other autophagy types, CMA substrates are selectively recognized by a cytosolic chaperone, one-by-one, and then addressed for degradation in lysosomes. The function of MA in cell cycle control, and its influence in cancer progression, are already well-established. However, regulation of the cell cycle by CMA, in the context of tumorigenesis, has not been fully addressed. This review aims to present and debate the molecular mechanisms by which CMA can interfere in the cell cycle, in the context of cancer. Thus, cell cycle modulators, such as MYC, hypoxia-inducible factor-1 subunit alpha (HIF-1α), and checkpoint kinase 1 (CHK1), regulated by CMA activity will be discussed. Finally, the review will focus on how CMA dysfunction may impact the cell cycle, and as consequence promote tumorigenesis.
      Citation: Cells
      PubDate: 2020-09-22
      DOI: 10.3390/cells9092140
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2141: Pimozide Suppresses the Growth of Brain Tumors
           by Targeting STAT3-Mediated Autophagy

    • Authors: Alok Ranjan, Itishree Kaushik, Sanjay K. Srivastava
      First page: 2141
      Abstract: Brain tumors are considered as one of the most aggressive and incurable forms of cancer. The majority of the patients with brain tumors have a median survival rate of 12%. Brain tumors are lethal despite the availability of advanced treatment options such as surgical removal, chemotherapy, and radiotherapy. In this study, we have evaluated the anti-cancer effects of pimozide, which is a neuroleptic drug used for the treatment of schizophrenia and chronic psychosis. Pimozide significantly reduced the proliferation of U-87MG, Daoy, GBM 28, and U-251MG brain cancer cell lines by inducing apoptosis with IC50 (Inhibitory concentration 50) ranging from 12 to 16 μM after 48 h of treatment. Our Western blotting analysis indicated that pimozide suppressed the phosphorylation of STAT3 at Tyr705 and Src at Tyr416, and it inhibited the expression of anti-apoptotic markers c-Myc, Mcl-1, and Bcl-2. Significant autophagy induction was observed with pimozide treatment. LC3B, Beclin-1, and ATG5 up-regulation along with autolysosome formation confirmed the induction of autophagy with pimozide treatment. Inhibiting autophagy using 3-methyladenine or LC3B siRNA significantly blocked the apoptosis-inducing effects of pimozide, suggesting that pimozide mediated its apoptotic effects by inducing autophagy. Oral administration of 25 mg/kg pimozide suppressed the intracranially implanted U-87MG tumor growth by 45% in athymic nude mice. The chronic administration of pimozide showed no general signs of toxicity, and the behavioral activity of the mice remained unchanged. Taken together, these results indicate that pimozide inhibits the growth of brain cancer by autophagy-mediated apoptosis.
      Citation: Cells
      PubDate: 2020-09-22
      DOI: 10.3390/cells9092141
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2142: Human Mesenchymal Stromal Cell Secretome
           Promotes the Immunoregulatory Phenotype and Phagocytosis Activity in Human

    • Authors: Minna Holopainen, Ulla Impola, Petri Lehenkari, Saara Laitinen, Erja Kerkelä
      First page: 2142
      Abstract: Human mesenchymal stromal/stem cells (hMSCs) show great promise in cell therapy due to their immunomodulatory properties. The overall immunomodulatory response of hMSCs resembles the resolution of inflammation, in which lipid mediators and regulatory macrophages (Mregs) play key roles. We investigated the effect of hMSC cell-cell contact and secretome on macrophages polarized and activated toward Mreg phenotype. Moreover, we studied the effect of supplemented polyunsaturated fatty acids (PUFAs): docosahexaenoic acid (DHA) and arachidonic acid, the precursors of lipid mediators, on hMSC immunomodulation. Our results show that unlike hMSC cell-cell contact, the hMSC secretome markedly increased the CD206 expression in both Mreg-polarized and Mreg-activated macrophages. Moreover, the secretome enhanced the expression of programmed death-ligand 1 on Mreg-polarized macrophages and Mer receptor tyrosine kinase on Mreg-activated macrophages. Remarkably, these changes were translated into improved Candida albicans phagocytosis activity of macrophages. Taken together, these results demonstrate that the hMSC secretome promotes the immunoregulatory and proresolving phenotype of Mregs. Intriguingly, DHA supplementation to hMSCs resulted in a more potentiated immunomodulation with increased CD163 expression and decreased gene expression of matrix metalloproteinase 2 in Mreg-polarized macrophages. These findings highlight the potential of PUFA supplementations as an easy and safe method to improve the hMSC therapeutic potential.
      Citation: Cells
      PubDate: 2020-09-22
      DOI: 10.3390/cells9092142
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2143: miR-9-Mediated Inhibition of EFEMP1 Contributes
           to the Acquisition of Pro-Tumoral Properties in Normal Fibroblasts

    • Authors: Giulia Cosentino, Sandra Romero-Cordoba, Ilaria Plantamura, Alessandra Cataldo, Marilena V. Iorio
      First page: 2143
      Abstract: Tumor growth and invasion occurs through a dynamic interaction between cancer and stromal cells, which support an aggressive niche. MicroRNAs are thought to act as tumor messengers to “corrupt” stromal cells. We previously demonstrated that miR-9, a known metastamiR, is released by triple negative breast cancer (TNBC) cells to enhance the transition of normal fibroblasts (NFs) into cancer-associated fibroblast (CAF)-like cells. EGF containing fibulin extracellular matrix protein 1 (EFEMP1), which encodes for the ECM glycoprotein fibulin-3, emerged as a miR-9 putative target upon miRNA’s exogenous upmodulation in NFs. Here we explored the impact of EFEMP1 downmodulation on fibroblast’s acquisition of CAF-like features, and how this phenotype influences neoplastic cells to gain chemoresistance. Indeed, upon miR-9 overexpression in NFs, EFEMP1 resulted downmodulated, both at RNA and protein levels. The luciferase reporter assay showed that miR-9 directly targets EFEMP1 and its silencing recapitulates miR-9-induced pro-tumoral phenotype in fibroblasts. In particular, EFEMP1 siRNA-transfected (si-EFEMP1) fibroblasts have an increased ability to migrate and invade. Moreover, TNBC cells conditioned with the supernatant of NFs transfected with miR-9 or si-EFEMP1 became more resistant to cisplatin. Overall, our results demonstrate that miR-9/EFEMP1 axis is crucial for the conversion of NFs to CAF-like cells under TNBC signaling.
      Citation: Cells
      PubDate: 2020-09-22
      DOI: 10.3390/cells9092143
      Issue No: Vol. 9, No. 9 (2020)
  • Cells, Vol. 9, Pages 2144: Thermal Neutron Relative Biological
           Effectiveness Factors for Boron Neutron Capture Therapy from In Vitro

    • Authors: María Pedrosa-Rivera, Javier Praena, Ignacio Porras, Manuel P. Sabariego, Ulli Köster, Michael Haertlein, V. Trevor Forsyth, José C. Ramírez, Clara Jover, Daniel Jimena, Juan L. Osorio, Patricia Álvarez, Carmen Ruiz-Ruiz, María J. Ruiz-Magaña
      First page: 2144
      Abstract: The experimental determination of the relative biological effectiveness of thermal neutron factors is fundamental in Boron Neutron Capture Therapy. The present values have been obtained while using mixed beams that consist of both neutrons and photons of various energies. A common weighting factor has been used for both thermal and fast neutron doses, although such an approach has been questioned. At the nuclear reactor of the Institut Laue-Langevin a pure low-energy neutron beam has been used to determine thermal neutron relative biological effectiveness factors. Different cancer cell lines, which correspond to glioblastoma, melanoma, and head and neck squamous cell carcinoma, and non-tumor cell lines (lung fibroblast and embryonic kidney), have been irradiated while using an experimental arrangement designed to minimize neutron-induced secondary gamma radiation. Additionally, the cells were irradiated with photons at a medical linear accelerator, providing reference data for comparison with that from neutron irradiation. The survival and proliferation were studied after irradiation, yielding the Relative Biological Effectiveness that corresponds to the damage of thermal neutrons for the different tissue types.
      Citation: Cells
      PubDate: 2020-09-23
      DOI: 10.3390/cells9102144
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2145: TNF Production and Release from Microglia via
           Extracellular Vesicles: Impact on Brain Functions

    • Authors: Stefano Raffaele, Marta Lombardi, Claudia Verderio, Marta Fumagalli
      First page: 2145
      Abstract: Tumor necrosis factor (TNF) is a pleiotropic cytokine powerfully influencing diverse processes of the central nervous system (CNS) under both physiological and pathological conditions. Here, we analyze current literature describing the molecular processes involved in TNF synthesis and release from microglia, the resident immune cells of the CNS and the main source of this cytokine both in brain development and neurodegenerative diseases. A special attention has been given to the unconventional vesicular pathway of TNF, based on the emerging role of microglia-derived extracellular vesicles (EVs) in the propagation of inflammatory signals and in mediating cell-to-cell communication. Moreover, we describe the contribution of microglial TNF in regulating important CNS functions, including the neuroinflammatory response following brain injury, the neuronal circuit formation and synaptic plasticity, and the processes of myelin damage and repair. Specifically, the available data on the functions mediated by microglial EVs carrying TNF have been scrutinized to gain insights on possible novel therapeutic strategies targeting TNF to foster CNS repair.
      Citation: Cells
      PubDate: 2020-09-23
      DOI: 10.3390/cells9102145
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2146: Cell Senescence, Multiple Organelle Dysfunction
           and Atherosclerosis

    • Authors: Gisela Machado-Oliveira, Cristiano Ramos, André R. A. Marques, Otília V. Vieira
      First page: 2146
      Abstract: Atherosclerosis is an age-related disorder associated with long-term exposure to cardiovascular risk factors. The asymptomatic progression of atherosclerotic plaques leads to major cardiovascular diseases (CVD), including acute myocardial infarctions or cerebral ischemic strokes in some cases. Senescence, a biological process associated with progressive structural and functional deterioration of cells, tissues and organs, is intricately linked to age-related diseases. Cell senescence involves coordinated modifications in cellular compartments and has been demonstrated to contribute to different stages of atheroma development. Senescence-based therapeutic strategies are currently being pursued to treat and prevent CVD in humans in the near-future. In addition, distinct experimental settings allowed researchers to unravel potential approaches to regulate anti-apoptotic pathways, facilitate excessive senescent cell clearance and eventually reverse atherogenesis to improve cardiovascular function. However, a deeper knowledge is required to fully understand cellular senescence, to clarify senescence and atherogenesis intertwining, allowing researchers to establish more effective treatments and to reduce the cardiovascular disorders’ burden. Here, we present an objective review of the key senescence-related alterations of the major intracellular organelles and analyze the role of relevant cell types for senescence and atherogenesis. In this context, we provide an updated analysis of therapeutic approaches, including clinically relevant experiments using senolytic drugs to counteract atherosclerosis.
      Citation: Cells
      PubDate: 2020-09-23
      DOI: 10.3390/cells9102146
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2147: Transmembrane BAX Inhibitor-1 Motif Containing
           Protein 5 (TMBIM5) Sustains Mitochondrial Structure, Shape, and Function
           by Impacting the Mitochondrial Protein Synthesis Machinery

    • Authors: Bruno Seitaj, Felicia Maull, Li Zhang, Verena Wüllner, Christina Wolf, Philipp Schippers, Rita La Rovere, Ute Distler, Stefan Tenzer, Jan B. Parys, Geert Bultynck, Axel Methner
      First page: 2147
      Abstract: The Transmembrane Bax Inhibitor-1 motif (TMBIM)-containing protein family is evolutionarily conserved and has been implicated in cell death susceptibility. The only member with a mitochondrial localization is TMBIM5 (also known as GHITM or MICS1), which affects cristae organization and associates with the Parkinson’s disease-associated protein CHCHD2 in the inner mitochondrial membrane. We here used CRISPR-Cas9-mediated knockout HAP1 cells to shed further light on the function of TMBIM5 in physiology and cell death susceptibility. We found that compared to wild type, TMBIM5-knockout cells were smaller and had a slower proliferation rate. In these cells, mitochondria were more fragmented with a vacuolar cristae structure. In addition, the mitochondrial membrane potential was reduced and respiration was attenuated, leading to a reduced mitochondrial ATP generation. TMBIM5 did not associate with Mic10 and Mic60, which are proteins of the mitochondrial contact site and cristae organizing system (MICOS), nor did TMBIM5 knockout affect their expression levels. TMBIM5-knockout cells were more sensitive to apoptosis elicited by staurosporine and BH3 mimetic inhibitors of Bcl-2 and Bcl-XL. An unbiased proteomic comparison identified a dramatic downregulation of proteins involved in the mitochondrial protein synthesis machinery in TMBIM5-knockout cells. We conclude that TMBIM5 is important to maintain the mitochondrial structure and function possibly through the control of mitochondrial biogenesis.
      Citation: Cells
      PubDate: 2020-09-23
      DOI: 10.3390/cells9102147
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2148: The Absence of NLRP3-inflammasome Modulates
           Hepatic Fibrosis Progression, Lipid Metabolism, and Inflammation in KO
           NLRP3 Mice during Aging

    • Authors: Paloma Gallego, Beatriz Castejón-Vega, José A. del Campo, Mario D. Cordero
      First page: 2148
      Abstract: Aging is associated with metabolic changes and low-grade inflammation in several organs, which may be due to NLRP3 inflammasome activation. Methods: Here, we asked whether age-related liver changes such as lipid metabolism and fibrosis are reduced in aged mice lacking the NLRP3 inflammasome. We report reduced protein levels of lipid markers (MTP, FASN, DGAT1), SOD activity, oxidative stress marker PTPRG, and the fibrotic markers TPM2β, COL1-α1 associated with increased GATA4, in NLRP3 deficient mice. Fibrotic, lipid, and oxidative reduction in liver tissues of mice was more pronounced in those old KO NLRP3 mice than in the younger ones, despite their greater liver damage. These results suggest that absence of the NLRP3 inflammasome attenuates age-related liver fibrotic pathology in mice, suggesting that pharmacological targeting may be beneficial.
      Citation: Cells
      PubDate: 2020-09-23
      DOI: 10.3390/cells9102148
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2149: In Vitro Studies to Define the Cell-Surface and
           Intracellular Targets of Polyarginine-Conjugated Sodium Borocaptate as a
           Potential Delivery Agent for Boron Neutron Capture Therapy

    • Authors: Atsushi Fujimura, Seiji Yasui, Kazuyo Igawa, Ai Ueda, Kaori Watanabe, Tadashi Hanafusa, Yasuaki Ichikawa, Sachiko Yoshihashi, Kazuki Tsuchida, Atsunori Kamiya, Shuichi Furuya
      First page: 2149
      Abstract: Boron neutron capture therapy (BNCT) requires pharmaceutical innovations and molecular-based evidence of effectiveness to become a standard cancer therapeutic in the future. Recently, in Japan, 4-borono-L-phenylalanine (BPA) was approved as a boron agent for BNCT against head and neck (H&N) cancers. H&N cancer appears to be a suitable target for BPA-BNCT, because the expression levels of L-type amino acid transporter 1 (LAT1), one of the amino acid transporters responsible for BPA uptake, are elevated in most cases of H&N cancer. However, in other types of cancer including malignant brain tumors, LAT1 is not always highly expressed. To expand the possibility of BNCT for these cases, we previously developed poly-arginine peptide (polyR)-conjugated mercaptoundecahydrododecaborate (BSH). PolyR confers the cell membrane permeability and tumor selectivity of BSH. However, the molecular determinants for the properties are not fully understood. In this present study, we have identified the cluster of differentiation 44 (CD44) protein and translational machinery proteins as a major cell surface target and intracellular targets of BSH-polyR, respectively. CD44, also known as a stem cell-associated maker in various types of cancer, is required for the cellular uptake of polyR-conjugated molecules. We showed that BSH-polyR was predominantly delivered to a CD44High cell population of cancer cells. Once delivered, BSH-polyR interacted with the translational machinery components, including the initiation factors, termination factors, and poly(A)-biding protein (PABP). As a proof of principle, we performed BSH-polyR-based BNCT against glioma stem-like cells and revealed that BSH-polyR successfully induced BNCT-dependent cell death specifically in CD44High cells. Bioinformatics analysis indicated that BSH-polyR would be suitable for certain types of malignant tumors. Our results shed light on the biochemical properties of BSH-polyR, which may further contribute to the therapeutic optimization of BSH-BNCT in the future.
      Citation: Cells
      PubDate: 2020-09-23
      DOI: 10.3390/cells9102149
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2150: Crosstalk Between Autophagy and
           Hypoxia-Inducible Factor-1α in Antifungal Immunity

    • Authors: Tim Quäschling, Dirk Friedrich, George S. Deepe, Rupp
      First page: 2150
      Abstract: Modern medicine is challenged by several potentially severe fungal pathogens such as Aspergillus fumigatus, Candida albicans, or Histoplasma capsulatum. Though not all fungal pathogens have evolved as primary pathogens, opportunistic pathogens can still cause fatal infections in immuno-compromised patients. After infection with these fungi, the ingestion and clearance by innate immune cells is an important part of the host immune response. Innate immune cells utilize two different autophagic pathways, the canonical pathway and the non-canonical pathway, also called microtubule-associated protein 1A/1B-light chain 3 (LC3) -associated pathway (LAP), to clear fungal pathogens from the intracellular environment. The outcome of autophagy-related host immune responses depends on the pathogen and cell type. Therefore, the understanding of underlying molecular mechanisms of autophagy is crucial for the development and improvement of antifungal therapies. One of those molecular mechanisms is the interaction of the transcription-factor hypoxia-inducible factor 1α (HIF-1α) with the autophagic immune response. During this review, we will focus on a comprehensive overview of the role of autophagy and HIF-1α on the outcome of fungal infections.
      Citation: Cells
      PubDate: 2020-09-23
      DOI: 10.3390/cells9102150
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2151: Two- and Three-Dimensional Tracking of MFA2
           mRNA Molecules in Mating Yeast

    • Authors: Polina Geva, Konstantin Komoshvili, Stella Liberman-Aronov
      First page: 2151
      Abstract: Intracellular mRNA transport contributes to the spatio-temporal regulation of mRNA function and localized translation. In the budding yeast, Saccharomyces cerevisiae, asymmetric mRNA transport localizes ~30 specific mRNAs including those encoding polarity and secretion factors, to the bud tip. The underlying process involves RNA-binding proteins (RBPs), molecular motors, processing bodies (PBs), and the actin cytoskeleton. Recently, pheromone a-factor expression in mating yeast was discovered to depend on proper localization of its mRNA, MFA2 mRNAs in conjunction with PBs cluster at the shmoo tip to form “mating bodies”, from which a-factor is locally expressed. The mechanism ensuring the correct targeting of mRNA to the shmoo tip is poorly understood. Here we analyzed the kinetics and trajectories of MFA2 mRNA transport in living, alpha-factor treated yeast. Two- (2D) and three-dimensional (3D) analyses allowed us to reconstruct the granule tracks and estimate granule velocities. Tracking analysis of single MFA2 mRNA granules, labeled using a fluorescent aptamer system, demonstrated three types movement: vibrational, oscillatory and translocational. The mRNA granule transport was complex; a granule could change its movement behavior and composition during its journey to the shmoo. Processing body assembly and the actin-based motor, Myo4p, were involved in movement of MFA2 mRNA to the shmoo, but neither was required, indicating that multiple mechanisms for translocation were at play. Our visualization studies present a dynamic view of the localization mechanism in shmoo-bearing cells.
      Citation: Cells
      PubDate: 2020-09-23
      DOI: 10.3390/cells9102151
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2152: ARID2 Chromatin Remodeler in Hepatocellular

    • Authors: Robin Loesch, Linda Chenane, Sabine Colnot
      First page: 2152
      Abstract: Chromatin remodelers are found highly mutated in cancer including hepatocellular carcinoma. These mutations frequently occur in ARID (AT-rich Interactive Domain) genes, encoding subunits of the ATP-dependent SWI/SNF remodelers. The increasingly prevalent complexity that surrounds the functions and specificities of the highly modular BAF (BG1/BRM-associated factors) and PBAF (polybromo-associated BAF) complexes, including ARID1A/B or ARID2, is baffling. The involvement of the SWI/SNF complexes in diverse tissues and processes, and especially in the regulation of gene expression, multiplies the specific outcomes of specific gene alterations. A better understanding of the molecular consequences of specific mutations impairing chromatin remodelers is needed. In this review, we summarize what we know about the tumor-modulating properties of ARID2 in hepatocellular carcinoma.
      Citation: Cells
      PubDate: 2020-09-23
      DOI: 10.3390/cells9102152
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2153: Systemic Inflammatory Markers Are Predictive of
           the Response to Brachytherapy in the Prostate

    • Authors: Daniel Taussky, Denis Soulieres, Miguel Chagnon, Guila Delouya, Houda Bahig
      First page: 2153
      Abstract: We analyzed the influence of the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) on the biochemical recurrence (BCR) in low-intermediate risk prostate cancer (PCa). A total of 604 patients treated with exclusive brachytherapy for low- and intermediate-risk cancers were included in this study. No patient received either androgen deprivation or brachytherapy as a boost. BCR was defined according to the Phoenix definition (nadir prostatic specific antigen (PSA) +2). The median follow-up was 60 months (IQR 44–48 months). An NLR > 3 was more frequent in statin users (p = 0.025), but not in diabetics (p = 0.079). In univariate analysis (UVA) and multivariate analysis (MVA), a NLR > 3 (MVA p = 0.03), as well as Cancer of the Prostate Risk Assessment (CAPRA) low- vs. intermediate-risk (MVA p = 0.04), were predictive of BCR. When combining the NLR score with the CAPRA risk group, CAPRA intermediate risk patients with an NLR ≤ 3 (n = 157) had the worst (p = 0.0276) BCR rates, with a 5-year recurrence-free survival (p = 0.004, Bonferroni correction for six comparisons p = 0.024). We were able to identify a subgroup of PCa patients with CAPRA intermediate-risk and an NLR ≤ 3 who had worse BCR. This is in contrast to most other cancers, which have a worse prognosis when the NLR is high.
      Citation: Cells
      PubDate: 2020-09-23
      DOI: 10.3390/cells9102153
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2154: c-Jun N-Terminal Kinase as a Therapeutic Target
           in Experimental Autoimmune Encephalomyelitis

    • Authors: Maud Bagnoud, Myriam Briner, Jana Remlinger, Ivo Meli, Sara Schuetz, Maximilian Pistor, Anke Salmen, Andrew Chan, Robert Hoepner
      First page: 2154
      Abstract: c-Jun N-terminal kinase (JNK) is upregulated during multiple sclerosis relapses and at the peak of experimental autoimmune encephalomyelitis (EAE). We aim to investigate the effects of pharmacological pan-JNK inhibition on the course of myelin oligodendrocyte glycoprotein (MOG35-55) EAE disease using in vivo and in vitro experimental models. EAE was induced in female C57BL/6JRj wild type mice using MOG35-55. SP600125 (SP), a reversible adenosine triphosphate competitive pan-JNK inhibitor, was then given orally after disease onset. Positive correlation between SP plasma and brain concentration was observed. Nine, but not three, consecutive days of SP treatment led to a significant dose-dependent decrease of mean cumulative MOG35-55 EAE severity that was associated with increased mRNA expression of interferon gamma (INF-γ) and tumor necrosis factor alpha (TNF-α) in the spinal cord. On a histological level, reduced spinal cord immune cell-infiltration predominantly of CD3+ T cells as well as increased activity of Iba1+ cells were observed in treated animals. In addition, in vitro incubation of murine and human CD3+ T cells with SP resulted in reduced T cell apoptosis and proliferation. In conclusion, our study demonstrates that pharmacological pan-JNK inhibition might be a treatment strategy for autoimmune central nervous system demyelination.
      Citation: Cells
      PubDate: 2020-09-23
      DOI: 10.3390/cells9102154
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2155: T3 Critically Affects the Mhrt/Brg1 Axis to
           Regulate the Cardiac MHC Switch: Role of an Epigenetic Cross-Talk

    • Authors: Francesca Forini, Giuseppina Nicolini, Claudia Kusmic, Romina D’Aurizio, Alberto Mercatanti, Giorgio Iervasi, Letizia Pitto
      First page: 2155
      Abstract: The LncRNA my-heart (Mhrt) and the chromatin remodeler Brg1 inhibit each other to respectively prevent or favor the maladaptive α-myosin-heavy-chain (Myh6) to β-myosin-heavy-chain (Myh7) switch, so their balance crucially guides the outcome of cardiac remodeling under stress conditions. Even though triiodothyronine (T3) has long been recognized as a critical regulator of the cardiac Myh isoform composition, its role as a modulator of the Mhrt/Brg1 axis is still unexplored. Here the effect of T3 on the Mhrt/Brg1 regulatory circuit has been analyzed in relation with chromatin remodeling and previously identified T3-dependent miRNAs. The expression levels of Mhrt, Brg1 and Myh6/Myh7 have been assessed in rat models of hyperthyroidism or acute myocardial ischemia/reperfusion (IR) treated with T3 replacement therapy. To gain mechanistic insights, in silico analyses and site-directed mutagenesis have been adopted in combination with gene reporter assays and loss or gain of function strategies in cultured cardiomyocytes. Our results indicate a pivotal role of Mhrt over-expression in the T3-dependent regulation of Myh switch. Mechanistically, T3 activates the Mhrt promoter at two putative thyroid hormone responsive elements (TRE) located in a crucial region that is necessary for both Mhrt activation and Brg1-dependent Mhrt repression. This newly identified T3 mode of action requires DNA chromatinization and is critically involved in mitigating the repressive function of the Brg1 protein on Mhrt promoter. In addition, T3 is also able to prevent the Brg1 over-expression observed in the post-IR setting through a pathway that might entail the T3-mediated up-regulation of miR-208a. Taken together, our data evidence a novel T3-responsive network of cross-talking epigenetic factors that dictates the cardiac Myh composition and could be of great translational relevance.
      Citation: Cells
      PubDate: 2020-09-24
      DOI: 10.3390/cells9102155
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2156: Principal Postulates of Centrosomal Biology.
           Version 2020

    • Authors: Rustem E. Uzbekov, Tomer Avidor-Reiss
      First page: 2156
      Abstract: The centrosome, which consists of two centrioles surrounded by pericentriolar material, is a unique structure that has retained its main features in organisms of various taxonomic groups from unicellular algae to mammals over one billion years of evolution. In addition to the most noticeable function of organizing the microtubule system in mitosis and interphase, the centrosome performs many other cell functions. In particular, centrioles are the basis for the formation of sensitive primary cilia and motile cilia and flagella. Another principal function of centrosomes is the concentration in one place of regulatory proteins responsible for the cell’s progression along the cell cycle. Despite the existing exceptions, the functioning of the centrosome is subject to general principles, which are discussed in this review.
      Citation: Cells
      PubDate: 2020-09-24
      DOI: 10.3390/cells9102156
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2157: Multitasking by the OC Lineage during Bone
           Infection: Bone Resorption, Immune Modulation, and Microbial Niche

    • Authors: Philip M. Roper, Christine Shao, Deborah J. Veis
      First page: 2157
      Abstract: Bone infections, also known as infectious osteomyelitis, are accompanied by significant inflammation, osteolysis, and necrosis. Osteoclasts (OCs) are the bone-resorbing cells that work in concert with osteoblasts and osteocytes to properly maintain skeletal health and are well known to respond to inflammation by increasing their resorptive activity. OCs have typically been viewed merely as effectors of pathologic bone resorption, but recent evidence suggests they may play an active role in the progression of infections through direct effects on pathogens and via the immune system. This review discusses the host- and pathogen-derived factors involved in the in generation of OCs during infection, the crosstalk between OCs and immune cells, and the role of OC lineage cells in the growth and survival of pathogens, and highlights unanswered questions in the field.
      Citation: Cells
      PubDate: 2020-09-24
      DOI: 10.3390/cells9102157
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2158: Development and Validation of a Fully
           GMP-Compliant Process for Manufacturing Stromal Vascular Fraction: A
           Cost-Effective Alternative to Automated Methods

    • Authors: Pauline François, Laurent Giraudo, Julie Veran, Baptiste Bertrand, Chloé Dumoulin, Houssein Aboudou, Fanny Grimaud, Marie Vogtensperger, Mélanie Velier, Laurent Arnaud, Luc Lyonnet, Stéphanie Simoncini, Benjamin Guillet, Françoise Dignat-George, Jérémy Magalon, Florence Sabatier
      First page: 2158
      Abstract: The therapeutic use of adipose-derived stromal vascular fraction (SVF) is expanding in multiple pathologies. Various processes have been proposed for manufacturing SVF but they must be revisited based on advanced therapy medicinal product (ATMP) regulations. We report here the development and validation of a fully good manufacturing practices (GMP)-compliant protocol for the isolation of SVF. Adipose tissue was collected from healthy volunteers undergoing lipoaspiration. The optimal conditions of collagenase digestion and washing were determined based on measurements of SVF cell viability, yield recovery, and cell subset distribution. Comparability of the SVF obtained using the newly developed manufacturing process (n = 6) and the Celution-based automated method (n = 33), used as a reference, was established using inter-donor analyses. Characteristics of SVF (n = 5) generated using both manufacturing protocols were analyzed for an intra-donor comparison. In addition, these comparisons also included the determination of colony-forming unit fibroblast frequency, in vitro angiogenic activity, and in vivo regenerative effects in a mouse ischemic cutaneous wound model. We successfully developed a process for the generation of SVF presenting higher cell viability and yield recovery compared to the Celution device-based protocol. Characteristics of the SVF including phenotype, capacity for angiogenesis, and wound-healing promotion attested to the comparability of the two manufacturing processes. We validated an optimized non-automated process that should allow for a GMP-compliant, more affordable, and reduced-cost strategy to exploit the potential of SVF-based regenerative therapies.
      Citation: Cells
      PubDate: 2020-09-24
      DOI: 10.3390/cells9102158
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2159: Characterization of Hematopoiesis in Sickle
           Cell Disease by Prospective Isolation of Stem and Progenitor Cells

    • Authors: Seda S. Tolu, Kai Wang, Zi Yan, Shouping Zhang, Karl Roberts, Andrew S. Crouch, Gracy Sebastian, Mark Chaitowitz, Eric D. Fornari, Evan M. Schwechter, Joan Uehlinger, Deepa Manwani, Caterina P. Minniti, Eric E. Bouhassira
      First page: 2159
      Abstract: The consequences of sickle cell disease (SCD) include ongoing hematopoietic stress, hemolysis, vascular damage, and effect of chronic therapies, such as blood transfusions and hydroxyurea, on hematopoietic stem and progenitor cell (HSPC) have been poorly characterized. We have quantified the frequencies of nine HSPC populations by flow cytometry in the peripheral blood of pediatric and adult patients, stratified by treatment and control cohorts. We observed broad differences between SCD patients and healthy controls. SCD is associated with 10 to 20-fold increase in CD34dim cells, a two to five-fold increase in CD34bright cells, a depletion in Megakaryocyte-Erythroid Progenitors, and an increase in hematopoietic stem cells, when compared to controls. SCD is also associated with abnormal expression of CD235a as well as high levels CD49f antigen expression. These findings were present to varying degrees in all patients with SCD, including those on chronic therapy and those who were therapy naive. HU treatment appeared to normalize many of these parameters. Chronic stress erythropoiesis and inflammation incited by SCD and HU therapy have long been suspected of causing premature aging of the hematopoietic system, and potentially increasing the risk of hematological malignancies. An important finding of this study was that the observed concentration of CD34bright cells and of all the HSPCs decreased logarithmically with time of treatment with HU. This correlation was independent of age and specific to HU treatment. Although the number of circulating HSPCs is influenced by many parameters, our findings suggest that HU treatment may decrease premature aging and hematologic malignancy risk compared to the other therapeutic modalities in SCD.
      Citation: Cells
      PubDate: 2020-09-24
      DOI: 10.3390/cells9102159
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2160: Tuberculosis-Associated MicroRNAs: From
           Pathogenesis to Disease Biomarkers

    • Authors: Alessandro Sinigaglia, Elektra Peta, Silvia Riccetti, Seshasailam Venkateswaran, Riccardo Manganelli, Luisa Barzon
      First page: 2160
      Abstract: Tuberculosis (TB) caused by Mycobacterium tuberculosis is one of the most lethal infectious diseases with estimates of approximately 1.4 million human deaths in 2018. M. tuberculosis has a well-established ability to circumvent the host immune system to ensure its intracellular survival and persistence in the host. Mechanisms include subversion of expression of key microRNAs (miRNAs) involved in the regulation of host innate and adaptive immune response against M. tuberculosis. Several studies have reported differential expression of miRNAs during active TB and latent tuberculosis infection (LTBI), suggesting their potential use as biomarkers of disease progression and response to anti-TB therapy. This review focused on the miRNAs involved in TB pathogenesis and on the mechanism through which miRNAs induced during TB modulate cell antimicrobial responses. An attentive study of the recent literature identifies a group of miRNAs, which are differentially expressed in active TB vs. LTBI or vs. treated TB and can be proposed as candidate biomarkers.
      Citation: Cells
      PubDate: 2020-09-24
      DOI: 10.3390/cells9102160
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2161: Increased Lamin B1 Levels Promote Cell
           Migration by Altering Perinuclear Actin Organization

    • Authors: Andrea Fracchia, Tal Asraf, Mali Salmon-Divon, Gabi Gerlitz
      First page: 2161
      Abstract: Cell migration requires reposition and reshaping of the cell nucleus. The nuclear lamina is highly important for migration of both primary and cancer cells. B-type lamins are important for proper migration of epicardial cells and neurons and increased lamin B to lamin A ratio accelerates cancer cell migration through confined spaces. Moreover, a positive association between lamin B1 levels and tumor formation and progression is found in various cancer types. Still, the molecular mechanism by which B-type lamins promote cell migration is not fully understood. To better understand this mechanism, we tested the effects of lamin B1 on perinuclear actin organization. Here we show that induction of melanoma cell migration leads to the formation of a cytosolic Linker of Nucleoskeleton and Cytoskeleton (LINC) complex-independent perinuclear actin rim, which has not been detected in migrating cells, yet. Significantly, increasing the levels of lamin B1 but not the levels of lamin A prevented perinuclear actin rim formation while accelerated the cellular migration rate. To interfere with the perinuclear actin rim, we generated a chimeric protein that is localized to the outer nuclear membrane and cleaves perinuclear actin filaments in a specific manner without disrupting other cytosolic actin filaments. Using this tool, we found that disruption of the perinuclear actin rim accelerated the cellular migration rate in a similar manner to lamin B1 over-expression. Taken together, our results suggest that increased lamin B1 levels can accelerate cell migration by inhibiting the association of the nuclear envelope with actin filaments that may reduce nuclear movement and deformability.
      Citation: Cells
      PubDate: 2020-09-24
      DOI: 10.3390/cells9102161
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2162: At the Forefront of the Mucosal Barrier: The
           Role of Macrophages in the Intestine

    • Authors: Barbara Ruder, Christoph Becker
      First page: 2162
      Abstract: Macrophages are part of the innate immunity and are key players for the maintenance of intestinal homeostasis. They belong to the group of mononuclear phagocytes, which exert bactericidal functions and help to clear apoptotic cells. Moreover, they play essential roles for the maintenance of epithelial integrity and tissue remodeling during wound healing processes and might be implicated in intestinal tumor development. Macrophages are antigen-presenting cells and secrete immune-modulatory factors, like chemokines and cytokines, which are necessary to activate other intestinal immune cells and therefore to shape immune responses in the gut. However, overwhelming activation or increased secretion of pro-inflammatory cytokines might also contribute to the pathogenesis of inflammatory bowel disease. Presently, intestinal macrophages are in the center of intense studies, which might help to develop new therapeutic strategies to counteract the development or treat already existing inflammatory diseases in the gut. In this review, we focus on the origin of intestinal macrophages and, based on current knowledge, discuss their role in the gut during homeostasis and inflammation, as well as during intestinal wound healing and tumor development.
      Citation: Cells
      PubDate: 2020-09-24
      DOI: 10.3390/cells9102162
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2163: FMO1 Is Involved in Excess Light Stress-Induced
           Signal Transduction and Cell Death Signaling

    • Authors: Weronika Czarnocka, Yosef Fichman, Maciej Bernacki, Elżbieta Różańska, Izabela Sańko-Sawczenko, Ron Mittler, Stanisław Karpiński
      First page: 2163
      Abstract: Because of their sessile nature, plants evolved integrated defense and acclimation mechanisms to simultaneously cope with adverse biotic and abiotic conditions. Among these are systemic acquired resistance (SAR) and systemic acquired acclimation (SAA). Growing evidence suggests that SAR and SAA activate similar cellular mechanisms and employ common signaling pathways for the induction of acclimatory and defense responses. It is therefore possible to consider these processes together, rather than separately, as a common systemic acquired acclimation and resistance (SAAR) mechanism.Arabidopsis thaliana flavin-dependent monooxygenase 1 (FMO1) was previously described as a regulator of plant resistance in response to pathogens as an important component of SAR. In the current study, we investigated its role in SAA, induced by a partial exposure of Arabidopsis rosette to local excess light stress. We demonstrate here that FMO1 expression is induced in leaves directly exposed to excess light stress as well as in systemic leaves remaining in low light. We also show that FMO1 is required for the systemic induction of ASCORBATE PEROXIDASE 2 (APX2) and ZINC-FINGER OF ARABIDOPSIS 10 (ZAT10) expression and spread of the reactive oxygen species (ROS) systemic signal in response to a local application of excess light treatment. Additionally, our results demonstrate that FMO1 is involved in the regulation of excess light-triggered systemic cell death, which is under control of LESION SIMULATING DISEASE 1 (LSD1). Our study indicates therefore that FMO1 plays an important role in triggering SAA response, supporting the hypothesis that SAA and SAR are tightly connected and use the same signaling pathways.
      Citation: Cells
      PubDate: 2020-09-24
      DOI: 10.3390/cells9102163
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2164: Integrative Multi-Omics Analysis in Calcific
           Aortic Valve Disease Reveals a Link to the Formation of Amyloid-Like

    • Authors: Marina A. Heuschkel, Nikolaos T. Skenteris, Joshua D. Hutcheson, Dewy D. van der Valk, Juliane Bremer, Philip Goody, Jesper Hjortnaes, Felix Jansen, Carlijn V.C. Bouten, Antoon van den Bogaerdt, Ljubica Matic, Nikolaus Marx, Claudia Goettsch
      First page: 2164
      Abstract: Calcific aortic valve disease (CAVD) is the most prevalent valvular heart disease in the developed world, yet no pharmacological therapy exists. Here, we hypothesize that the integration of multiple omic data represents an approach towards unveiling novel molecular networks in CAVD. Databases were searched for CAVD omic studies. Differentially expressed molecules from calcified and control samples were retrieved, identifying 32 micro RNAs (miRNA), 596 mRNAs and 80 proteins. Over-representation pathway analysis revealed platelet degranulation and complement/coagulation cascade as dysregulated pathways. Multi-omics integration of overlapping proteome/transcriptome molecules, with the miRNAs, identified a CAVD protein–protein interaction network containing seven seed genes (apolipoprotein A1 (APOA1), hemoglobin subunit β (HBB), transferrin (TF), α-2-macroglobulin (A2M), transforming growth factor β-induced protein (TGFBI), serpin family A member 1 (SERPINA1), lipopolysaccharide binding protein (LBP), inter-α-trypsin inhibitor heavy chain 3 (ITIH3) and immunoglobulin κ constant (IGKC)), four input miRNAs (miR-335-5p, miR-3663-3p, miR-21-5p, miR-93-5p) and two connector genes (amyloid beta precursor protein (APP) and transthyretin (TTR)). In a metabolite–gene–disease network, Alzheimer’s disease exhibited the highest degree of betweenness. To further strengthen the associations based on the multi-omics approach, we validated the presence of APP and TTR in calcified valves from CAVD patients by immunohistochemistry. Our study suggests a novel molecular CAVD network potentially linked to the formation of amyloid-like structures. Further investigations on the associated mechanisms and therapeutic potential of targeting amyloid-like deposits in CAVD may offer significant health benefits.
      Citation: Cells
      PubDate: 2020-09-24
      DOI: 10.3390/cells9102164
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2165: Correction: Nemade, H.; et al. Cyclooxygenases
           Inhibitors Efficiently Induce Cardiomyogenesis in Human Pluripotent Stem
           Cells. Cells 2020, 9, 554

    • Authors: Harshal Nemade, Aviseka Acharya, Umesh Chaudhari, Erastus Nembo, Filomain Nguemo, Nicole Riet, Hinrich Abken, Jürgen Hescheler, Symeon Papadopoulos, Agapios Sachinidis
      First page: 2165
      Abstract: The authors wish to make the following corrections to this paper [...]
      Citation: Cells
      PubDate: 2020-09-24
      DOI: 10.3390/cells9102165
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2166: Presenilin-2 and Calcium Handling: Molecules,
           Organelles, Cells and Brain Networks

    • Authors: Paola Pizzo, Emy Basso, Riccardo Filadi, Elisa Greotti, Alessandro Leparulo, Diana Pendin, Nelly Redolfi, Michela Rossini, Nicola Vajente, Tullio Pozzan, Cristina Fasolato
      First page: 2166
      Abstract: Presenilin-2 (PS2) is one of the three proteins that are dominantly mutated in familial Alzheimer’s disease (FAD). It forms the catalytic core of the γ-secretase complex—a function shared with its homolog presenilin-1 (PS1)—the enzyme ultimately responsible of amyloid-β (Aβ) formation. Besides its enzymatic activity, PS2 is a multifunctional protein, being specifically involved, independently of γ-secretase activity, in the modulation of several cellular processes, such as Ca2+ signaling, mitochondrial function, inter-organelle communication, and autophagy. As for the former, evidence has accumulated that supports the involvement of PS2 at different levels, ranging from organelle Ca2+ handling to Ca2+ entry through plasma membrane channels. Thus FAD-linked PS2 mutations impact on multiple aspects of cell and tissue physiology, including bioenergetics and brain network excitability. In this contribution, we summarize the main findings on PS2, primarily as a modulator of Ca2+ homeostasis, with particular emphasis on the role of its mutations in the pathogenesis of FAD. Identification of cell pathways and molecules that are specifically targeted by PS2 mutants, as well as of common targets shared with PS1 mutants, will be fundamental to disentangle the complexity of memory loss and brain degeneration that occurs in Alzheimer’s disease (AD).
      Citation: Cells
      PubDate: 2020-09-25
      DOI: 10.3390/cells9102166
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2167: Rho GTPases: Big Players in Breast Cancer
           Initiation, Metastasis and Therapeutic Responses

    • Authors: Brock Humphries, Zhishan Wang, Chengfeng Yang
      First page: 2167
      Abstract: Rho GTPases, a family of the Ras GTPase superfamily, are key regulators of the actin cytoskeleton. They were originally thought to primarily affect cell migration and invasion; however, recent advances in our understanding of the biology and function of Rho GTPases have demonstrated their diverse roles within the cell, including membrane trafficking, gene transcription, migration, invasion, adhesion, survival and growth. As these processes are critically involved in cancer initiation, metastasis and therapeutic responses, it is not surprising that studies have demonstrated important roles of Rho GTPases in cancer. Although the majority of data indicates an oncogenic role of Rho GTPases, tumor suppressor functions of Rho GTPases have also been revealed, suggesting a context and cell-type specific function for Rho GTPases in cancer. This review aims to summarize recent progresses in our understanding of the regulation and functions of Rho GTPases, specifically in the context of breast cancer. The potential of Rho GTPases as therapeutic targets and prognostic tools for breast cancer patients are also discussed.
      Citation: Cells
      PubDate: 2020-09-25
      DOI: 10.3390/cells9102167
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2168: Rapid Detection of Free Cancer Cells in
           Intraoperative Peritoneal Lavage Using One-Step Nucleic Acid Amplification
           (OSNA) in Gastric Cancer Patients

    • Authors: Katarzyna Gęca, Karol Rawicz-Pruszyński, Jerzy Mielko, Radosław Mlak, Katarzyna Sędłak, Wojciech P. Polkowski
      First page: 2168
      Abstract: Cytokeratin-19 (CK19) has been proven to be commonly expressed by cancer cells in a variety of solid tumors and may serve as a suitable marker of metastases in gastric cancer (GC). Since objective assessment of peritoneal lavage or fluid for free cancer cells (FCC) is essential for clinical decision making in patients with GC, it is important to develop a quantitative and reproducible method for such evaluation. We assessed the possible application of One-Step Nucleic Acid amplification (OSNA) assay as a rapid method for FCC detection in intraoperative peritoneal lavage or fluid of GC patients. Seventy-eight intraoperative peritoneal lavage or fluid samples were eligible for the analysis by conventional cytology and OSNA examination. The concentration of CK19 mRNA in intraoperative peritoneal lavage and fluid was compared with the conventional cytological assessment. CK19 mRNA concentration was detected by OSNA assay. For peritoneal lavage samples, sensitivity and specificity were 83.3% and 87.8%, respectively. In peritoneal fluid, significantly higher CK19 values were observed in patients with serosal infiltration (medians: 100 copies/µL vs. 415.7 copies/µL; p = 0.0335) and lymph node metastases (medians: 2.48 copies/µL vs. 334.8 copies/µL). OSNA assay turns out to be an objective, fast, and reproducible quantitative method of FCC assessment.
      Citation: Cells
      PubDate: 2020-09-25
      DOI: 10.3390/cells9102168
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2169: Tick-Borne Encephalitis: A Differential Pattern
           of Intrathecal Humoral Immune Response and Inflammatory Cell Composition
           Compared with Other Viral CNS Infections

    • Authors: Makbule Senel, Daniel Rapp, Benjamin Mayer, Sarah Jesse, Sigurd D. Süssmuth, Markus Otto, Jan Lewerenz, Hayrettin Tumani
      First page: 2169
      Abstract: To investigate whether and how cerebrospinal fluid (CSF) findings can contribute to distinguish tick-borne encephalitis (TBE) from herpes simplex virus (HSV) and varicella zoster virus (VZV) induced central nervous system (CNS) infections (HSV-I, VZV-I). Chart review and identification of TBE, HSV- I, and VZV-I was carried out, fulfilling the following criteria: (1) clinical signs of encephalitis and/or meningitis, (2) complete CSF analysis and confirmed viral etiology by either PCR or antibody testing in CSF, (3) hospitalized patients, and (4) available brain magnetic resonance imaging (MRI). Fifty-nine patients with 118 CSF/serum pairs were included. These comprised 21 with TBE (35 CSF/serum pairs), 20 (40 CSF/serum pairs) with HSV-I, and 18 (43 CSF/serum pairs) with VZV-I. In contrast to HSV-I and VZV-I, CSF cell differentiation in TBE showed more often an increased (>20%) proportion of granulocytes (p < 0.01) and a more frequent quantitative intrathecal IgM synthesis (p = 0.001 and p < 0.01, respectively), while the second was even more pronounced when follow-up CSF analyses were included (p < 0.001). CSF findings help to distinguish TBE from other viral infections. In cases with CSF pleocytosis and a positive history for a stay in or near an endemic area, TBE antibodies in CSF and serum should be determined, especially if granulocytes in CSF cell differentiation and/or an intrathecal IgM synthesis is present.
      Citation: Cells
      PubDate: 2020-09-25
      DOI: 10.3390/cells9102169
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2170: Epac1 Is Crucial for Maintenance of Endothelial
           Barrier Function through A Mechanism Partly Independent of Rac1

    • Authors: Alexander García-Ponce, Katharina Schuster, Stein-Ove Døskeland, Rolf K. Reed, Fitz-Roy E. Curry, Jens Waschke, Mariya Y. Radeva
      First page: 2170
      Abstract: Epac1 (exchange protein activated by cAMP) stabilizes the endothelial barrier, but detailed studies are limited by the side effects of pharmacological Epac1 modulators and transient transfections. Here, we compare the key properties of barriers between endothelial cells derived from wild-type (WT) and Epac1-knockout (KO) mice myocardium. We found that KO cell layers, unlike WT layers, had low and cAMP-insensitive trans-endothelial resistance (TER). They also had fragmented VE-cadherin staining despite having augmented cAMP levels and increased protein expression of Rap1, Rac1, RhoA, and VE-cadherin. The simultaneous direct activation of Rac1 and RhoA by CN04 compensated Epac1 loss, since TER was increased. In KO-cells, inhibition of Rac1 activity had no additional effect on TER, suggesting that other mechanisms compensate the inhibition of the Rac1 function to preserve barrier properties. In summary, Epac1 is crucial for baseline and cAMP-mediated barrier stabilization through mechanisms that are at least partially independent of Rac1.
      Citation: Cells
      PubDate: 2020-09-25
      DOI: 10.3390/cells9102170
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2171: In Situ Gel Incorporating Disulfiram
           Nanoparticles Rescues the Retinal Dysfunction via ATP Collapse in Otsuka
           Long–Evans Tokushima Fatty Rats

    • Authors: Saori Deguchi, Fumihiko Ogata, Mizuki Yamaguchi, Misa Minami, Hiroko Otake, Kazutaka Kanai, Naohito Kawasaki, Noriaki Nagai
      First page: 2171
      Abstract: We attempted to design an ophthalmic in situ gel formulation incorporating disulfiram (DIS) nanoparticles (Dis-NPs/ISG) and demonstrated the therapeutic effect of Dis-NPs/ISG on retinal dysfunction in 15-month-old Otsuka Long–Evans Tokushima Fatty (OLETF) rats, a rat model of diabetes. The DIS particles were crushed using a bead mill to prepare the nanoparticles, and the Dis-NPs/ISG was prepared using a combination of the DIS nanoparticles and an in situ gelling system based on methylcellulose (MC). The particle size of the Dis-NPs/ISG was 80–250 nm, and there was no detectable precipitation or aggregation for 1 month. Moreover, the Dis-NPs/ISG was gelled at 37 °C, and the drug was delivered into the retina by instillation. Only diethyldithiocarbamate (DDC) was detected in the retina (DIS was not detected) when the Dis-NPs/ISG was instilled in the right eye, and the DDC levels in the right retina were significantly higher than those in the left retina. In addition, the retinal residence time of the drug was prolonged by the application of the in situ gelling system, since the DDC levels in the retinas of rats instilled with Dis-NPs/ISG were higher than those in DIS nanoparticles without MC. Furthermore, repetitive instillation of the Dis-NPs/ISG attenuated the deterioration of electroretinograms (ERGs) in 15-month-old OLETF rats by preventing the collapse of ATP production via excessive nitric oxide and recovered the decrease in retinal function. These findings provide important information for the development of novel therapeutic approaches to diabetic retinopathy.
      Citation: Cells
      PubDate: 2020-09-25
      DOI: 10.3390/cells9102171
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2172: AQP2: Mutations Associated with Congenital
           Nephrogenic Diabetes Insipidus and Regulation by Post-Translational
           Modifications and Protein-Protein Interactions

    • Authors: Chao Gao, Paul J. Higgins, Wenzheng Zhang
      First page: 2172
      Abstract: As a rare hereditary disease, congenital nephrogenic diabetes insipidus (NDI) is clinically characterized by polyuria with hyposthenuria and polydipsia. NDI results from collecting duct principal cell hyporesponsiveness or insensitivity to the antidiuretic action of arginine vasopressin (AVP). The principal cell-specific water channel aquaporin-2 (AQP2) plays an essential role in water reabsorption along osmotic gradients. The capacity to accumulate AQP2 in the apical plasma membrane in response to decreased fluid volume or increased plasma osmolality is critically regulated by the antidiuretic hormone AVP and its receptor 2 (AVPR2). Mutations in AVPR2 result in X-linked recessive NDI, the most common form of inherited NDI. Genetic defects in AQP2 cause autosomal recessive or dominant NDI. In this review, we provide an updated overview of the genetic and molecular mechanisms of congenital NDI, with a focus on the potential disease-causing mutations in AVPR2 and AQP2, the molecular defects in the AVPR2 and AQP2 mutants, post-translational modifications (i.e., phosphorylation, ubiquitination, and glycosylation) and various protein-protein interactions that regulate phosphorylation, ubiquitination, tetramerization, trafficking, stability, and degradation of AQP2.
      Citation: Cells
      PubDate: 2020-09-26
      DOI: 10.3390/cells9102172
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2173: Astrocytic Factors Controlling Synaptogenesis:
           A Team Play

    • Authors: Giuliana Fossati, Michela Matteoli, Elisabetta Menna
      First page: 2173
      Abstract: Astrocytes are essential players in brain circuit development and homeostasis, controlling many aspects of synapse formation, function, plasticity and elimination both during development and adulthood. Accordingly, alterations in astrocyte morphogenesis and physiology may severely affect proper brain development, causing neurological or neuropsychiatric conditions. Recent findings revealed a huge astrocyte heterogeneity among different brain areas, which is likely at the foundation of the different synaptogenic potential of these cells in selected brain regions. This review highlights recent findings on novel mechanisms that regulate astrocyte-mediated synaptogenesis during development, and the control of synapse number in the critical period or upon synaptic plasticity.
      Citation: Cells
      PubDate: 2020-09-26
      DOI: 10.3390/cells9102173
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2174: Sex-Specific Control of Muscle Mass: Elevated
           IGFBP Proteolysis and Reductions of IGF-1 Levels Are Associated with
           Substantial Loss of Carcass Weight in Male DU6PxIGFBP-2 Transgenic Mice

    • Authors: Daniela Ohde, Michael Walz, Christina Walz, Antonia Noce, Julia Brenmoehl, Martina Langhammer, Andreas Hoeflich
      First page: 2174
      Abstract: In farmed animals, carcass weight represents an important economic trait. Since we had demonstrated that IGFBP-2 represents a potent inhibitor of muscle accretion in inbred mice, we wanted to quantify the inhibitory effects of IGFBP-2 under conditions of elevated protein mass in growth selected non-inbred mice (DU6P). Therefore, we crossed male DU6P mice with female IGFBP-2 transgenic mice. Male IGFBP-2 transgenic offspring (DU6P/IGFBP-2) were characterized by more than 20% reductions of carcass mass compared to male non-transgenic littermates. The carcass mass in males was also significantly lower (p < 0.001) than in transgenic female DU6P/IGFBP-2 mice, which showed a reduction of less than 10% (p < 0.05) compared to non-transgenic female DU6P/IGFBP-2 mice. Although transgene expression was elevated in the muscle of both sexes (p < 0.001), serum levels were normal in female, but significantly reduced in male transgenic DU6P/IGFBP-2 mice (p < 0.001). In this group, also IGFBP-3 and IGFBP-4 were significantly reduced in the circulation (p < 0.01). Particularly in male transgenic mice, we were able to identify proteolytic activity against recombinant IGFBP-2 included in diluted serum. IGFBP-proteolysis in males correlated with massive reductions of IGF-1 in serum samples and the presence of elevated levels of IGFBP-2 fragments. From our data, we conclude that elevated tissue expression of IGFBP-2 is an essential effector of muscle accretion and may block more than 20% of carcass mass. However, in the circulation, intact IGFBP-2 contained no reliable biomarker content. Notably, for the estimation of breeding values in meat-producing animal species, monitoring of IGFBP-2 expression in muscle appears to be supported by the present study in a model system.
      Citation: Cells
      PubDate: 2020-09-26
      DOI: 10.3390/cells9102174
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2175: Integrated Transcriptome and Proteome Analyses
           Reveal the Regulatory Role of miR-146a in Human Limbal Epithelium via
           Notch Signaling

    • Authors: Adam J. Poe, Mangesh Kulkarni, Aleksandra Leszczynska, Jie Tang, Ruchi Shah, Yasaman Jami-Alahmadi, Jason Wang, Andrei A. Kramerov, James Wohlschlegel, Vasu Punj, Alexander V. Ljubimov, Mehrnoosh Saghizadeh
      First page: 2175
      Abstract: MiR-146a is upregulated in the stem cell-enriched limbal region vs. central human cornea and can mediate corneal epithelial wound healing. The aim of this study was to identify miR-146a targets in human primary limbal epithelial cells (LECs) using genomic and proteomic analyses. RNA-seq combined with quantitative proteomics based on multiplexed isobaric tandem mass tag labeling was performed in LECs transfected with miR-146a mimic vs. mimic control. Western blot and immunostaining were used to confirm the expression of some targeted genes/proteins. A total of 251 differentially expressed mRNAs and 163 proteins were identified. We found that miR-146a regulates the expression of multiple genes in different pathways, such as the Notch system. In LECs and organ-cultured corneas, miR-146a increased Notch-1 expression possibly by downregulating its inhibitor Numb, but decreased Notch-2. Integrated transcriptome and proteome analyses revealed the regulatory role of miR-146a in several other processes, including anchoring junctions, TNF-α, Hedgehog signaling, adherens junctions, TGF-β, mTORC2, and epidermal growth factor receptor (EGFR) signaling, which mediate wound healing, inflammation, and stem cell maintenance and differentiation. Our results provide insights into the regulatory network of miR-146a and its role in fine-tuning of Notch-1 and Notch-2 expressions in limbal epithelium, which could be a balancing factor in stem cell maintenance and differentiation.
      Citation: Cells
      PubDate: 2020-09-26
      DOI: 10.3390/cells9102175
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2176: Neuron-Glia Interactions in Neurodevelopmental

    • Authors: Yoo Sung Kim, Juwon Choi, Bo-Eun Yoon
      First page: 2176
      Abstract: Recent studies have revealed synaptic dysfunction to be a hallmark of various psychiatric diseases, and that glial cells participate in synapse formation, development, and plasticity. Glial cells contribute to neuroinflammation and synaptic homeostasis, the latter being essential for maintaining the physiological function of the central nervous system (CNS). In particular, glial cells undergo gliotransmission and regulate neuronal activity in tripartite synapses via ion channels (gap junction hemichannel, volume regulated anion channel, and bestrophin-1), receptors (for neurotransmitters and cytokines), or transporters (GLT-1, GLAST, and GATs) that are expressed on glial cell membranes. In this review, we propose that dysfunction in neuron-glia interactions may contribute to the pathogenesis of neurodevelopmental disorders. Understanding the mechanisms of neuron-glia interaction for synapse formation and maturation will contribute to the development of novel therapeutic targets of neurodevelopmental disorders.
      Citation: Cells
      PubDate: 2020-09-27
      DOI: 10.3390/cells9102176
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2177: GPR91 Receptor Mediates Protection against
           Doxorubicin-Induced Cardiotoxicity without Altering Its Anticancer
           Efficacy. An In Vitro Study on H9C2 Cardiomyoblasts and Breast
           Cancer-Derived MCF-7 Cells

    • Authors: Matthieu Dallons, Esma Alpan, Corentin Schepkens, Vanessa Tagliatti, Jean-Marie Colet
      First page: 2177
      Abstract: Doxorubicin (DOX) is an anticancer drug widely used in oncology, especially for breast cancer. The main limitation of DOX treatment is its cardiotoxicity due to the cumulative dose. Clinically, DOX-induced cardiomyopathy develops as a progressive heart failure caused by a progressive cardiomyocyte’s death. For long, the oxidative stress induced by DOX was considered as the main toxic mechanism responsible for heart damage, but it is now controverted, and other processes are investigated to develop cardioprotective strategies. Previously, we studied DOX-induced cardiotoxicity and dexrazoxane (DEX), the only cardioprotective compound authorized by the FDA, by 1H-NMR metabonomics in H9C2 cells. We observed an increased succinate secretion in the extracellular fluid of DEX-exposed cardiomyocytes, a finding that led us to the hypothesis of a possible protective role of this agonist of the GPR91 receptor. The objective of the present work was to study the effect of succinate (SUC) and cis-epoxysuccinate (cis-ES), two agonists of the GPR91 receptor, on DOX-induced cardiotoxicity to H9C2 cells. To this purpose, several toxicity parameters, including cell viability, oxidative stress and apoptosis, as well as the GPR91 expression, were measured to assess the effects of DEX, SUC and cis-ES either alone or in combination with DOX in H9C2 cells. A 1H-NMR-based metabonomic study was carried out on cellular fluids collected after 24 h to highlight the metabolic changes induced by those protective compounds. Moreover, the effects of each agonist given either alone or in combination with DOX were evaluated on MCF-7 breast cancer cells. GPR91 expression was confirmed in H9C2 cells, while no expression was found in MCF-7 cells. Under such experimental conditions, both SUC and cis-ES decreased partially the cellular mortality, the oxidative stress and the apoptosis induced by DOX. The SUC protective effect was similar to the DEX effect, but the protective effect of cis-ES was higher on oxidative stress and apoptosis. In addition, the metabonomics findings pointed out several metabolic pathways involved in the cardioprotective effects of both GPR91 agonists: the stimulation of aerobic metabolism with glucose as the main fuel, redox balance and phospholipids synthesis. Finally, none of the GPR91 agonists jeopardized the pharmacological effects of DOX on MCF-7 breast cancer cells.
      Citation: Cells
      PubDate: 2020-09-27
      DOI: 10.3390/cells9102177
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2178: 3D Stem Cell Culture

    • Authors: Joni H. Ylostalo
      First page: 2178
      Abstract: Much interest has been directed towards stem cells, both in basic and translational research, to understand basic stem cell biology and to develop new therapies for many disorders. In general, stem cells can be cultured with relative ease, however, most common culture methods for stem cells employ 2D techniques using plastic. These cultures do not well represent the stem cell niches in the body, which are delicate microenvironments composed of not only stem cells, but also supporting stromal cells, extracellular matrix, and growth factors. Therefore, researchers and clinicians have been seeking optimal stem cell preparations for basic research and clinical applications, and these might be attainable through 3D culture of stem cells. The 3D cultures recapitulate the in vivo cell-to-cell and cell-to-matrix interactions more effectively, and the cells in 3D cultures exhibit many unique and desirable characteristics. The culture of stem cells in 3D may employ various matrices or scaffolds, in addition to the cells, to support the complex structures. The goal of this Special Issue is to bring together recent research on 3D cultures of various stem cells to increase the basic understanding of stem cells and culture techniques, and also highlight stem cell preparations for possible novel therapeutic applications.
      Citation: Cells
      PubDate: 2020-09-27
      DOI: 10.3390/cells9102178
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2179: Serum Levels of Bone Morphogenetic Proteins 2
           and 4 in Patients with Acute Myocardial Infarction

    • Authors: Maria Kercheva, Anna M. Gusakova, Tamara R. Ryabova, Tatiana E. Suslova, Julia Kzhyshkowska, Vyacheslav V. Ryabov
      First page: 2179
      Abstract: Background: Bone morphogenetic proteins-2 and -4 (BMPs) have been implicated in left ventricular remodeling (LVR) processes such as an inflammation and fibrogenesis. We hypothesized that this knowledge could be translated into clinics. Methods: We studied the dynamics of serum levels of BMPs, its correlation with markers of LVR and with parameters of echocardiography in patients (n = 31) during the six-month follow-up period after myocardial infarction (MI). Results: Elevated serum levels of BMPs decreased by the six-month follow-up period. BMP-2 decreased from the first day after MI, and BMP-4 decreased from the Day 14. The elevated level of BMP-2 at Day 1 was associated with a lower level of troponin I, reperfusion time and better left ventricular ejection fraction (LV EF) at the six-month follow-up. Elevated serum level of BMP-4 at Day 1 was associated with a lower level of a soluble isoform of suppression of tumorigenicity 2 (sST2), age and reperfusion time. An elevated level of BMP-2 at the six-month follow-up was associated with higher levels of BMP-4, high-sensitivity C-reactive protein (hCRP) and sST2. High serum level of BMP-2 correlated with high levels of hCRP and matrix metalloproteinase (MMP)-9 on Day 7. High serum level of BMP-4 correlated with low levels of hCRP, MMP-9 at Day 3, sST2 at Day 1 and with decreased LV EF on Day 7. The findings of multivariate analysis support the involvement of BMP-2 in the development of post-infarction LVR. Conclusions: Our research translates experimental data about the BMPs in the development of adverse LVR into the clinic. Elevated serum levels of BMPs decreased by the end of the six-month period after MI. BMP-2 decreased from the first day and BMP-4 decreased from Day 14. BMP-2 and BMP-4 were associated with the development of LVR. Their correlations with markers of inflammation, degradation of the extracellular matrix, hemodynamic stress and markers of myocardial damage further support our hypothesis. Diagnostic and predictive values of these BMPs at the development of post-infarction LVR in vivo should be investigated further.
      Citation: Cells
      PubDate: 2020-09-27
      DOI: 10.3390/cells9102179
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2180: Diverse Defenses: A Perspective Comparing
           Dipteran Piwi-piRNA Pathways

    • Authors: Stephanie Gamez, Satyam Srivastav, Omar S. Akbari, Nelson C. Lau
      First page: 2180
      Abstract: Animals face the dual threat of virus infections hijacking cellular function and transposons proliferating in germline genomes. For insects, the deeply conserved RNA interference (RNAi) pathways and other chromatin regulators provide an important line of defense against both viruses and transposons. For example, this innate immune system displays adaptiveness to new invasions by generating cognate small RNAs for targeting gene silencing measures against the viral and genomic intruders. However, within the Dipteran clade of insects, Drosophilid fruit flies and Culicids mosquitoes have evolved several unique mechanistic aspects of their RNAi defenses to combat invading transposons and viruses, with the Piwi-piRNA arm of the RNAi pathways showing the greatest degree of novel evolution. Whereas central features of Piwi-piRNA pathways are conserved between Drosophilids and Culicids, multiple lineage-specific innovations have arisen that may reflect distinct genome composition differences and specific ecological and physiological features dividing these two branches of Dipterans. This perspective review focuses on the most recent findings illuminating the Piwi/piRNA pathway distinctions between fruit flies and mosquitoes, and raises open questions that need to be addressed in order to ameliorate human diseases caused by pathogenic viruses that mosquitoes transmit as vectors.
      Citation: Cells
      PubDate: 2020-09-27
      DOI: 10.3390/cells9102180
      Issue No: Vol. 9, No. 10 (2020)
  • Cells, Vol. 9, Pages 2181: Epitranscriptomics of Mammalian Mitochondrial
           Ribosomal RNA

    • Authors: Laptev, Dontsova, Sergiev
      First page: 2181
      Abstract: Modified nucleotides are present in all ribosomal RNA molecules. Mitochondrial ribosomes are unique to have a set of methylated residues that includes universally conserved ones, those that could be found either in bacterial or in archaeal/eukaryotic cytosolic ribosomes and those that are present exclusively in mitochondria. A single pseudouridine within the mt-rRNA is located in the peptidyltransferase center at a position similar to that in bacteria. After recent completion of the list of enzymes responsible for the modification of mammalian mitochondrial rRNA it became possible to summarize an evolutionary history, functional role of mt-rRNA modification enzymes and an interplay of the mt-rRNA modification and mitoribosome assembly process, which is a goal of this review.
      Citation: Cells
      PubDate: 2020-09-27
      DOI: 10.3390/cells9102181
      Issue No: Vol. 9, No. 10 (2020)
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