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Cells, Volume 7, Issue 2 (February 2018)

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Cover Story (view full-size image) Innate immunity and tumor cells constantly engage each other in a dynamic process that can prevent [...] Read more.
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Open AccessFeature PaperReview Impaired Cargo Clearance in the Retinal Pigment Epithelium (RPE) Underlies Irreversible Blinding Diseases
Received: 28 January 2018 / Revised: 20 February 2018 / Accepted: 22 February 2018 / Published: 23 February 2018
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Abstract
Chronic degeneration of the Retinal Pigment Epithelium (RPE) is a precursor to pathological changes in the outer retina. The RPE monolayer, which lies beneath the neuroretina, daily internalises and digests large volumes of spent photoreceptor outer segments. Impaired cargo handling and processing in
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Chronic degeneration of the Retinal Pigment Epithelium (RPE) is a precursor to pathological changes in the outer retina. The RPE monolayer, which lies beneath the neuroretina, daily internalises and digests large volumes of spent photoreceptor outer segments. Impaired cargo handling and processing in the endocytic/phagosome and autophagy pathways lead to the accumulation of lipofuscin and pyridinium bis-retinoid A2E aggregates and chemically modified compounds such as malondialdehyde and 4-hydroxynonenal within RPE. These contribute to increased proteolytic and oxidative stress, resulting in irreversible damage to post-mitotic RPE cells and development of blinding conditions such as age-related macular degeneration, Stargardt disease and choroideremia. Here, we review how impaired cargo handling in the RPE results in their dysfunction, discuss new findings from our laboratory and consider how newly discovered roles for lysosomes and the autophagy pathway could provide insights into retinopathies. Studies of these dynamic, molecular events have also been spurred on by recent advances in optics and imaging technology. Mechanisms underpinning lysosomal impairment in other degenerative conditions including storage disorders, α-synuclein pathologies and Alzheimer’s disease are also discussed. Collectively, these findings help transcend conventional understanding of these intracellular compartments as simple waste disposal bags to bring about a paradigm shift in the way lysosomes are perceived. Full article
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Open AccessFeature PaperArticle Nutrient Limitation Inactivates Mrc1-to-Cds1 Checkpoint Signalling in Schizosaccharomyces pombe
Received: 11 February 2018 / Revised: 21 February 2018 / Accepted: 21 February 2018 / Published: 23 February 2018
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Abstract
The S. pombe checkpoint kinase, Cds1, protects the integrity of stalled DNA replication forks after its phosphorylation at threonine-11 by Rad3 (ATR). Modified Cds1 associates through its N-terminal forkhead-associated domain (FHA)-domain with Mrc1 (Claspin) at stalled forks. We report here that nutrient starvation
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The S. pombe checkpoint kinase, Cds1, protects the integrity of stalled DNA replication forks after its phosphorylation at threonine-11 by Rad3 (ATR). Modified Cds1 associates through its N-terminal forkhead-associated domain (FHA)-domain with Mrc1 (Claspin) at stalled forks. We report here that nutrient starvation results in post-translational changes to Cds1 and the loss of Mrc1. A drop in glucose after a down-shift from 3% to 0.1–0.3%, or when cells enter the stationary phase, triggers a sharp decline in Mrc1 and the accumulation of insoluble Cds1. Before this transition, Cds1 is transiently activated and phosphorylated by Rad3 when glucose levels fall. Because this coincides with the phosphorylation of histone 2AX at S129 by Rad3, an event that occurs towards the end of every unperturbed S phase, we suggest that a glucose limitation promotes the exit from the S phase. Since nitrogen starvation also depletes Mrc1 while Cds1 is post-translationally modified, we suggest that nutrient limitation is the general signal that promotes exit from S phase before it inactivates the Mrc1–Cds1 signalling component. Why Cds1 accumulates in resting cells while its activator Mrc1 declines is, as yet, unclear but suggests a novel function of Cds1 in non-replicating cells. Full article
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Open AccessFeature PaperReview The Yeast Saccharomyces cerevisiae as a Model for Understanding RAS Proteins and their Role in Human Tumorigenesis
Received: 25 December 2017 / Revised: 5 February 2018 / Accepted: 12 February 2018 / Published: 19 February 2018
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Abstract
The exploitation of the yeast Saccharomyces cerevisiae as a biological model for the investigation of complex molecular processes conserved in multicellular organisms, such as humans, has allowed fundamental biological discoveries. When comparing yeast and human proteins, it is clear that both amino acid
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The exploitation of the yeast Saccharomyces cerevisiae as a biological model for the investigation of complex molecular processes conserved in multicellular organisms, such as humans, has allowed fundamental biological discoveries. When comparing yeast and human proteins, it is clear that both amino acid sequences and protein functions are often very well conserved. One example of the high degree of conservation between human and yeast proteins is highlighted by the members of the RAS family. Indeed, the study of the signaling pathways regulated by RAS in yeast cells led to the discovery of properties that were often found interchangeable with RAS proto-oncogenes in human pathways, and vice versa. In this work, we performed an updated critical literature review on human and yeast RAS pathways, specifically highlighting the similarities and differences between them. Moreover, we emphasized the contribution of studying yeast RAS pathways for the understanding of human RAS and how this model organism can contribute to unveil the roles of RAS oncoproteins in the regulation of mechanisms important in the tumorigenic process, like autophagy. Full article
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Open AccessArticle Linear Regression QSAR Models for Polo-Like Kinase-1 Inhibitors
Received: 27 November 2017 / Revised: 23 January 2018 / Accepted: 2 February 2018 / Published: 14 February 2018
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Abstract
A structurally diverse dataset of 530 polo-like kinase-1 (PLK1) inhibitors is compiled from the ChEMBL database and studied by means of a conformation-independent quantitative structure-activity relationship (QSAR) approach. A large number (26,761) of molecular descriptors are explored with the main intention of capturing
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A structurally diverse dataset of 530 polo-like kinase-1 (PLK1) inhibitors is compiled from the ChEMBL database and studied by means of a conformation-independent quantitative structure-activity relationship (QSAR) approach. A large number (26,761) of molecular descriptors are explored with the main intention of capturing the most relevant structural characteristics affecting the bioactivity. The structural descriptors are derived with different freeware, such as PaDEL, Mold2, and QuBiLs-MAS; such descriptor software complements each other and improves the QSAR results. The best multivariable linear regression models are found with the replacement method variable subset selection technique. The balanced subsets method partitions the dataset into training, validation, and test sets. It is found that the proposed linear QSAR model improves previously reported models by leading to a simpler alternative structure-activity relationship. Full article
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Open AccessFeature PaperReview MiRNAs at the Crossroads between Innate Immunity and Cancer: Focus on Macrophages
Received: 27 December 2017 / Revised: 1 February 2018 / Accepted: 6 February 2018 / Published: 8 February 2018
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Abstract
Innate immune cells form an integrative component of the tumor microenvironment (TME), which can control or prevent tumor initiation and progression, due to the simultaneous processing of both anti- and pro-growth signals. This decision-making process is a consequence of gene expression changes, which
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Innate immune cells form an integrative component of the tumor microenvironment (TME), which can control or prevent tumor initiation and progression, due to the simultaneous processing of both anti- and pro-growth signals. This decision-making process is a consequence of gene expression changes, which are in part dependent on post-transcriptional regulatory mechanisms. In this context, microRNAs have been shown to regulate both recruitment and activation of specific tumor-associated immune cells in the TME. This review aims to describe the most important microRNAs that target cancer-related innate immune pathways. The role of exosomal microRNAs in tumor progression and microRNA-based therapeutic strategies are also discussed. Full article
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Open AccessReview Consequences of Lamin B1 and Lamin B Receptor Downregulation in Senescence
Received: 4 December 2017 / Revised: 24 January 2018 / Accepted: 31 January 2018 / Published: 6 February 2018
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Abstract
Anchoring of heterochromatin to the nuclear envelope appears to be an important process ensuring the spatial organization of the chromatin structure and genome function in eukaryotic nuclei. Proteins of the inner nuclear membrane (INM) mediating these interactions are able to recognize lamina-associated heterochromatin
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Anchoring of heterochromatin to the nuclear envelope appears to be an important process ensuring the spatial organization of the chromatin structure and genome function in eukaryotic nuclei. Proteins of the inner nuclear membrane (INM) mediating these interactions are able to recognize lamina-associated heterochromatin domains (termed LAD) and simultaneously bind either lamin A/C or lamin B1. One of these proteins is the lamin B receptor (LBR) that binds lamin B1 and tethers heterochromatin to the INM in embryonic and undifferentiated cells. It is replaced by lamin A/C with specific lamin A/C binding proteins at the beginning of cell differentiation and in differentiated cells. Our functional experiments in cancer cell lines show that heterochromatin in cancer cells is tethered to the INM by LBR, which is downregulated together with lamin B1 at the onset of cell transition to senescence. The downregulation of these proteins in senescent cells leads to the detachment of centromeric repetitive sequences from INM, their relocation to the nucleoplasm, and distension. In cells, the expression of LBR and LB1 is highly coordinated as evidenced by the reduction of both proteins in LBR shRNA lines. The loss of the constitutive heterochromatin structure containing LADs results in changes in chromatin architecture and genome function and can be the reason for the permanent loss of cell proliferation in senescence. Full article
(This article belongs to the collection Lamins and Laminopathies)
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Open AccessArticle Optimization of Polycistronic Anti-CCR5 Artificial microRNA Leads to Improved Accuracy of Its Lentiviral Vector Transfer and More Potent Inhibition of HIV-1 in CD4+ T-Cells
Received: 15 December 2017 / Revised: 18 January 2018 / Accepted: 2 February 2018 / Published: 4 February 2018
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Abstract
C-C chemokine receptor type 5 (CCR5) is utilized by human immunodeficiency virus (HIV) as a co-receptor for cell entry. Suppression of the CCR5 gene by artificial microRNAs (amiRNAs) could confer cell resistance. In previous work, we created a lentivector that encoded the polycistron
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C-C chemokine receptor type 5 (CCR5) is utilized by human immunodeficiency virus (HIV) as a co-receptor for cell entry. Suppression of the CCR5 gene by artificial microRNAs (amiRNAs) could confer cell resistance. In previous work, we created a lentivector that encoded the polycistron of two identical amiRNAs that could effectively suppress CCR5. However, tandem repeats in lentiviral vectors led to deletions of the repeated sequences during reverse transcription of the vector RNA. To solve this problem, we have created a new amiRNA against CCR5, mic1002, which has a different microRNA scaffold and targets a different sequence. Replacing one of the two identical tandem amiRNAs in the polycistron with the mic1002 amiRNA increased the accuracy of its lentiviral vector transfer while retaining its ability to effectively suppress CCR5. A lentiviral vector containing two heterogenic amiRNAs significantly inhibited HIV replication in a vector-transduced human CD4+ lymphocyte culture. Full article
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Open AccessFeature PaperCommunication Identification of Novel Hemangioblast Genes in the Early Chick Embryo
Received: 10 December 2017 / Revised: 17 January 2018 / Accepted: 27 January 2018 / Published: 31 January 2018
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Abstract
During early vertebrate embryogenesis, both hematopoietic and endothelial lineages derive from a common progenitor known as the hemangioblast. Hemangioblasts derive from mesodermal cells that migrate from the posterior primitive streak into the extraembryonic yolk sac. In addition to primitive hematopoietic cells, recent evidence
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During early vertebrate embryogenesis, both hematopoietic and endothelial lineages derive from a common progenitor known as the hemangioblast. Hemangioblasts derive from mesodermal cells that migrate from the posterior primitive streak into the extraembryonic yolk sac. In addition to primitive hematopoietic cells, recent evidence revealed that yolk sac hemangioblasts also give rise to tissue-resident macrophages and to definitive hematopoietic stem/progenitor cells. In our previous work, we used a novel hemangioblast-specific reporter to isolate the population of chick yolk sac hemangioblasts and characterize its gene expression profile using microarrays. Here we report the microarray profile analysis and the identification of upregulated genes not yet described in hemangioblasts. These include the solute carrier transporters SLC15A1 and SCL32A1, the cytoskeletal protein RhoGap6, the serine protease CTSG, the transmembrane receptor MRC1, the transcription factors LHX8, CITED4 and PITX1, and the previously uncharacterized gene DIA1R. Expression analysis by in situ hybridization showed that chick DIA1R is expressed not only in yolk sac hemangioblasts but also in particular intraembryonic populations of hemogenic endothelial cells, suggesting a potential role in the hemangioblast-derived hemogenic lineage. Future research into the function of these newly identified genes may reveal novel important regulators of hemangioblast development. Full article
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