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Correction: Path Similarity Analysis: A Method for Quantifying Macromolecular Pathways
[This corrects the article DOI: 10.1371/journal.pcbi.1004568.].
Journal Article
Senescence and cancer — role and therapeutic opportunities
Cellular senescence is a state of stable, terminal cell cycle arrest associated with various macromolecular changes and a hypersecretory, pro-inflammatory phenotype. Entry of cells into senescence can act as a barrier to tumorigenesis and, thus, could in principle constitute a desired outcome for any anticancer therapy. Paradoxically, studies published in the past decade have demonstrated that, in certain conditions and contexts, malignant and non-malignant cells with lastingly persistent senescence can acquire pro-tumorigenic properties. In this Review, we first discuss the major mechanisms involved in the antitumorigenic functions of senescent cells and then consider the cell-intrinsic and cell-extrinsic factors that participate in their switch towards a tumour-promoting role, providing an overview of major translational and emerging clinical findings. Finally, we comprehensively describe various senolytic and senomorphic therapies and their potential to benefit patients with cancer.The entry of cells into senescence can act as a barrier to tumorigenesis; however, in certain contexts senescent malignant and non-malignant cells can acquire pro-tumorigenic properties. The authors of this Review discuss the cell-intrinsic and cell-extrinsic mechanisms involved in both the antitumorigenic and tumour-promoting roles of senescent cells, and describe the potential of various senolytic and senomorphic therapeutic approaches in oncology.
Journal Article
Marine Biological Macromolecules and Chemically Modified Macromolecules; Potential Anticoagulants
Coagulation is a potential defense mechanism that involves activating a series of zymogens to convert soluble fibrinogen to insoluble fibrin clots to prevent bleeding and hemorrhagic complications. To prevent the extra formation and diffusion of clots, the counterbalance inhibitory mechanism is activated at levels of the coagulation pathway. Contrariwise, this system can evade normal control due to either inherited or acquired defects or aging which leads to unusual clots formation. The abnormal formations and deposition of excess fibrin trigger serious arterial and cardiovascular diseases. Although heparin and heparin-based anticoagulants are a widely prescribed class of anticoagulants, the clinical use of heparin has limitations due to the unpredictable anticoagulation, risk of bleeding, and other complications. Hence, significant interest has been established over the years to investigate alternative therapeutic anticoagulants from natural sources, especially from marine sources with good safety and potency due to their unique chemical structure and biological activity. This review summarizes the coagulation cascade and potential macromolecular anticoagulants derived from marine flora and fauna.
Journal Article
Critical population and error threshold on the sharp peak landscape for a Moran model
The goal of this work is to propose a finite population counterpart to Eigen's model, which incorporates stochastic effects. The author considers a Moran model describing the evolution of a population of size m of chromosomes of length \\ell over an alphabet of cardinality \\kappa. The mutation probability per locus is q. He deals only with the sharp peak landscape: the replication rate is \\sigma>1 for the master sequence and 1 for the other sequences. He studies the equilibrium distribution of the process in the regime where \\ell\\to +\\infty,\\qquad m\\to +\\infty,\\qquad q\\to 0, {\\ell q} \\to a\\in ]0,+\\infty[, \\qquad\\frac{m}{\\ell}\\to\\alpha\\in [0,+\\infty].
eBook
The molecular basis for cellular function of intrinsically disordered protein regions
Intrinsically disordered protein regions exist in a collection of dynamic interconverting conformations that lack a stable 3D structure. These regions are structurally heterogeneous, ubiquitous and found across all kingdoms of life. Despite the absence of a defined 3D structure, disordered regions are essential for cellular processes ranging from transcriptional control and cell signalling to subcellular organization. Through their conformational malleability and adaptability, disordered regions extend the repertoire of macromolecular interactions and are readily tunable by their structural and chemical context, making them ideal responders to regulatory cues. Recent work has led to major advances in understanding the link between protein sequence and conformational behaviour in disordered regions, yet the link between sequence and molecular function is less well defined. Here we consider the biochemical and biophysical foundations that underlie how and why disordered regions can engage in productive cellular functions, provide examples of emerging concepts and discuss how protein disorder contributes to intracellular information processing and regulation of cellular function.Intrinsically disordered regions of proteins lack a defined 3D structure and exist in a collection of interconverting conformations. Recent work is shedding light on how — through their conformational malleability and adaptability — intrinsically disordered regions extend the repertoire of macromolecular interactions in the cell and contribute to key cellular functions.
Journal Article
On the Focusing Mechanism in Thermal Field-Flow Fractionation of Macromolecules
The potential of separation of the macromolecules in solution by focusing thermal field-flow fractionation is critically analyzed. The experimental conditions of the high-performance separations of particulate species by this technique were extensively studied in the past and are well determined. On the other hand, very scarce and contradictory knowledge exists on the effective use of focusing thermal field-flow fractionation for the separation of macromolecules in solution. An important requirement is to apply the sufficient relaxation time to establish the initial steady-state distribution of the sample across the separation channel thickness, as close to the accumulation wall as possible, otherwise a serious zone broadening and false retention may occur. The concentration of the fractionated sample solution should be minimal, but allowing an accurate detector response, to avoid the viscous fingering and Rayleigh–Taylor hydrodynamic instabilities, and it should not exceed the critical concentration at which the macromolecular chains begin to overlap. The important conditions which enable or limit such separations are discussed.
Journal Article
Gut microbiota in colorectal cancer development and therapy
Colorectal cancer (CRC) is one of the commonest cancers globally. A unique aspect of CRC is its intimate association with the gut microbiota, which forms an essential part of the tumour microenvironment. Research over the past decade has established that dysbiosis of gut bacteria, fungi, viruses and Archaea accompanies colorectal tumorigenesis, and these changes might be causative. Data from mechanistic studies demonstrate the ability of the gut microbiota to interact with the colonic epithelia and immune cells of the host via the release of a diverse range of metabolites, proteins and macromolecules that regulate CRC development. Preclinical and some clinical evidence also underscores the role of the gut microbiota in modifying the therapeutic responses of patients with CRC to chemotherapy and immunotherapy. Herein, we summarize our current understanding of the role of gut microbiota in CRC and outline the potential translational and clinical implications for CRC diagnosis, prevention and treatment. Emphasis is placed on how the gut microbiota could now be better harnessed by developing targeted microbial therapeutics as chemopreventive agents against colorectal tumorigenesis, as adjuvants for chemotherapy and immunotherapy to boost drug efficacy and safety, and as non-invasive biomarkers for CRC screening and patient stratification. Finally, we highlight the hurdles and potential solutions to translating our knowledge of the gut microbiota into clinical practice.Emerging data indicate a central role for the microbiota in all aspects of colorectal cancer (CRC). Despite this general consensus, understanding the role of specific components of the microbiota in such a way that enables the development of clinical interventions or tools to inform clinical decision-making has thus far proved challenging. In this Review, the authors summarize the role of the microbiota in CRC, including in prevention, in interactions with treatment and as a source of novel biomarkers.
Journal Article