The Importance of DNA Repair in Tumor Suppression

The transition from a normal to cancerous cell requires a number of highly specific mutations that affect cell cycle regulation, apoptosis, differentiation, and many other cell functions. One hallmark of cancerous genomes is genomic instability, with mutation rates far greater than those of normal cells. In microsatellite instability (MIN tumors), these are often caused by damage to mismatch repair genes, allowing further mutation of the genome and tumor progression. These mutation rates may lie near the error catastrophe found in the quasispecies model of adaptive RNA genomes, suggesting that further increasing mutation rates will destroy cancerous genomes. However, recent results have demonstrated that DNA genomes exhibit an error threshold at mutation rates far lower than their conservative counterparts. Furthermore, while the maximum viable mutation rate in conservative systems increases indefinitely with increasing master sequence fitness, the semiconservative threshold plateaus at a relatively low value. This implies a paradox, wherein inaccessible mutation rates are found in viable tumor cells. In this paper, we address this paradox, demonstrating an isomorphism between the conservatively replicating (RNA) quasispecies model and the semiconservative (DNA) model with post-methylation DNA repair mechanisms impaired. Thus, as DNA repair becomes inactivated, the maximum viable mutation rate increases smoothly to that of a conservatively replicating system on a transformed landscape, with an upper bound that is dependent on replication rates. We postulate that inactivation of post-methylation repair mechanisms are fundamental to the progression of a tumor cell and hence these mechanisms act as a method for prevention and destruction of cancerous genomes.Comment: 7 pages, 5 figures; Approximation replaced with exact calculation; Minor error corrected; Minor changes to model syste

Computational models for inferring biochemical networks

Biochemical networks are of great practical importance. The interaction of biological compounds in cells has been enforced to a proper understanding by the numerous bioinformatics projects, which contributed to a vast amount of biological information. The construction of biochemical systems (systems of chemical reactions), which include both topology and kinetic constants of the chemical reactions, is NP-hard and is a well-studied system biology problem. In this paper, we propose a hybrid architecture, which combines genetic programming and simulated annealing in order to generate and optimize both the topology (the network) and the reaction rates of a biochemical system. Simulations and analysis of an artificial model and three real models (two models and the noisy version of one of them) show promising results for the proposed method.The Romanian National Authority for Scientific Research, CNDI–UEFISCDI, Project No. PN-II-PT-PCCA-2011-3.2-0917

A phenomenological approach to the simulation of metabolism and proliferation dynamics of large tumour cell populations

A major goal of modern computational biology is to simulate the collective behaviour of large cell populations starting from the intricate web of molecular interactions occurring at the microscopic level. In this paper we describe a simplified model of cell metabolism, growth and proliferation, suitable for inclusion in a multicell simulator, now under development (Chignola R and Milotti E 2004 Physica A 338 261-6). Nutrients regulate the proliferation dynamics of tumor cells which adapt their behaviour to respond to changes in the biochemical composition of the environment. This modeling of nutrient metabolism and cell cycle at a mesoscopic scale level leads to a continuous flow of information between the two disparate spatiotemporal scales of molecular and cellular dynamics that can be simulated with modern computers and tested experimentally.Comment: 58 pages, 7 figures, 3 tables, pdf onl

Spectral decomposition of internal gravity wave sea surface height in global models

Two global ocean models ranging in horizontal resolution from 1/12° to 1/48° are used to study the space and time scales of sea surface height (SSH) signals associated with internal gravity waves (IGWs). Frequency‐horizontal wavenumber SSH spectral densities are computed over seven regions of the world ocean from two simulations of the HYbrid Coordinate Ocean Model (HYCOM) and three simulations of the Massachusetts Institute of Technology general circulation model (MITgcm). High wavenumber, high‐frequency SSH variance follows the predicted IGW linear dispersion curves. The realism of high‐frequency motions (>0.87  cpd) in the models is tested through comparison of the frequency spectral density of dynamic height variance computed from the highest‐resolution runs of each model (1/25° HYCOM and 1/48° MITgcm) with dynamic height variance frequency spectral density computed from nine in situ profiling instruments. These high‐frequency motions are of particular interest because of their contributions to the small‐scale SSH variability that will be observed on a global scale in the upcoming Surface Water and Ocean Topography (SWOT) satellite altimetry mission. The variance at supertidal frequencies can be comparable to the tidal and low‐frequency variance for high wavenumbers (length scales smaller than ∼50 km), especially in the higher‐resolution simulations. In the highest‐resolution simulations, the high‐frequency variance can be greater than the low‐frequency variance at these scales.Key PointsTwo high‐resolution ocean models compare well against data in frequency spectral density of dynamic heightSea surface height frequency‐horizontal wavenumber spectral densities show high variance along internal gravity wave dispersion curvesTwo high‐resolution ocean models give different estimates of variance in high‐frequency, high wavenumber phenomenaPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/1/jgrc22465-sup-0002-2017JC013009-fs01.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/2/jgrc22465-sup-0003-2017JC013009-fs02.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/3/jgrc22465_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/4/jgrc22465.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/5/jgrc22465-sup-0007-2017JC013009-fs06.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/6/jgrc22465-sup-0009-2017JC013009-fs08.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/7/jgrc22465-sup-0004-2017JC013009-fs03.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/8/jgrc22465-sup-0005-2017JC013009-fs04.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/9/jgrc22465-sup-0006-2017JC013009-fs05.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/10/jgrc22465-sup-0001-2017JC013009-s01.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/11/jgrc22465-sup-0008-2017JC013009-fs07.pd

Interstitial Cell Remodeling Promotes Aberrant Adipogenesis in Dystrophic Muscles.

Fibrosis and fat replacement in skeletal muscle are major complications that lead to a loss of mobility in chronic muscle disorders, such as muscular dystrophy. However, the in vivo properties of adipogenic stem and precursor cells remain unclear, mainly due to the high cell heterogeneity in skeletal muscles. Here, we use single-cell RNA sequencing to decomplexify interstitial cell populations in healthy and dystrophic skeletal muscles. We identify an interstitial CD142-positive cell population in mice and humans that is responsible for the inhibition of adipogenesis through GDF10 secretion. Furthermore, we show that the interstitial cell composition is completely altered in muscular dystrophy, with a near absence of CD142-positive cells. The identification of these adipo-regulatory cells in the skeletal muscle aids our understanding of the aberrant fat deposition in muscular dystrophy, paving the way for treatments that could counteract degeneration in patients with muscular dystrophy

Molecular crowding defines a common origin for the Warburg effect in proliferating cells and the lactate threshold in muscle physiology

Aerobic glycolysis is a seemingly wasteful mode of ATP production that is seen both in rapidly proliferating mammalian cells and highly active contracting muscles, but whether there is a common origin for its presence in these widely different systems is unknown. To study this issue, here we develop a model of human central metabolism that incorporates a solvent capacity constraint of metabolic enzymes and mitochondria, accounting for their occupied volume densities, while assuming glucose and/or fatty acid utilization. The model demonstrates that activation of aerobic glycolysis is favored above a threshold metabolic rate in both rapidly proliferating cells and heavily contracting muscles, because it provides higher ATP yield per volume density than mitochondrial oxidative phosphorylation. In the case of muscle physiology, the model also predicts that before the lactate switch, fatty acid oxidation increases, reaches a maximum, and then decreases to zero with concomitant increase in glucose utilization, in agreement with the empirical evidence. These results are further corroborated by a larger scale model, including biosynthesis of major cell biomass components. The larger scale model also predicts that in proliferating cells the lactate switch is accompanied by activation of glutaminolysis, another distinctive feature of the Warburg effect. In conclusion, intracellular molecular crowding is a fundamental constraint for cell metabolism in both rapidly proliferating- and non-proliferating cells with high metabolic demand. Addition of this constraint to metabolic flux balance models can explain several observations of mammalian cell metabolism under steady state conditions

Increase of Direct C-C Coupling Reaction Yield by Identifying Structural and Electronic Properties of High-Spin Iron Tetra-azamacrocyclic Complexes

Macrocyclic ligands have been explored extensively as scaffolds for transition metal catalysts for oxygen and hydrogen atom transfer reactions. C–C reactions facilitated using earth abundant metals bound to macrocyclic ligands have not been well-understood but could be a green alternative to replacing the current expensive and toxic precious metal systems most commonly used for these processes. Therefore, the yields from direct Suzuki–Miyaura C–C coupling of phenylboronic acid and pyrrole to produce 2-phenylpyrrole facilitated by eight high-spin iron complexes ([Fe3+L1(Cl)2]+, [Fe3+L4(Cl)2]+, [Fe2+L5(Cl)]+, [Fe2+L6(Cl)2], [Fe3+L7(Cl)2]+, [Fe3+L8(Cl)2]+, [Fe2+L9(Cl)]+, and [Fe2+L10(Cl)]+) were compared to identify the effect of structural and electronic properties on catalytic efficiency. Specifically, catalyst complexes were compared to evaluate the effect of five properties on catalyst reaction yields: (1) the coordination requirements of the catalyst, (2) redox half-potential of each complex, (3) topological constraint/rigidity, (4) N atom modification(s) increasing oxidative stability of the complex, and (5) geometric parameters. The need for two labile cis-coordination sites was confirmed based on a 42% decrease in catalytic reaction yield observed when complexes containing pentadentate ligands were used in place of complexes with tetradentate ligands. A strong correlation between iron(III/II) redox potential and catalytic reaction yields was also observed, with [Fe2+L6(Cl)2] providing the highest yield (81%, −405 mV). A Lorentzian fitting of redox potential versus yields predicts that these catalysts can undergo more fine-tuning to further increase yields. Interestingly, the remaining properties explored did not show a direct, strong relationship to catalytic reaction yields. Altogether, these results show that modifications to the ligand scaffold using fundamental concepts of inorganic coordination chemistry can be used to control the catalytic activity of macrocyclic iron complexes by controlling redox chemistry of the iron center. Furthermore, the data provide direction for the design of improved catalysts for this reaction and strategies to understand the impact of a ligand scaffold on catalytic activity of other reactions

Combined Single-Cell Functional and Gene Expression Analysis Resolves Heterogeneity within Stem Cell Populations.

Heterogeneity within the self-renewal durability of adult hematopoietic stem cells (HSCs) challenges our understanding of the molecular framework underlying HSC function. Gene expression studies have been hampered by the presence of multiple HSC subtypes and contaminating non-HSCs in bulk HSC populations. To gain deeper insight into the gene expression program of murine HSCs, we combined single-cell functional assays with flow cytometric index sorting and single-cell gene expression assays. Through bioinformatic integration of these datasets, we designed an unbiased sorting strategy that separates non-HSCs away from HSCs, and single-cell transplantation experiments using the enriched population were combined with RNA-seq data to identify key molecules that associate with long-term durable self-renewal, producing a single-cell molecular dataset that is linked to functional stem cell activity. Finally, we demonstrated the broader applicability of this approach for linking key molecules with defined cellular functions in another stem cell system.Work in the author’s laboratory is supported by grants from the Leukaemia and Lymphoma Research, the Medical Research Council, Cancer Research UK, Biotechnology and Biological Sciences Research Council, Leukemia Lymphoma Society, and the National Institute for Health Research Cambridge Biomedical Research Centre and core support grants by the Wellcome Trust to the Cambridge Institute for Medical Research and Wellcome Trust-MRC Cambridge Stem Cell Institute. D.G.K. is the recipient of a Canadian Institutes of Health Research Postdoctoral Fellowship. F.B. and F.J.T. are funded by the European Research Council (starting grant “LatentCauses”). For funding for the open access charge, the core support grant was provided by the Wellcome Trust-MRC Cambridge Stem Cell Institute. We acknowledge the support of the University of Cambridge, Cancer Research UK Institute (core grant C14303/A17197), and Hutchison Whampoa Limited.This is the final published version. It first appeared at http://www.cell.com/cell-stem-cell/abstract/S1934-5909%2815%2900162-9