Cellular survival over genomic perfection.
Ontology highlight
ABSTRACT:
SUBMITTER: Nik-Zainal S
PROVIDER: S-EPMC6872451 | biostudies-literature | 2019 Nov
REPOSITORIES: biostudies-literature
Publications
Cellular survival over genomic perfection.
Nik-Zainal Serena S Hall Benjamin A BA
Science (New York, N.Y.) 20191101 6467
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Project description:BackgroundHuman adenoviruses, such as serotype 5 (Ad5), encode several proteins that can perturb cellular mechanisms that regulate cell cycle progression and apoptosis, as well as those that mediate mRNA production and translation. However, a global view of the effects of Ad5 infection on such programs in normal human cells is not available, despite widespread efforts to develop adenoviruses for therapeutic applications.ResultsWe used two-color hybridization and oligonucleotide microarrays to monitor changes in cellular RNA concentrations as a function of time after Ad5 infection of quiescent, normal human fibroblasts. We observed that the expression of some 2,000 genes, about 10% of those examined, increased or decreased by a factor of two or greater following Ad5 infection, but were not altered in mock-infected cells. Consensus k-means clustering established that the temporal patterns of these changes were unexpectedly complex. Gene Ontology terms associated with cell proliferation were significantly over-represented in several clusters. The results of comparative analyses demonstrate that Ad5 infection induces reversal of the quiescence program and recapitulation of the core serum response, and that only a small subset of the observed changes in cellular gene expression can be ascribed to well characterized functions of the viral E1A and E1B proteins.ConclusionThese findings establish that the impact of adenovirus infection on host cell programs is far greater than appreciated hitherto. Furthermore, they provide a new framework for investigating the molecular functions of viral early proteins and information relevant to the design of conditionally replicating adenoviral vectors.
| S-EPMC1896011 | biostudies-literature
Project description:Moving to nanoscale is a path to get perfect materials with superior properties. Yet defects, such as stacking faults (SFs), are still forming during the synthesis of nanomaterials and, according to common notion, degrade the properties. Here, we demonstrate the possibility of engineering defects to, surprisingly, achieve mechanical properties beyond those of the corresponding perfect structures. We show that introducing SFs with high density increases the Young's Modulus and the critical stress under compressive loading of the nanowires above those of a perfect structure. The physics can be explained by the increase in intrinsic strain due to the presence of SFs and overlapping of the corresponding strain fields. We have used the molecular dynamics technique and considered ZnO as our model material due to its technological importance for a wide range of electromechanical applications. The results are consistent with recent experiments and propose a novel approach for the fabrication of stronger materials.
| S-EPMC6641029 | biostudies-literature
Project description:We present results on polymorphism and perfection, as observed in the spontaneous crystallization of freely jointed polymers of hard spheres, obtained in an unprecedentedly long Monte Carlo (MC) simulation on a system of 54 chains of 1000 monomers. Starting from a purely amorphous configuration, after an initial dominance of the hexagonal closed packed (HCP) polymorph and a transitory random hexagonal close packed (rHCP) morphology, the system crystallizes in a final, stable, face centered cubic (FCC) crystal of very high perfection. An analysis of chain conformational characteristics, of the spatial distribution of monomers and of the volume accessible to them shows that the phase transition is caused by an increase in translational entropy that is larger than the loss of conformational entropy of the chains in the crystal, compared to the amorphous state. In spite of the significant local re-arrangements, as reflected in the bending and torsion angle distributions, the average chain size remains unaltered during crystallization. Polymers in the crystal adopt ideal random walk statistics as their great length renders local conformational details, imposed by the geometry of the FCC crystal, irrelevant.
| S-EPMC9612263 | biostudies-literature
Project description:Advances in long-read sequencing technologies and genome assembly methods have enabled the recent completion of the first telomere-to-telomere human genome assembly, which resolves complex segmental duplications and large tandem repeats, including centromeric satellite arrays in a complete hydatidiform mole (CHM13). Although derived from highly accurate sequences, evaluation revealed evidence of small errors and structural misassemblies in the initial draft assembly. To correct these errors, we designed a new repeat-aware polishing strategy that made accurate assembly corrections in large repeats without overcorrection, ultimately fixing 51% of the existing errors and improving the assembly quality value from 70.2 to 73.9 measured from PacBio high-fidelity and Illumina k-mers. By comparing our results to standard automated polishing tools, we outline common polishing errors and offer practical suggestions for genome projects with limited resources. We also show how sequencing biases in both high-fidelity and Oxford Nanopore Technologies reads cause signature assembly errors that can be corrected with a diverse panel of sequencing technologies.
| S-EPMC9812399 | biostudies-literature
Project description:IntroductionA majority of familial frontotemporal lobar dementia and amyotrophic lateral sclerosis cases are associated with a large repeat expansion in a non-coding region of the C9ORF72 gene. Currently, little is known about the normal function and the expression pattern of the C9ORF72 protein. The aims of this study were to characterize the expression pattern and cellular localization of the three reported mouse isoforms of C9orf72, over a developmental time-course in primary cultured cortical neurons and brain tissue from C57BL/6 mice.ResultsWe demonstrated that the different isoforms of C9ORF72 at the mRNA and protein level undergo alterations in expression during development and into adulthood. Cellular fractionation and immunofluorescence demonstrated that levels of nuclear and cytoplasmic expression of isoforms changed significantly over the time course. Additionally, immunofluorescence studies showed C9ORF72 labeling as puncta throughout neurons, extending beyond the microtubule cytoskeleton into actin-rich structures such as filopodia and growth cones. Finally, synaptosome preparations demonstrated the presence of C9ORF72 isoform 1 in synaptic-rich fractions from adult mouse brain.ConclusionIn summary, the presence of C9ORF72 as puncta and within synaptic-rich fractions may indicate involvement at the synapse and differential expression of isoforms in nuclei and cytoplasm may suggest distinct roles for the isoforms. Determining the physiological role of C9ORF72 protein may help to determine the role it plays in disease.
| S-EPMC4582620 | biostudies-literature
Project description:Comparative transcriptome profiling of fruit flesh and peel between low and high crop load treatments
| PRJNA1004866 | ENA
Project description:During early infection, viruses activate cellular stress-response proteins such as heat-shock proteins (Hsps) to counteract apoptosis, but later on, they modulate these proteins to stimulate apoptosis for efficient viral dissemination. Hsp70 has been attributed to modulate viral entry, transcription, nuclear translocation and virion formation. It also exerts its anti-apoptotic function by binding to apoptosis protease-activating factor 1 (Apaf-1) and disrupting apoptosome formation. Here, we show that influenza A virus can regulate the anti-apoptotic function of Hsp70 through viral protein M1 (matrix 1). M1 itself did not induce apoptosis, but enhanced the effects of apoptotic inducers. M1-small-interfering RNA inhibits virus-induced apoptosis in cells after either virus infection or overexpression of the M1 protein. M1 binds to Hsp70, which results in reduced interaction between Hsp70 and Apaf-1. In a cell-free system, the M1 protein mediates procaspase-9 activation induced by cytochrome c/deoxyadenosine triphosphate. A study involving deletion mutants confirmed the role of the C-terminus substrate-binding domain (EEVD) of Hsp70 and amino acids 128-165 of M1 for this association. The M1 mutants, which did not co-immunoprecipitate with Hsp70, failed to induce apoptosis. Overall, the study confirms the proapoptotic function of the M1 protein during influenza virus infection.
| S-EPMC3186897 | biostudies-literature
Project description:Colloidal superlattices are fascinating materials made of ordered nanocrystals, yet they are rarely called "atomically precise". That is unsurprising, given how challenging it is to quantify the degree of structural order in these materials. However, once that order crosses a certain threshold, the constructive interference of X-rays diffracted by the nanocrystals dominates the diffraction pattern, offering a wealth of structural information. By treating nanocrystals as scattering sources forming a self-probing interferometer, we developed a multilayer diffraction method that enabled the accurate determination of the nanocrystal size, interparticle spacing, and their fluctuations for samples of self-assembled CsPbBr3 and PbS nanomaterials. The multilayer diffraction method requires only a laboratory-grade diffractometer and an open-source fitting algorithm for data analysis. The average nanocrystal displacement of 0.33 to 1.43 Å in the studied superlattices provides a figure of merit for their structural perfection and approaches the atomic displacement parameters found in traditional crystals.
| S-EPMC8155329 | biostudies-literature
Project description:Although much is known about the regulation of eukaryotic transcription, the global controls which determine rates of total transcription within a cell are not well understood. We have investigated the effects that the DNA to protein ratio has on both total cellular transcription and the transcription of individual mRNA genes in the unicellular eukaryote fission yeast. Mutants altered in cell size and those blocked in cell cycle progression were used to vary the DNA to protein ratio over a fivefold range around the wild type value. We find that cells of sizes within twofold of wild type value regulate global transcription to maintain similar transcription rates per protein regardless of the cellular DNA content. These changes in total transcription were correlated with coordinated changes in gene occupancy by RNA polymerase II. In large cell cycle arrested mutants, when the DNA to protein ratio falls to a low level, total transcription rates plateau as DNA becomes limiting for transcription1. Unexpectedly, expression levels of individual genes remained tightly coordinated with each other over the entire range of cell sizes. We propose that there is a coordinated, global cellular control which determines the rate of transcription of most genes in the genome and that this control plays a role in regulating the overall growth rate of the cell. Normalized data generated using protocol P-TABM-1335 is available in file ZHURINSKY_NORMALISED_DATA.txt in the additional data archive.
2011-09-23 | E-TABM-1075 | biostudies-arrayexpress
Project description:Oxygen is a key modulator of many cellular pathways, but current devices permitting in vitro oxygen modulation fail to meet the needs of biomedical research. A microfabricated insert for multiwell plates has been developed to more effectively control the temporal and spatial oxygen concentration to better model physiological phenomena found in vivo. The platform consists of a polydimethylsiloxane insert that nests into a standard multiwell plate and serves as a passive microfluidic gas network with a gas-permeable membrane aimed to modulate oxygen delivery to adherent cells. Equilibration time is on the order of minutes and a wide variety of oxygen profiles can be attained based on the device design, such as the cyclic profile achieved in this study, and even oxygen gradients to mimic those found in vivo. The proper biological consequences of the device's oxygen delivery were confirmed in cellular models via a proliferation assay and western analysis of the upregulation of hypoxia inducible transcription factor-1alpha. These experiments serve as a demonstration for the platform as a viable tool to increase experimental throughput and permit novel experimental possibilities in any biomedical research lab.
| S-EPMC2731542 | biostudies-literature