scholarly journals Origins and Consequences of Chromosomal Instability: From Cellular Adaptation to Genome Chaos-Mediated System Survival

Genes ◽  
2020 ◽  
Vol 11 (10) ◽  
pp. 1162 ◽  
Author(s):  
Christine J. Ye ◽  
Zachary Sharpe ◽  
Henry H. Heng
Keyword(s):  
Chromosomal Instability ◽  
Molecular Mechanisms ◽  
Evolutionary Model ◽  
Common Mechanism ◽  
Cancer Evolution ◽  
Two Phase ◽  
Cellular Adaptation ◽  
Somatic Evolution ◽  
New Research ◽  
Genome Chaos

When discussing chromosomal instability, most of the literature focuses on the characterization of individual molecular mechanisms. These studies search for genomic and environmental causes and consequences of chromosomal instability in cancer, aiming to identify key triggering factors useful to control chromosomal instability and apply this knowledge in the clinic. Since cancer is a phenomenon of new system emergence from normal tissue driven by somatic evolution, such studies should be done in the context of new genome system emergence during evolution. In this perspective, both the origin and key outcome of chromosomal instability are examined using the genome theory of cancer evolution. Specifically, chromosomal instability was linked to a spectrum of genomic and non-genomic variants, from epigenetic alterations to drastic genome chaos. These highly diverse factors were then unified by the evolutionary mechanism of cancer. Following identification of the hidden link between cellular adaptation (positive and essential) and its trade-off (unavoidable and negative) of chromosomal instability, why chromosomal instability is the main player in the macro-cellular evolution of cancer is briefly discussed. Finally, new research directions are suggested, including searching for a common mechanism of evolutionary phase transition, establishing chromosomal instability as an evolutionary biomarker, validating the new two-phase evolutionary model of cancer, and applying such a model to improve clinical outcomes and to understand the genome-defined mechanism of organismal evolution.

scholarly journals Micronuclei and Genome Chaos: Changing the System Inheritance

Genes ◽  
2019 ◽  
Vol 10 (5) ◽  
pp. 366 ◽  
Author(s):  
Christine J. Ye ◽  
Zachary Sharpe ◽  
Sarah Alemara ◽  
Stephanie Mackenzie ◽  
Guo Liu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Genome Instability ◽  
Common Mechanism ◽  
Cancer Evolution ◽  
Somatic Evolution ◽  
Causative Relationship ◽  
Key Issues ◽  
The Common ◽  
Genome Chaos ◽  
Genome Theory

Micronuclei research has regained its popularity due to the realization that genome chaos, a rapid and massive genome re-organization under stress, represents a major common mechanism for punctuated cancer evolution. The molecular link between micronuclei and chromothripsis (one subtype of genome chaos which has a selection advantage due to the limited local scales of chromosome re-organization), has recently become a hot topic, especially since the link between micronuclei and immune activation has been identified. Many diverse molecular mechanisms have been illustrated to explain the causative relationship between micronuclei and genome chaos. However, the newly revealed complexity also causes confusion regarding the common mechanisms of micronuclei and their impact on genomic systems. To make sense of these diverse and even conflicting observations, the genome theory is applied in order to explain a stress mediated common mechanism of the generation of micronuclei and their contribution to somatic evolution by altering the original set of information and system inheritance in which cellular selection functions. To achieve this goal, a history and a current new trend of micronuclei research is briefly reviewed, followed by a review of arising key issues essential in advancing the field, including the re-classification of micronuclei and how to unify diverse molecular characterizations. The mechanistic understanding of micronuclei and their biological function is re-examined based on the genome theory. Specifically, such analyses propose that micronuclei represent an effective way in changing the system inheritance by altering the coding of chromosomes, which belongs to the common evolutionary mechanism of cellular adaptation and its trade-off. Further studies of the role of micronuclei in disease need to be focused on the behavior of the adaptive system rather than specific molecular mechanisms that generate micronuclei. This new model can clarify issues important to stress induced micronuclei and genome instability, the formation and maintenance of genomic information, and cellular evolution essential in many common and complex diseases such as cancer.

scholarly journals Genome Chaos, Information Creation, and Cancer Emergence: Searching for New Frameworks on the 50th Anniversary of the “War on Cancer”

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 101
Author(s):  
Julie Heng ◽  
Henry H. Heng
Keyword(s):  
Cancer Research ◽  
Cancer Biology ◽  
Molecular Mechanisms ◽  
50Th Anniversary ◽  
Genome Project ◽  
Cancer Genes ◽  
Cancer Evolution ◽  
Volume Data ◽  
Architecture Theory ◽  
Genome Chaos

The year 2021 marks the 50th anniversary of the National Cancer Act, signed by President Nixon, which declared a national “war on cancer.” Powered by enormous financial support, this past half-century has witnessed remarkable progress in understanding the individual molecular mechanisms of cancer, primarily through the characterization of cancer genes and the phenotypes associated with their pathways. Despite millions of publications and the overwhelming volume data generated from the Cancer Genome Project, clinical benefits are still lacking. In fact, the massive, diverse data also unexpectedly challenge the current somatic gene mutation theory of cancer, as well as the initial rationales behind sequencing so many cancer samples. Therefore, what should we do next? Should we continue to sequence more samples and push for further molecular characterizations, or should we take a moment to pause and think about the biological meaning of the data we have, integrating new ideas in cancer biology? On this special anniversary, we implore that it is time for the latter. We review the Genome Architecture Theory, an alternative conceptual framework that departs from gene-based theories. Specifically, we discuss the relationship between genes, genomes, and information-based platforms for future cancer research. This discussion will reinforce some newly proposed concepts that are essential for advancing cancer research, including two-phased cancer evolution (which reconciles evolutionary contributions from karyotypes and genes), stress-induced genome chaos (which creates new system information essential for macroevolution), the evolutionary mechanism of cancer (which unifies diverse molecular mechanisms to create new karyotype coding during evolution), and cellular adaptation and cancer emergence (which explains why cancer exists in the first place). We hope that these ideas will usher in new genomic and evolutionary conceptual frameworks and strategies for the next 50 years of cancer research.

Multiple mechanisms are responsible for altered expression of gap junction genes during oncogenesis in rat liver

1994 ◽  
Vol 107 (1) ◽  
pp. 83-95
Author(s):  
M.J. Neveu ◽  
J.R. Hully ◽  
K.L. Babcock ◽  
E.L. Hertzberg ◽  
B.J. Nicholson ◽  
...  
Keyword(s):  
Gap Junction ◽  
Cellular Localization ◽  
Molecular Mechanisms ◽  
Northern Blotting ◽  
Mrna Abundance ◽  
Common Mechanism ◽  
Cx43 Expression ◽  
Bile Duct Proliferation ◽  
Altered Expression ◽  
Connexin Expression

Although several abnormalities in gap junction (GJ) structure and/or function have been described in neoplasms, the molecular mechanisms responsible for many of the alterations remain unknown. The identification of a family of GJ proteins, termed connexins, prompted this study of connexin32 (Cx32), connexin26 (Cx26) and connexin43 (Cx43) expression during rat hepatocarcinogenesis. Using antibody, cDNA and cRNA probes, we investigated connexin mRNA and protein expression in preneoplastic and neoplastic rat livers. In normal liver, Cx32 is expressed in hepatocytes throughout the hepatic acinus, Cx26 is restricted to periportal hepatocytes, and Cx43 is expressed by mesothelial cells forming Glisson's capsule. Most preneoplastic altered hepatic foci generated by diethylnitrosamine (DEN) initiation and either phenobarbital (PB) or 2,3,7,8-dichlorodibenzo-p-dioxin (TCDD) promotion exhibited decreased Cx32 or increased Cx26 staining. Foci from either protocol failed to display Cx43 immunoreactivity. In the majority of PB-promoted foci, Cx32 immunoreactivity decreased independently of changes in mRNA abundance. Continuous thymidine labeling, following cessation of PB promotion, showed that downregulation of Cx32 staining is reversible in foci that are promoter-dependent for growth, but irreversible in lesions that are promoter-independent for growth. Hepatic neoplasms from rats initiated with DEN and promoted with PB or TCDD also displayed modified connexin expression. While all 24 neoplasms studied were deficient in normal punctate Cx32 and Cx26 staining, altered cellular localization of these proteins was apparent in some tumors. Immunoblotting of crude tissue extracts revealed that neoplasms with disordered Cx32 staining showed immunoreactive bands with altered electrophoretic mobility. These observations show that hepatomas may downregulate Cx32 expression through changes in the primary structure of Cx32 or by post-translational modifications. Northern blotting of total tumor mRNAs failed to demonstrate consistent changes in the abundance of Cx32, Cx26 or Cx43 transcripts. Some tumors expressed steady-state transcripts without observable immunoreactivity, indicating that some hepatomas downregulate connexin immunoreactivity independently of mRNA abundance. Increased levels of Cx43 mRNA and protein were found in several neoplasms, but immunostaining was always localized to nonparenchymal cells. Areas of bile duct proliferation and cholangiomas displayed Cx43 staining, whereas, cholangiocarcinomas were deficient in immunoreactivity. These findings show that alterations in the expression of connexins, by either downregulation or differential induction, represent common modifications during hepatocarcinogenesis. Although our results imply that connexins represent useful markers for the boundary between tumor promotion and progression, preneoplastic and neoplastic rat hepatocytes fail to use a common mechanism to modify connexin expression.

Cross-species Transcriptomes Reveal Species-specific and Shared Molecular Adaptations for Plants Development on Iron-rich Rocky Outcrops Soils

2021 ◽  
Author(s):  
Mariana Costa Dias ◽  
Cecílio Caldeira ◽  
Markus Gastauer ◽  
Silvio Ramos ◽  
Guilherme Oliveira
Keyword(s):  
Circadian Rhythm ◽  
Differential Expression ◽  
Native Species ◽  
Molecular Mechanisms ◽  
Light Stimulus ◽  
Differential Expression Analysis ◽  
Common Mechanism ◽  
Dependent Manner ◽  
Rocky Outcrops ◽  
Species Specific

Abstract BackgroundCanga is the Brazilian term for the savanna-like vegetation harboring several endemic species on iron-rich rocky outcrops, usually considered for mining activities. Parkia platycephala Benth. and Stryphnodendron pulcherrimum (Willd.) Hochr. naturally occur in the cangas of Serra dos Carajás (eastern Amazonia, Brazil) and the surrounding forest, indicating high phenotypic plasticity. The morphological and physiological mechanisms of the plants’ establishment in the canga environment are well studied, but the molecular adaptative responses are still unknown. We aimed to identify molecular mechanisms that allow the establishment of these plants in the canga environment.ResultsPlants were grown in canga and forest substrates collected in the Carajás Mineral Province. RNA was extracted from pooled leaf tissue, and RNA-seq paired-end reads were assembled into representative transcriptomes for P. platycephala and S. pulcherrimum containing 31,728 and 31,311 primary transcripts, respectively. We identified both species-specific and core molecular responses in plants grown in the canga substrate using differential expression analyses. In the species-specific analysis, we identified 1,112 and 838 differentially expressed genes for P. platycephala and S. pulcherrimum, respectively. Enrichment analyses showed unique biological processes and metabolic pathways affected for each species. Comparative differential expression analysis was based on shared single-copy orthologs. The overall pattern of ortholog expression was species-specific. Even so, almost 300 altered genes were identified between plants in canga and forest substrates, responding the same way in both species. The genes were functionally associated with the response to light stimulus and the circadian rhythm pathway.ConclusionsPlants possess species-specific adaptative responses to cope with the substrates. Our results also suggest that plants adapted to both canga and forest environments can adjust the circadian rhythm in a substrate-dependent manner. The circadian clock gene modulation might be a central mechanism regulating the plants’ development in the canga substrate in the studied legume species. The mechanism may be shared as a common mechanism to abiotic stress compensation in other native species.

Analysis of the molecular mechanisms by flavonoids with potential use for osteoporosis prevention or therapy

2021 ◽  
Vol 28 ◽  
Author(s):  
Valeria Rodríguez ◽  
María Rivoira ◽  
Gabriela Picotto ◽  
Gabriela Díaz de Barboza ◽  
Alejandro Collin ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Osteoporosis Treatment ◽  
Epidemiological Studies ◽  
Common Mechanism ◽  
Osteoporotic Bone ◽  
Osteoporosis Prevention ◽  
Mineral Density ◽  
Pubmed Database ◽  
Molecular Aspects ◽  
Potential Use

Background: Osteoporosis is the most common skeletal disorder worldwide. Flavonoids have the potential to alleviate bone alterations in osteoporotic patients with the advantage of being safer and less expensive than the conventional therapies. Objective: The main objective is to analyze the molecular mechanisms triggered in bone by different subclasses of flavonoids. In addition, this review provides an up-to-date overview on the cellular and molecular aspects of osteoporotic bones versus healthy bones, and a brief description of some epidemiological studies indicating that flavonoids could be useful for osteoporosis treatment. Methods: The PubMed database was searched in the range of years 2001- 2021 using the keywords osteoporosis, flavonoids, and their subclasses such as flavones, flavonols, flavanols, isoflavones, flavanones and anthocyanins, focusing the data on the molecular mechanisms triggered in bone. Results: Although flavonoids comprise many compounds that differ in structure, their effects on bone loss in postmenopausal women or in ovariectomized-induced osteoporotic animals are quite similar. Most of them increase bone mineral density and bone strength, which occur through enhancement of osteoblastogenesis and osteoclast apoptosis, decrease in osteoclastogenesis as well as increase in neovascularization on the site of the osteoporotic fracture. Conclusion: Several molecules of signaling pathways are involved in the effect of flavonoids on osteoporotic bone. Whether all flavonoids have a common mechanism or they act as ligands of estrogen receptors remain to be established. More clinical trials are necessary to know better their safety, efficacy, delivery and bioavailability in humans, as well as comparative studies with conventional therapies.

Convolutional Neural Networks for the Localization of Plastic Velocity Gradient Tensor in Polycrystalline Microstructures

2021 ◽  
pp. 1-41
Author(s):  
David Montes de Oca Zapiain ◽  
Apaar Shanker ◽  
Surya Kalidindi
Keyword(s):  
Neural Networks ◽  
Convolutional Neural Networks ◽  
Velocity Gradient ◽  
Optimization Problems ◽  
Computational Cost ◽  
Two Phase ◽  
Design And Optimization ◽  
Gradient Fields ◽  
Generalized Spherical Harmonics ◽  
New Research

Abstract Recent work has demonstrated the potential of convolutional neural networks (CNNs) in producing low-computational cost surrogate models for the localization of mechanical fields in two-phase microstructures. The extension of the same CNNs to polycrystalline microstructures is hindered by the lack of an efficient formalism for the representation of the crystal lattice orientation in the input channels of the CNNs. In this paper, we demonstrate the benefits of using generalized spherical harmonics (GSH) for addressing this challenge. A CNN model was successfully trained to predict the local plastic velocity gradient fields in polycrystalline microstructures subjected to a macroscopically imposed loading condition. Specifically, it is demonstrated that the proposed approach improves significantly the accuracy of the CNN models, when compared with the direct use of Bunge-Euler angles to represent the crystal orientations in the input channels. Since the proposed approach implicitly satisfies the expected crystal symmetries in the specification of the input microstructure to the CNN, it opens new research directions for the adoption of CNNs in addressing a broad range of polycrystalline microstructure design and optimization problems.

scholarly journals Understanding the Effects of General Anesthetics on Cortical Network Activity Using Ex Vivo Preparations

2019 ◽  
Vol 130 (6) ◽  
pp. 1049-1063 ◽  
Author(s):  
Logan J. Voss ◽  
Paul S. García ◽  
Harald Hentschke ◽  
Matthew I. Banks
Keyword(s):  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Brain Slices ◽  
Brain Regions ◽  
Cortical Network ◽  
Network Activity ◽  
Common Mechanism ◽  
General Anesthetics ◽  
Neural Basis

Abstract General anesthetics have been used to ablate consciousness during surgery for more than 150 yr. Despite significant advances in our understanding of their molecular-level pharmacologic effects, comparatively little is known about how anesthetics alter brain dynamics to cause unconsciousness. Consequently, while anesthesia practice is now routine and safe, there are many vagaries that remain unexplained. In this paper, the authors review the evidence that cortical network activity is particularly sensitive to general anesthetics, and suggest that disruption to communication in, and/or among, cortical brain regions is a common mechanism of anesthesia that ultimately produces loss of consciousness. The authors review data from acute brain slices and organotypic cultures showing that anesthetics with differing molecular mechanisms of action share in common the ability to impair neurophysiologic communication. While many questions remain, together, ex vivo and in vivo investigations suggest that a unified understanding of both clinical anesthesia and the neural basis of consciousness is attainable.

scholarly journals Cyclophilin a as a Mediator of Tissue Injure and Nephrotoxicity

2012 ◽  
Vol 4 (2) ◽  
pp. 42-44
Author(s):  
Grace Moscoso-Solorzano ◽  
Gianna Mastroianni-Kirsztajn
Keyword(s):  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Cyclophilin A ◽  
Common Mechanism ◽  
Ppiase Activity ◽  
Expression Of Genes ◽  
Inflammatory Stimuli ◽  
Genes Encoding ◽  
Inflammatory Processes

Cyclophilin A (CypA) belongs to the peptidyl-prolil isomerase (PPlase) family of proteins and it is also known as the cellular receptor for cyclosporine A (CsA). CsA binds to CypA and inhibits the PPIase activity, but the CypA-CsA complex also binds to calcineurin that promotes the expression of genes encoding cytokines and other proteins required for immune response. In addition, the polymorphism variation of CypA promoter seems to have an influence on the expression of CypA in in vitro studies. CypA was also implicated in inflammatory processes (such as, among others, those observed in rheumatoid arthritis, atherosclerotic disease, nephrotoxicity) and it can be secreted by cells in response to inflammatory stimuli. CypA can also have a role in the molecular mechanisms by which CsA induces nephroxicity but these remain poorly understood. Recent studies suggest that CsA inhibition of CypA PPlase activity is a possible mechanism of this drug toxicity. In addition, CypA overexpression could be protective against CsA nephrotoxicity. Finally, the putative common mechanism by which CypA could be involved in CsA nephrotoxicity and tissue injury is related to its proinflammatory effects in cells.

scholarly journals Somatic evolution and global expansion of an ancient transmissible cancer lineage

Science ◽  
2019 ◽  
Vol 365 (6452) ◽  
pp. eaau9923 ◽  
Author(s):  
Adrian Baez-Ortega ◽  
Kevin Gori ◽  
Andrea Strakova ◽  
Janice L. Allen ◽  
Karen M. Allum ◽  
...  
Keyword(s):  
Cancer Evolution ◽  
Time Resolved ◽  
Somatic Evolution ◽  
Dominant Feature ◽  
Transmissible Cancer ◽  
Clonal Organisms ◽  
Context Specific ◽  
Neutral Genetic Drift ◽  
Mutational Process

The canine transmissible venereal tumor (CTVT) is a cancer lineage that arose several millennia ago and survives by “metastasizing” between hosts through cell transfer. The somatic mutations in this cancer record its phylogeography and evolutionary history. We constructed a time-resolved phylogeny from 546 CTVT exomes and describe the lineage’s worldwide expansion. Examining variation in mutational exposure, we identify a highly context-specific mutational process that operated early in the cancer’s evolution but subsequently vanished, correlate ultraviolet-light mutagenesis with tumor latitude, and describe tumors with heritable hyperactivity of an endogenous mutational process. CTVT displays little evidence of ongoing positive selection, and negative selection is detectable only in essential genes. We illustrate how long-lived clonal organisms capture changing mutagenic environments, and reveal that neutral genetic drift is the dominant feature of long-term cancer evolution.

Identification of an octamer element required for in vivo expression of the TIE1 gene in endothelial cells

2001 ◽  
Vol 360 (1) ◽  
pp. 23-29 ◽  
Author(s):  
Stephane C. BOUTET ◽  
Thomas QUERTERMOUS ◽  
Bahaa M. FADEL
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Molecular Mechanisms ◽  
Vascular Development ◽  
Common Mechanism ◽  
Tyrosine Kinase Receptor ◽  
Wild Type ◽  
Binding Studies ◽  
In Vivo Expression

TIE1, an endothelial-cell-specific tyrosine kinase receptor, is required for the survival and growth of microvascular endothelial cells during the capillary sprouting phase of vascular development. To investigate the molecular mechanisms that regulate the expression of TIE1 in the endothelium, we analysed transgenic mouse embryos carrying wild-type or mutant TIE1 promoter/LacZ constructs. Our data indicate that an upstream DNA octamer element (5′-ATGCAAAT-3′) is required for the in vivo expression of TIE1 in embryonic endothelial cells. Transgenic embryos carrying the wild-type TIE1 promoter (−466 to +78bp) fused to LacZ and spanning the octamer element demonstrate endothelial-cell-specific expression of the reporter transgene. Point mutations introduced within the octamer element result in a significant decrease of endothelial LacZ expression, suggesting that the octamer site functions as a positive regulator for TIE1 gene expression in endothelial cells. DNA–protein binding studies show that the octamer element exhibits an endothelial-cell-specific pattern of binding via interaction with endothelial-cell-restricted factor(s). Our findings suggest an important role for the octamer element in regulating the expression of the TIE1 receptor in the embryonic endothelium and suggest a common mechanism for the regulation of the angiogenic and cell-specific TIE1 and TIE2 genes during vascular development.

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