Chromatin and associated epigenetic mechanisms stabilize gene expression and cellular states while also facilitating appropriate responses to developmental or environmental cues. Genetic, ...environmental, or metabolic insults can induce overly restrictive or overly permissive epigenetic landscapes that contribute to pathogenesis of cancer and other diseases. Restrictive chromatin states may prevent appropriate induction of tumor suppressor programs or block differentiation. By contrast, permissive or "plastic" states may allow stochastic oncogene activation or nonphysiologic cell fate transitions. Whereas many stochastic events will be inconsequential "passengers," some will confer a fitness advantage to a cell and be selected as "drivers." We review the broad roles played by epigenetic aberrations in tumor initiation and evolution and their potential to give rise to all classic hallmarks of cancer.
The genome of the protozoan parasite Toxoplasma gondii was found to contain two genes encoding tyrosine hydroxylase; that produces L-DOPA. The encoded enzymes metabolize phenylalanine as well as ...tyrosine with substrate preference for tyrosine. Thus the enzymes catabolize phenylalanine to tyrosine and tyrosine to L-DOPA. The catalytic domain descriptive of this class of enzymes is conserved with the parasite enzyme and exhibits similar kinetic properties to metazoan tyrosine hydroxylases, but contains a unique N-terminal extension with a signal sequence motif. One of the genes, TgAaaH1, is constitutively expressed while the other gene, TgAaaH2, is induced during formation of the bradyzoites of the cyst stages of the life cycle. This is the first description of an aromatic amino acid hydroxylase in an apicomplexan parasite. Extensive searching of apicomplexan genome sequences revealed an ortholog in Neospora caninum but not in Eimeria, Cryptosporidium, Theileria, or Plasmodium. Possible role(s) of these bi-functional enzymes during host infection are discussed.
The highly prevalent parasite Toxoplasma gondii manipulates its host's behavior. In infected rodents, the behavioral changes increase the likelihood that the parasite will be transmitted back to its ...definitive cat host, an essential step in completion of the parasite's life cycle. The mechanism(s) responsible for behavioral changes in the host is unknown but two lines of published evidence suggest that the parasite alters neurotransmitter signal transduction: the disruption of the parasite-induced behavioral changes with medications used to treat psychiatric disease (specifically dopamine antagonists) and identification of a tyrosine hydroxylase encoded in the parasite genome. In this study, infection of mammalian dopaminergic cells with T. gondii enhanced the levels of K+-induced release of dopamine several-fold, with a direct correlation between the number of infected cells and the quantity of dopamine released. Immunostaining brain sections of infected mice with dopamine antibody showed intense staining of encysted parasites. Based on these analyses, T. gondii orchestrates a significant increase in dopamine metabolism in neural cells. Tyrosine hydroxylase, the rate-limiting enzyme for dopamine synthesis, was also found in intracellular tissue cysts in brain tissue with antibodies specific for the parasite-encoded tyrosine hydroxylase. These observations provide a mechanism for parasite-induced behavioral changes. The observed effects on dopamine metabolism could also be relevant in interpreting reports of psychobehavioral changes in toxoplasmosis-infected humans.
Mary Barton Gaskell, Elizabeth
2017, 2017-06-06
eBook
A tale of love, class, and murder during the era of the trade-union movement in nineteenth-century England, from the author of North and South. In Manchester, long-suffering John Barton and his ...daughter, Mary, both want a better future for each other. John toils away with the trades' union for better wages for his fellow workers in the textile mill, while Mary must consider whom she will marry. She decides to leave the working-class Jem Wilson, hoping instead to wed Harry Carson, the wealthy mill owner's son. But when Harry is shot down in the street, Jem becomes the prime suspect—and learning the truth may yield a future Mary cannot bear. A portrait of the working class's struggles during the Victorian era, Mary Barton was Elizabeth Gaskell's first novel. She went on to write classics such as Wives and Daughters and was the creator of the town of Cranford, the setting for several BBC series.
Secrets and scandals steer a young woman's life as she comes of age and finds love in Victorian England. Seventeen-year-old Molly Gibson has grown up under the watchful eye of her widowed father, the ...doctor Mr. Gibson. After one of his apprentices develops an interest in Molly, Mr. Gibson feels the only way to protect her is to send her to live with the Hamley family. With his daughter away, Gibson decides to remarry, giving Molly a new mother and sister. Although her stepmother is manipulative, Molly gains an ally in her stepsister, Cynthia, who is educated, worldly, and irresistible to just about any man she meets. Growing closer to the Hamleys and her new stepsister, Molly also finds herself mired in their scandals—and the town's gossip. If she hopes to set things right, she must risk her own reputation, as well as the man she secretly loves. By the author of Mary Barton and North and South, this is a story of love, family, and the challenges of both, as relevant today as it was in the nineteenth century.
Cranford Gaskell, Elizabeth
2017, 2018, 2017-06-06
eBook
The women of an English country village star in this Victorian classic that inspired a BBC series, from the author of North and South. Welcome to Cranford, where everyone knows one another and a cow ...wears pajamas. It's a community built on friendship and kindness, where women hold court and most of the houses—and men—are rarely seen. Two colorful spinster sisters at the heart of Cranford, Miss Matty and Miss Deborah Jenkyns, are daughters of the former rector, and when they're not playing cards or drinking tea, they're feeding an endless appetite for scandal and weathering commotions to their peaceful lives, from financial troubles to thieves to an unexpected face from the past. First published in installments in Household Words, a magazine edited by Charles Dickens, Cranford was a hit of its time and today offers modern readers a glimpse into a small English town during the mid-nineteenth century.
A tragic affair blooms between a working-class orphan and a wealthy rake in this classic novel of Victorian England. Although Ruth Hilton is kind, life does not treat her kindly in return. An ...orphaned young seamstress, she works long hours at a sweatshop in a small English town. When she is sent to a fancy ball to repair the ladies' dresses, she catches the eye of a gentleman, Henry Bellingham. Falling for Henry leads to the loss of her job and her home, and Ruth quickly finds herself raising a child alone. Overcome with grief and shame, she must now make her way in a world where society has turned its back on her and all she can rely on is hope. A moving novel from the author of North and South and Mary Barton, Ruth offers a unique look at British life during the mid-nineteenth century.
An unforgettable story of love and strife set during the industrial revolution
After a decade spent living with her aunt in London, nineteen-year-old Margaret Hale returns home to her beloved village ...of Helstone only to discover that her pastor father has had a crisis of faith and is moving the family to the North of England. In the industrial town of Milton, Margaret is horrified by the dirty air, the shocking poverty, and the pervasive mistreatment of the working class. John Thornton, a student of Margaret's father and the self-made owner of a local textile mill, finds Margaret haughty and naive, but is drawn to her beauty nevertheless. As tensions between workers and masters mount, a strike appears inevitable. Margaret's sympathies lie with the downtrodden laborers of Milton, but her heart increasingly yearns for Thornton, whose strength and depth of character will be revealed in a time of profound crisis. Both a timeless romance and a richly detailed social novel,North and Southis a masterpiece of Victorian literature. This ebook has been professionally proofread to ensure accuracy and readability on all devices.
Moorland Cottage Gaskell, Elizabeth
2011, 2016, 2011, 2009-05-01
eBook
Looking for an engaging and emotionally resonant read from a novelist who was inspired by the works of both Charles Dickens and Charlotte Bronte? Elizabeth Gaskell's 1850 short novel The Moorland ...Cottage offers up a unflinching slice of nineteenth-century family life, with a particular focus on family dynamics in an era where sons were openly favored.
Early developmental specification can be modeled by differentiating embryonic stem cells (ESCs) to embryoid bodies (EBs), a heterogeneous mixture of three germ layers. Here, we combine single-cell ...transcriptomics and genetic recording to characterize EB differentiation. We map transcriptional states along a time course and model cell fate trajectories and branchpoints as cells progress to distinct germ layers. To validate this inferential model, we propose an innovative inducible genetic recording technique that leverages recombination to generate cell-specific, timestamp barcodes in a narrow temporal window. We validate trajectory architecture and key branchpoints, including early specification of a primordial germ cell (PGC)-like lineage from preimplantation epiblast-like cells. We further identify a temporally defined role of DNA methylation in this PGC-epiblast decision. Our study provides a high-resolution lineage map for an organoid model of embryogenesis, insights into epigenetic determinants of fate specification, and a strategy for lineage mapping of rapid differentiation processes.
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•Single-cell trajectory map of the embryoid body model of early embryogenesis•A temporally precise genetic recording system for lineage tracing•PGC-like lineage commitment in EBs occurs at the preimplantation epiblast-like stage•DNA methylation determines PGC-fate choice in a narrow developmental window
Kim et al. present a temporally precise genetic recording system for lineage tracing and transcriptomics analysis of single cells. They generate a trajectory map and single-cell transcriptional atlas of developing embryoid bodies, an organoid model of pre-gastrulation embryogenesis. These data reveal transcriptional and epigenetic regulators of early cell fate decisions.
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