Sep 10, Andrea MacPherson rated it it was ok Well. I was intrigued by the premise of the book--a father who blindfolds his twin daughters' eyes after their mother's death, to protect them from the world and, ultimately, turning them blind--but the premise was only the smallest seed of the novel to come.
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This article has been cited by other articles in PMC. Abstract Pharmacologic stimulation of innate immune processes represents an attractive strategy to achieve multiple therapeutic outcomes including inhibition of virus replication, boosting antitumor immunity, and enhancing vaccine immunogenicity.
This led to the establishment of a cellular state that prevented replication of emerging Alphavirus species including Chikungunya virus, Venezuelan Equine Encephalitis virus, and Sindbis virus.
Thus the compound may represent the first synthetic small molecule characterized as an indirect activator of human STING-dependent phenotypes. In vivo stimulation of STING-dependent activity by an unrelated small molecule in a mouse model of Chikungunya virus infection blocked viremia demonstrating that pharmacologic activation of this signaling pathway may represent a feasible strategy for combating emerging Alphaviruses.
Author Summary STING is a pattern recognition receptor of cyclic dinucleotides as well as an innate immune adaptor protein that enables signaling from cytoplasmic receptors to the transcription factor interferon regulatory factor 3.
Initiation of these pathways leads to the expression of type I interferons and proteins associated with antiviral and antitumor immunity. Small molecules capable of triggering STING-dependent cellular processes are effective at blocking virus replication, enhancing vaccine efficacy, and facilitating immune response to cancer cells.
Here we describe the first synthetic small molecule capable of activating STING-mediated signaling in human cells. In addition, we show that exposure of cells to the compound renders them refractory to replication by interferon-sensitive emerging Alphaviruses. Ultimately this work may lead to the utilization of STING as a target for multiple immune-mediated therapies.
Introduction The innate immune system includes an array of sentinel proteins termed pattern recognition receptors PRRs that sense and react to microbe- and danger-associated molecular patterns reviewed in [ 1 ].
These patterns are often constituents or replication intermediates of intracellular especially viral pathogens. PRRs respond to this engagement by initiating signaling pathways that bring about the expression or processing of cytokines, chemokines, and effector molecules that both directly block microbial replication and facilitate related adaptive immune processes.
As such, PRRs represent an essential first line of immunological defense against infection and are the target of both microbial inhibitory phenotypes as well as pharmacologic manipulation for therapeutic purposes reviewed in [ 2 ].
This occurs primarily through pathways that utilize specific adaptor proteins acting as integration points for upstream PRRs. Given the importance of these pathways for innate immune activation and antimicrobial protection they have been the focus of broad and intense research aimed at both understanding their physiological effects and harnessing their potential for contributions to immune-based therapeutics.
Given the ability of the IFN system to render cells and tissues refractory to replication of a wide array of virus types as well as its role in coordinating adaptive immune responses, pharmacologic IFN stimulation has been suggested as a broad spectrum antiviral strategy [ 219 — 22 ].
Moreover, factors capable of yielding therapeutic effects via activation of IRF3-mediated responses have been identified and biologically validated. This includes agonists of TLRs shown to block replication of some chronic viruses [ 23 — 25 ] as well as enhance vaccine immunity reviewed in [ 26 ].
Both molecules block multiple, even drug-resistant viruses [ 2931 — 33 ]. Intriguingly, DMXAA exhibits other immunotherapeutic effects including vaccine adjuvanticity [ 3435 ], anti-angiogenic vascular disruption promoting tumor necrosis [ 3637 ], and immune-mediated clearance of solid tumors [ 38 ].
Unfortunately, CMA and DMXAA were found to only function in mouse, not human cells and tissues [ 39 — 41 ] and thus were not effective in clinical trials. While analogs of cross-specific stimulatory CDNs have been synthesized [ 38 ], to our knowledge there exists no published biological characterization of novel synthetic molecular entities that activate human STING-dependent innate responses, despite the high and multi-pronged therapeutic potential of exploiting this important immunological protein.
Members of the Alphavirus genus include mosquito-transmitted agents that are re-emerging worldwide and can lead to significant morbidity and mortality reviewed in [ 42 ]. Since it first arrived in the Western hemisphere in December over one million suspected and confirmed cases are estimated to have occurred [ 43 ].The first third of the novel had me hooked; I was fascinated by the characters and by the sadness which seemed to envelope each of the voices of the book.
But somewhere along the plot line, Slayter lost me/5. Rebecca is a pillar of the community, a devoutly religious woman in her seventies. When she is accused of witchcraft, it makes the Reverend Hale pause and reconsider whether the .
Rumaan Alam’s latest novel, “That Kind of Mother,” offers an in-depth and, at times, unsettling examination of transracial adoption. Photograph by Eve Arnold / Magnum Rebecca meets Priscilla.
In this novel, Rebecca, the dead and unfaithful former wife is a dominant figure in each character’s life. Meanwhile, Mrs.
de Winter, who is young and inexperienced, has trouble gaining the respect and appreciation of the characters including her husband. Rebecca study guide contains a biography of Daphne Du Maurier, literature essays, quiz questions, major themes, characters, and a full summary and analysis.
Rebecca Questions and Answers. Alternaria fungi are important pathogens infecting a wide variety of organisms, including humans, animals and plants, and most species of this genus are important plant pathogens, infecting a wide range of plant species .Pear black spot caused by Alternaria spp.
is a serious disease that occurs in the pear-production areas of China, Japan and Korea [1, 15].