Is DNA methylation of tumour suppressor genes epigenetic?

In colorectal cancer cells, a non-epigenetic transcriptional pathway that is mediated by an oncogene maintains DNA methylation of tumour suppressor gene

The Illusion of Self Revisited: Replies to Critics

Anand Vaidya, Sean Smith, and Mark Siderits have presented thoughtful comments and provocative challenges to my article “What Kind of an Illusion is the Illusion of Self?” Their challenges raise significant questions about the nature of illusion, whether Buddhism is denying the self in all senses of the term, whether there could be a self that exists for some limited duration of time and has at least some measure of control, whether there is a phenomenal illusion of self, whether the neuropsychological assumptions embedded in Thomas Metzinger’s Phenomenal Self Model is consistent with Buddhist metaphysics, the usefulness of evolutionary psychology in explaining why we have the illusion of self, whether the I-sense is a result of natural selection or cultural selection, vipassanā meditation as a form of verification and its usefulness for extinguishing the I-sense. The discussion here is my response to these criticisms through which I further clarify and develop my arguments and, in some ways, amend my positio

What Kind of an Illusion is the Illusion of Self

Both early and later forms of Buddhism developed a set of arguments to demonstrate that the self is an illusion. This article begins with a brief review of some of the arguments but then proceeds to show that these arguments are not themselves sufficient to dispel the illusion. It analyzes three ways in which the illusion of self manifests itself – as wish fulfillment, as a cognitive illusion, and as a phenomenal illusion (what might be called the “I” sense). With respect to this last, the article reviews some recent developments in cognitive neuropsychology and neuroscience to discuss the way in which the phenomenal illusion of self is encoded within our brain processes. This article also considers the way in which the illusion of self is constructed through social interaction, by episodic memory, and by narrative construction. Finally, it focuses on how the illusion of self developed as an evolutionary necessity to make it possible for the human organism to navigate physical and social reality; and that it continues to be useful today. This poses a dilemma for the Buddhist soteriological project of extinguishing the illusion of self. Specifically, while it is possible to develop a non-self perspective though the continued practice of vipassanā (mindfulness meditation), it is not possible to maintain it consistently. The article concludes that even fully enlightened individuals must sometimes oscillate between a non-self perspective and a self-perspective and suggests an analogy between this oscillation and what occurs in the Kanizsa square illusion

Nuclear Access and Action of Notch In Vivo

AbstractThe Drosophila Notch (N) gene encodes a conserved single-pass transmembrane receptor that transduces extracellular signals controlling cell fate. Here, we present evidence that the intracellular domain of Notch gains access to the nucleus in response to ligand, possibly through a mechanism involving proteolytic cleavage and release from the remainder of the protein. In addition, our results suggest that signal transduction by Notch depends on the ability of the intracellular domain, particularly the portion containing the CDC10 repeats, to reach the nucleus and to participate in the transcriptional activation of downstream target genes

Control of Drosophila wing size by morphogen range and hormonal gating

The stereotyped dimensions of animal bodies and their component parts result from tight constraints on growth. Yet, the mechanisms that stop growth when organs reach the right size are unknown. Growth of the Drosophila wing—a classic paradigm—is governed by two morphogens, Decapentaplegic (Dpp, a BMP) and Wingless (Wg, a Wnt). Wing growth during larval life ceases when the primordium attains full size, concomitant with the larval-to-pupal molt orchestrated by the steroid hormone ecdysone. Here, we block the molt by genetically dampening ecdysone production, creating an experimental paradigm in which the wing stops growing at the correct size while the larva continues to feed and gain body mass. Under these conditions, we show that wing growth is limited by the ranges of Dpp and Wg, and by ecdysone, which regulates the cellular response to their signaling activities. Further, we present evidence that growth terminates because of the loss of two distinct modes of morphogen action: 1) maintenance of growth within the wing proper and 2) induced growth of surrounding “pre-wing” cells and their recruitment into the wing. Our results provide a precedent for the control of organ size by morphogen range and the hormonal gating of morphogen action

MiR-27b targets PPARγ to inhibit growth, tumor progression, and the inflammatory response in neuroblastoma cells

The PPARγ nuclear receptor pathway is involved in cancer, but it appears to have both tumor suppressor and oncogenic functions. In neuroblastoma cells, miR-27b targets the 3′UTR of PPARγ and inhibits its mRNA and protein expression. miR-27b overexpression or PPARγ inhibition blocks cell growth in vitro and tumor growth in mouse xenografts. PPARγ activates expression of the pH regulator NHE1, which is associated with tumor progression. Lastly, miR-27b through PPARγ regulates NF-κB activity and transcription of inflammatory target genes. Thus, in neuroblastoma, miR-27b functions as a tumor suppressor by inhibiting the tumor-promoting function of PPARγ, which triggers an increased inflammatory response. In contrast, in breast cancer cells, PPARγ inhibits NHE1 expression and the inflammatory response, and it functions as a tumor suppressor. We suggest that the ability of PPARγ to promote or suppress tumor formation is linked to cell-type specific differences in regulation of NHE1 and other target genes

Information flow and optimization in transcriptional control

In the simplest view of transcriptional regulation, the expression of a gene is turned on or off by changes in the concentration of a transcription factor (TF). We use recent data on noise levels in gene expression to show that it should be possible to transmit much more than just one regulatory bit. Realizing this optimal information capacity would require that the dynamic range of TF concentrations used by the cell, the input/output relation of the regulatory module, and the noise levels of binding and transcription satisfy certain matching relations. This parameter-free prediction is in good agreement with recent experiments on the Bicoid/Hunchback system in the early Drosophila embryo, and this system achieves ~90% of its theoretical maximum information transmission.Comment: 5 pages, 4 figure