Soluble components of Notch signalling can be applied to manipulate a central pathway essential for the development of metazoans and often deregulated in illnesses such as stroke, cancer or cardiovascular diseases. Commonly, the Notch cascade is inhibited by small compound inhibitors, which either block the proteolysis of Notch receptors by γ‐secretases or interfere with the transcriptional activity of the Notch intracellular domain. Specific antibodies can also be used to inhibit ligand‐induced activation of Notch receptors. Alternatively, (...) naturally occurring endogenous inhibitors of Notch signalling might offer a specific way to block receptor activation. Examples are the soluble variants of the canonical Notch ligand Jagged1 and the non‐canonical Notch ligand Dlk1, both deprived of their transmembrane regions upon ectodomain shedding, or the bona fide secreted molecule EGFL7. We present frequently used methods to decrease Notch signalling, and we discuss how soluble Notch inhibitors may be used to treat diseases. (shrink)

The activity of Wnt and Notch signalling is central to many cell fate decisions during development and to the maintenance and differentiation of stem cell populations in homeostasis. While classical views refer to these pathways as independent signal transduction devices that co‐operate in different systems, recent work has revealed intricate connections between their components. These observations suggest that rather than operating as two separate pathways, elements of Wnt and Notch signalling configure an integrated molecular device whose main function (...) is to regulate transitions between cell states in development and homeostasis. Here, we propose a general framework for the structure and function of the interactions between these signalling systems that is focused on the notion of ‘transition states’, i.e. intermediates that arise during cell fate decision processes. These intermediates act as checkpoints in cell fate decision processes and are characterised by the mixed molecular identities of the states involved in these processes.Editor's suggested further reading in BioEssays: Notch: Implications of endogenous inhibitors for therapy Abstract. (shrink)

Both Notch and NFκB signaling pathways are well‐known for regulating proliferation, differentiation and apoptosis. Recent studies have presented several lines of evidence supporting an integration of the Notch and NFκB signaling pathways in differentiation/maturation of a diverse range of cell types. It is notable that Notch and NFκB signaling pathways share many common features: (i) both are activated by common stimuli such as TNF‐α and hypoxia, (ii) activated Notch (NICD) and NFκB mediate transcription by regulating corepressors (...) such as SMRT/N‐COR, and (iii) both regulate similar target genes such as Hes‐1 and IκBα. This review expands on how the collaboration between these pathways may play an important role in the CNS. We will speculate on the mechanisms by which Notch and NFκB signaling may collaborate to regulate stem cell renewal and differentiation during brain development and function. BioEssays 29:1039–1047, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The Notch proteins play a vital role in cell fate decisions in both invertebrate and vertebrate development. Careful analysis of this role has led to a model of signalling downstream of these receptors, via the CSL (CBF1, Suppressor of Hairless, Lag-1) family of transcription factors. There have been suggestions, however, that Notch can signal through other pathways. In the current paper, Ramain et al.1 provide compelling evidence for Notch signalling through a CSL-independent pathway and they demonstrate that (...) the cytoplasmic protein, Deltex, is required for this signal. In addition, they show that Wnt signalling may regulate this Deltex-dependent signal. (shrink)

The evolutionarily conserved Notch signaling pathway regulates a broad spectrum of cell fate decisions and differentiation processes during fetal and postnatal life. It is involved in embryonic organogenesis as well as in the maintenance of homeostasis of self‐renewing systems. In this article, we review the role of Notch signaling in the hematopoietic system with particular emphasis on lymphocyte development and highlight the similarities in Notch function between Drosophila and mammalian differentiation processes. Recent studies indicating that aberrant (...) class='Hi'>NOTCH signaling is frequently linked to the induction of T leukemia in humans will also be discussed. BioEssays 27:1117–1128, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

BackgroundTinnitus is a common disease, and sound therapy is an effective method to alleviate it. Previous studies have shown that notched sound not only changes levels of cortical blood oxygen, but affects blood oxygen in specific cerebral cortical areas, such as Brodmann area 46, which is associated with emotion. Extensive evidence has confirmed that tinnitus is closely related to emotion. Whether notched sound plays a role in regulating the emotional center is still unclear.MethodsThis study included 29 patients with newly diagnosed (...) chronic tinnitus who were treated with notched sound. Functional near-infrared spectroscopy was conducted before and after treatment to observe bilateral changes in cortical blood oxygen in the cerebral hemispheres. We compared the changes in connectivity between the two regions of interest, as wells as other cortical regions before and after treatment.ResultsThe results showed That global connectivity between the bilateral auditory cortex of the superior temporal sulcus and the ipsilateral cortex did not change significantly between baseline and the completion of treatment, and That the connectivity between channel 14 and the right superior temporal sulcus decreased after treatment. The overall connectivity between the right BA46 region and the right cortex decreased after treatment, and decreases in connectivity after treatment were specifically found for channels 10 and 14 in the right parietal lobe and channels 16, 20, 21, and 22 in the frontal lobe, while there was no significant change on the left side. There were no significant changes in the questionnaire measures of tinnitus, anxiety, or depression before and after treatment.ConclusionThe results of the study indicate that cerebral cortex reorganization occurs in tinnitus patients after submitted to treatment with notched sound for 1 month, and that notched sound decreases the connectivity between the auditory cortex and specific brain regions.SignificanceNotched sound not only regulates the auditory center through lateral inhibition, but also alleviates tinnitus by reorganizing the emotional control center. (shrink)

Cells in multicellular organisms often do not intermingle freely with each other. Differential cell affinities can contribute to organizing cells into different tissues. Drosophila limbs and the vertebrate central nervous system are subdivided into compartments. Cells in adjacent compartments do not mix. Cell interactions mediated by Notch-family receptors have been implicated in the specification of these compartment boundaries. Two recent reports analyze the role of the Notch signaling pathway in the generation of an affinity boundary in the Drosophila (...) wing.1,2 The first report1 analyzes the connection between Notch and the actin cytoskeleton. The second report2 analyzes the differential requirements of Notch and the transcription factor Supressor of Hairless in generating the affinity boundary. BioEssays 28: 113–116, 2006. © 2006 Wiley periodicals, Inc. (shrink)

Notch is a mechanosensitive receptor that requires direct cell–cell contact for its activation. Both the strength and the range of notch signaling depend on the size and geometry of the contact sites between cells. These properties of cell–cell contacts in turn depend on cell shape and polarity. At the molecular level, the E3 ubiquitin ligase Neuralized links receptor activation with epithelial cell remodeling. Neur regulates the endocytosis of the Notch ligand Delta, hence Notch activation. It also (...) targets the apical polarity protein Stardust to promote the endocytosis of the Crumbs complex, thereby contributing to epithelium remodeling. Here, we review the interplay between Notch signaling and cell polarity and discuss the possible significance of linking Notch signaling with epithelial cell polarity via a common regulator. Notch receptor activation depends on direct cell–cell contacts that in turn depends on cell shape and cellular polarity. The size and geometry of cell–cell contacts have an impact on the strength and range of signaling. The E3 ubiquitin ligase Neuralized regulates the endocytosis and signaling activity of Delta. The activity of Neuralized is tightly regulated during development. Neuralized also modulates epithelial cell polarity by targeting the apical polarity protein Stardust and by promoting the endocytosis of Crumbs. Thus, the cell-specific expression of Neuralized couples Notch receptor activation with cell polarity regulation in epithelia. (shrink)

Vascular development entails multiple cell‐fate decisions to specify a diverse array of vascular structures. Notch proteins are signaling receptors that regulate cell‐fate determination in a variety of cell types. The finding that Notch genes are robustly expressed in the vasculature suggests roles for Notch in guiding endothelial and associated mural cells through the myriad of cell‐fate decisions needed to form the vasculature. In fact, mice with defects in genes encoding Notch, Notch ligands, and components of (...) the Notch signaling cascade invariably display vascular defects. Human Notch genes are linked to Alagille's Syndrome, a developmental disorder with vascular defects, and CADASIL, a cerebral arteriopathy. Studies in zebrafish, mice and humans indicate that Notch works in conjunction with other angiogenic pathways to pattern and stabilize the vasculature. Here, we will focus on established functions for Notch in vascular remodeling and arterial/venous specification and more speculative roles in vascular homeostasis and organ‐specific angiogenesis. BioEssays 26:225–234, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Previous work has suggested that many stem cells can be found in microanatomic niches, where adjacent somatic cells of the niche control the differentiation and proliferation states of their resident stem cells. Recently published work examining intestinal stem cells (ISCs) in the adult Drosophila midgut suggests a new paradigm where some stem cells actively control the cell fate decisions of their daughters. Here, we review recent literature(1) demonstrating that, in the absence of a detectable stem cell niche, multipotent Drosophila ISCs (...) modulate the Notch signaling pathway in their adjacent daughter cells in order to specify the differentiated lineages of their descendants. These observations made in Drosophila are challenging and advancing our understanding of stem cell biology. BioEssays 30:107–109, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Notch signaling plays an essential role in the processes of embryogenesis and cellular differentiation, and it is believed that the oncogenic effects of dysregulated Notch signaling are an anomalous reflection of the normal functions of this cascade. Nonetheless, the cellular events associated with oncogenic Notch signaling have thus far remained elusive. In a recent report, Ferres‐Marco et al.1 described how they used the Drosphila eye as a model system and found that elevated Notch signaling in combination (...) with activation of components of the Polycomb complex of transcriptional repressors led to metastatic growth of tumors through epigenetic silencing of the Rbf gene. Rbf is the Drosophila homologue of the retinoblastoma tumor‐suppressor gene (Rb), thus it represents a novel link between Notch signaling, tumor growth and metastasis. BioEssays 28: 692–695, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Signaling through both the transforming growth factor β (TGFβ) superfamily of growth factors and Notch play crucial roles during embryonic pattern formation and cell fate determination. Although both pathways are able to exert similar biological responses in certain cell types, a functional interaction between these two signaling pathways has not been described. Now, three papers provide evidence of both synergy and antagonism between TGFβ and Notch signaling.1-3 These reports describe a requirement for Notch signal transducers in TGFβ- (...) and BMP-induced expression of Notch target genes, as well as in BMP-controlled cell differentiation and migration. These papers uncover a direct link between the Notch and TGFβ pathways and suggest a critical role for Notch in some of the biological responses to TGFβ family signaling. BioEssays 27:115–118, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Development and maintenance of diverse organ systems require context‐specific regulation of stem cell behaviour. We hypothesize that this is achieved via reciprocal regulation between the cell cycle machinery and differentiation factors. This idea is supported by the parallel evolutionary emergence of differentiation pathways, cell cycle components and complex multicellularity. In addition, the activities of different cell cycle phases have been found to bias cells towards stem cell maintenance or differentiation. Finally, several direct mechanistic links between these two processes have been (...) established. Here, we focus on interactions between cyclin‐CDK complexes and differentiation regulators of the Notch pathway and Sox family of transcription factors within the context of pluripotent and neural stem cells. Thus, this hypothesis formalizes the links between these two processes as an integrated network. Since such factors are common to all stem cells, better understanding their interconnections will help to explain their behaviour in health and disease. (shrink)

The formation of blood vessels within the vascular system entails a variety of cellular processes, including proliferation, migration and differentiation. In many cases, these diverse processes need to be finely coordinated among neighbouring endothelial cells in order to establish a functional vascular network. For instance, during angiogenic sprouting specialized endothelial tip cells follow guidance cues and migrate extensively into avascular tissues while trailing stalk cells must stay connected to the patent blood vessel. The vascular endothelial growth factor (VEGF) and (...) class='Hi'>Notch signalling pathways have emerged as the major players in governing these different cellular behaviours. In particular, recent work indicates an important role for Notch signalling in determining how an endothelial cell responds to VEGF. In this review, we provide an overview of these biochemically distinct pathways and discuss how they may interact during endothelial cell differentiation and angiogenesis. BioEssays 30:303–313, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

In pursuit of moralities and beliefs in the grey area of culture, the researchers carried out a study on Top Notch series to pinpoint the trace of ethics. This paper seeks to unfold the representation of ethics as an indubitable part of culture in Top Notch series. After having extracted all culturally and ethically-related topics and texts of Top Notch Series, 25 instances, featuring 6 patterns, were collected. Later these 6 patterns were dubbed as: violence, superstition, modesty,individualised (...) ethics, religion, and modernity. Having analysed these 6 themes, well representing beliefs and moralities, the researchers came to the conclusion that both misrepresentation of ethics and underrepresentation and overrepresentation of different cultures are at work. The results show a reconsideration of therepresentation of ethics, or better to say reconsideration of misrepresentation of ethics which might find its root in wrong dominance of culture over ethics. (shrink)

Establishment of cell lineage identity from multipotent progenitors is controlled by cooperative actions of lineage‐specific and stably expressed transcription factors, combined with input from environmental signals. Lineage‐specific master transcription factors activate and repress gene expression by recruiting consistently expressed transcription factors and chromatin modifiers to their target loci. Recent technical advances in genome‐wide and multi‐omics analysis have shed light on unexpected mechanisms that underlie more complicated actions of transcription factors in cell fate decisions. In this review, we discuss functional dynamics (...) of stably expressed and continuously required factors, Notch and Runx family members, throughout developmental stages of early T cell development in the thymus. Pre‐ and post‐commitment stage‐specific transcription factors induce dynamic redeployment of Notch and Runx binding genomic regions. Thus, together with stage‐specific transcription factors, shared transcription factors across distinct developmental stages regulate acquisition of T lineage identity. (shrink)

Abstractβ‐Catenin/CTNNB1 is critical for leukemia initiation or the stem cell capacity of several hematological malignancies. This review focuses on a general evaluation of β‐catenin function in normal T‐cell development and T‐cell acute lymphoblastic leukemia (T‐ALL). The integration of the existing literature offers a state‐of‐the‐art dissection of the complexity of β‐catenin function in leukemia initiation and maintenance in both Notch‐dependent and independent contexts. In addition, β‐catenin mutations are screened for in T‐ALL primary samples, and it is found that they are (...) rare and with little clinical relevance. Transcriptional analysis of Wnt family members (Ctnnb1, Axin2, Tcf7, and Lef1) and Myc in different publicly available T‐ALL cohorts indicates that the expression of these genes may correlate with T‐ALL subtypes and/or therapy outcomes. (shrink)

Pericytes, like vascular smooth muscle cells, are perivascular cells closely associated with blood vessels throughout the body. Pericytes are necessary for vascular development and homeostasis, with particularly critical roles in the brain, where they are involved in regulating cerebral blood flow and establishing the blood-brain barrier. A role for pericytes during neurovascular disease pathogenesis is less clear—while some studies associate decreased pericyte coverage with select neurovascular diseases, others suggest increased pericyte infiltration in response to hypoxia or traumatic brain injury. Here, (...) we used an endothelial loss-of-function Recombination signal binding protein for immunoglobulin kappa J region (Rbpj)/Notch mediated mouse model of brain arteriovenous malformation (AVM) to investigate effects on pericytes during neurovascular disease pathogenesis. We tested the hypothesis that pericyte expansion, via morphological changes, and Platelet-derived growth factor B/Platelet-derived growth factor receptor β (Pdgf-B/Pdgfrβ)-dependent endothelial cell-pericyte communication are affected, during the pathogenesis of Rbpj mediated brain AVM in mice. Our data show that pericyte coverage of vascular endothelium expanded pathologically, to maintain coverage of vascular abnormalities in brain and retina, following endothelial deletion of Rbpj. In Rbpj-mutant brain, pericyte expansion was likely attributed to cytoplasmic process extension and not to increased pericyte proliferation. Despite expanding overall area of vessel coverage, pericytes from Rbpj-mutant brains showed decreased expression of Pdgfrβ, Neural (N)-cadherin, and cluster of differentiation (CD)146, as compared to controls, which likely affected Pdgf-B/Pdgfrβ-dependent communication and appositional associations between endothelial cells and pericytes in Rbpj-mutant brain microvessels. By contrast, and perhaps by compensatory mechanism, endothelial cells showed increased expression of N-cadherin. Our data identify cellular and molecular effects on brain pericytes, following endothelial deletion of Rbpj, and suggest pericytes as potential therapeutic targets for Rbpj/Notch related brain AVM. (shrink)

1. Animal Cruelty Industrial farming is appallingly abusive to animals. Pigs. In America, nine-tenths of pregnant sows live in “gestation crates. ” These pens are so small that the animals can barely move. When the sows are first crated, they may flail around, in an attempt to get out. But soon they give up. Crated pigs often show signs of depression: they engage meaningless, repetitive behavior, like chewing the air or biting the bars of the stall. The sows live like (...) this for four months. Gestation crates will be phased out in Europe by the end of 2012, but they will still be used in America.1 In nature, pigs nurse their young for about thirteen weeks. But in industrial farms, piglets are taken from their mothers after about ten days. Because the piglets are weaned prematurely, they develop a lifelong craving to suck and chew. But the farmers don’t want them sucking and chewing on other pigs’ tails. So the growers routinely snip off the tails of all their pigs. They do this with a pair of pliers and no anesthetic. However, the whole tail is not removed; a tender stump remains. The point is to render the area sensitive, so the pigs being chewed on will fight back. Which they do.2 Over 113 million pigs are slaughtered each year in America.3 Typically, these pigs are castrated, their needle teeth are clipped, and one of their ears is notched for identification —all without pain relief.4 In nature, pigs spend up to three quarters of their waking hours foraging and exploring their environment.5 But in the factory farms, “tens of thousands of hogs spend their entire lives ignorant of earth or straw or sunshine, crowded together beneath a metal roof standing on metal slats suspended over a septic tank. ”6 Bored, and in constant pain, the pigs must perpetually inhale the fumes of their own waste. These pigs often get sick, and their ill health is exacerbated by the overcrowding. In 2000, the U.S. Department of Agriculture compared hog farms containing over 10,000 pigs—which is the norm—with farms containing under 2,000 pigs. (shrink)

Scientists and policy‐makers have long understood that the products of research can often be used for good or evil. Nuclear fission research can be used to generate electricity or create a powerful bomb. Studies on the genetics of human populations can be used to understand relationships between different groups or to perpetuate racist ideologies. While the notion that scientific research often has beneficial and harmful uses has been discussed before, the threat of bioterrorism—a concern that has only grown since 2001—has (...) led to increased awareness about the need to prevent the misuse of biomedical research, particularly when it involves dangerous pathogens or toxins. In 2012, the concern was ratcheted up another notch by two papers reporting the results of research on genetically engineered strains of the H5N1 avian influenza virus. Although the H5N1 papers have potential scientific and social value, some scientists and policy‐makers opposed their publication because they feared that terrorists (or others with nefarious motives) could use the research to create a bioweapon that could trigger a global pandemic. The H5N1 papers raise difficult questions concerning the ethics of knowledge. Should scientific research with dangerous applications be published? Should some types of research be kept secret or not be conducted at all? What type of government oversight of dangerous research is appropriate? In this essay, I will develop a framework for thinking about the ethics of knowledge and apply it to the H5N1 controversy, focusing on issues related to publication. I will argue that redacted publication would have been a reasonable response to the dilemmas posed by the H5N1 papers if not for practical and legal problems with this option. Given these problems, full publication seems appropriate. (shrink)

"The book provides an excellent historical summary of the debates over continental drift theory in this century." —Contemporary Sociology "This is a useful discussion of the way that science works. The book will be of value to philosophers of science... " —Choice "... will find an important place in university and department libraries, and will interest afficionados of the factual and intellectual history of the earth sciences." —Terra Nova "... an excellent core analysis... " —The Times Higher Education Supplement "... (...) an ambitious and important contribution to the new sociology of science." —American Journal of Sociology "... Stewart's book is a noble effort, an interesting and readable discussion, and another higher notch on the scoreboard of critical scholarship that deserves wide examination and close attention." —Geophysics This fascinating book describes the rise and fall and rebirth of continental drift theory in this century. It uses the recent revolution in geoscientinsts' beliefs about the earth to examine questions such as, How does scientific knowledge develop and change? The book also explores how well different perspectives help us to understand revolutionary change in science. (shrink)

This article offers some hypotheses to explain Later Stone Age lithic miniaturization: the systematic creation of small stone flakes on the finest-grained materials. Fundamentally, this phenomenon appears to represent the prioritization of stone tool sharpness over longevity, and a disposable mode of using stone tools. Ethnographic evidence from Australasia, the Andaman Islands, and Africa is used to suggest some specific functions for miniaturized lithics, as well as their relationship to other aspects of Later Stone Age material culture, including ochre crayons, (...) shell beads, and notched bones. Miniaturized lithic functions are hypothesized to have a common basis in the cognitive capacity for abstraction: having ideas about ideas. The technological and social affordances of abstraction may have given laterHomo sapienssignificant adaptive advantages over other members of our genus. (shrink)

We assemble here in this time and place to discuss the thesis that conscious attention can provide knowledge of reference of perceptual demonstratives. I shall focus my commentary on what this claim means, and on the main argument for it found in the first five chapters of "Reference and Consciousness". The middle term of that argument is an account of what attention does: what its job or function is. There is much that is admirable in this account, and I am (...) confident that it will be the foundation, the launching-pad, for much future work on the subject. But in the end I will argue that Campbell's picture makes the mechanisms of attention too smart: smarter than they are, smarter than they could be. If we come to a more realistic appraisal of the skills and capacities of our sub-personal minions, the "knowledge of reference" which they yield will have to be taken down a notch or two. (shrink)

We assemble here in this time and place to discuss the thesis that conscious attention can provide knowledge of reference of perceptual demonstratives. I shall focus my commentary on what this claim means, and on the main argument for it found in the first five chapters of Reference and Consciousness. The middle term of that argument is an account of what attention does: what its job or function is. There is much that is admirable in this account, and I am (...) confident that it will be the foundation, the launching-pad, for much future work on the subject. But in the end I will argue that Campbell's picture makes the mechanisms of attention too smart: smarter than they are, smarter than they could be. If we come to a more realistic appraisal of the skills and capacities of our subpersonal minions, the "knowledge of reference" which they yield will have to be taken down a notch or two. But first let us clarify what the argument is. (shrink)

Somites are transient structures which represent the most overt segmental feature of the vertebrate embryo. The strict temporal regulation of somitogenesis is of critical developmental importance since many segmental structures adopt a periodicity based on that of the somites. Until recently, the mechanisms underlying the periodicity of somitogenesis were largely unknown. Based on the oscillations of c-hairy1 and lunatic fringe RNA, we now have evidence for an intrinsic segmentation clock in presomitic cells. Translation of this temporal periodicity into a spatial (...) periodicity, through somite formation, requires Notch signaling. While the Hox genes are certainly involved, it remains unknown how the metameric vertebrate axis becomes regionalized along the antero–posterior (AP) dimension into the occipital, cervical, thoracic, lumbar, and sacral domains. We discuss the implications of cell division as a clock mechanism underlying the regionalization of somites and their derivatives along the AP axis. Possible links between the segmentation clock and axial regionalization are also discussed. (shrink)

Philosophers have long debated whether abstract objects such as numbers and properties exist, but in recent years philosophical debate about what things exist has been ratcheted up more than a notch to question whether even ordinary objects such as pineapples and tables exist. One view has it that all existence questions are difficult questions whose answers hang on achieving an ontological theory that succeeds in carving nature at its joints. Some proponents of this view further claim to have succeeded (...) in that carving, even without the benefit of any instrument sharper than the a priori arguments conjured in their armchairs, and to have discovered, alas, that no ordinary concrete objects exist. Naturally, many of us have been made to wonder what premise in the argument for that conclusion enjoys a plausibility greater than that of the negation of the argument's conclusion. In her remarkable new book, Ontology Made Easy, Amie Thomasson strives to do much more than that in defense of common‐sense ontology. But not only for common‐sense ontology. She propounds a unified approach to all existence questions—whether about the existence of dogs, shoes or tables, or about the existence of numbers, propositions or fictional characters—according to which existence questions “are not deep and difficult subjects for metaphysical dispute, but rather questions to be resolved straightforwardly by employing our conceptual competence, often combining this with empirical investigations” (20). Thomasson calls her way of resolving existence questions the easy approach to ontology, and to that I now turn. (shrink)

Vulval development in the Caenorhabditis elegans hermaphrodite represents a simple, genetically tractable system for studying how cell signaling events control cell fata decisions. Current models suggest that proper specification of vulval cell fates relies on the integration of multiple signaling systems, including one that involves a receptor tyrosine kinase (RTK)→Ras→mitogen activated protein kinase (MAPK) cascade and one that involves a LIN‐12/Notch family receptor. In this review, we first discuss how genetic strategies are being used to identify and analyze components (...) that control vulval cell fate decisions. We then describe the different signaling systems that have been elucidated and how they relate to one another. Finally, we highlight several recently characterized genes that encode positive regulators, negative regulators or potential targets of the RTK→Ras→MAPK cascade involved in vulval induction. (shrink)

Somites are transient structures which represent the most overt segmental feature of the vertebrate embryo. The strict temporal regulation of somitogenesis is of critical developmental importance since many segmental structures adopt a periodicity based on that of the somites. Until recently, the mechanisms underlying the periodicity of somitogenesis were largely unknown. Based on the oscillations of c-hairy1 and lunatic fringe RNA, we now have evidence for an intrinsic segmentation clock in presomitic cells. Translation of this temporal periodicity into a spatial (...) periodicity, through somite formation, requires Notch signaling. While the Hox genes are certainly involved, it remains unknown how the metameric vertebrate axis becomes regionalized along the antero–posterior (AP) dimension into the occipital, cervical, thoracic, lumbar, and sacral domains. We discuss the implications of cell division as a clock mechanism underlying the regionalization of somites and their derivatives along the AP axis. Possible links between the segmentation clock and axial regionalization are also discussed. BioEssays 22:72–83, 2000. ©2000 John Wiley & Sons, Inc. (shrink)

During the sixties, a most curious symbiosis took hold between Heinz von Foerster then the Director of a top-notch and lavishly funded US laboratory [Biological Computer Laboratory, 1958–1975] and the Chilean neuroscientist Humberto R. Maturana professor at the Universidad de Chile. The chance encounter between them triggered a long-lasting friendship and a fundamental change in our understanding of Systems Science. In particular the contributions of Biology of Cognition and Autopoiesis are important to understand this change and the years 1968–1973 (...) are particularly relevant. In this period, Maturana published, as a Technical Report of BCL, the foundational document The Neurophysiology of Cognition. Later, in 1973, the book De Maquinas y Seres Vivos put forward the notion of Autopoietic Systems. Also, between 1971 and 1973, the Allende government tried to cybernitize the Chilean economy with the SYNCO project. In that project, Maturana and von Foerster played a role by teaching Cybernetics to the engineers and administrators of this technological dream. During this same time, Cybernetics was important in Chile and Professors Maturana and von Foerster although not directly involved in the day-to-day running of SYNCO were important in that unique effort. When a military coup deposed Allende and sent Chile into a tailspin of right-wing retribution, von Foerster, a foreigner who loved Chile and its people, did his outmost to assure the safety of many people involved in this unique Latin American Cybernetics dream. (shrink)

Determination of cell fate in the developing eye of Drosophila depends on a precise sequence of cellular interactions which generate the stereotypic array of ommatidia. In the eye imaginal disc, an initially unpatterned epithelial sheath of cells, the first step in this process may be the specification of R8 photoreceptor cells at regular intervals. Genes such as Notch and scabrous, known to be involved in bristle development, alos participate in this process, suggesting that the specification of ommatidial founder cells (...) and the formation of sensory organs in the adult epidermis may involve a similar mechanism, that of lateral inhibition. The subsequent steps of ommatidial assembly, following R8 assignment, involve a different mechanism: Undetermined cells read their position based on the contacts they make with neighbors that have already begun to differentiate. The development of the R7 photoreceptor cell, one of the eight photoreceptor cells in the ommatidium, is best understood. An important role seems to be played by sevenless, a receptor tyrosine kinase on the surface of the R7 precursor. It transmits the positional information– most likely encoded by the boss protein on the neighboring R8 cell membrane – into the cell via its tyrosine kinase, which activates a signal transduction cascade. Constitutive activation of the sevenless kinase by overexpression of an N‐terminally truncated form results in the diversion of other ommatidial cells into the R7 pathway suggesting that activation of the sevenless signalling pathway is sufficient to specify R7 development. Genetic dissection of this pathway should therefore identify components of a signalling cascade activated by a tyrosine kinase. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Ethics & the Environment 8.2 (2003) 8-30 [Access article in PDF] Dialogue, Responsibility, and Oil and Gas Leasing on Montana's Rocky Mountain Front Scott Friskics "How does nature speak to our concern? That is the question" (Bugbee 1978, 11). It's a late afternoon in mid-March and I'm standing outside my friends' house on the southwest edge of Augusta, Montana, a small town of about 500 residents. I'm here to (...) meet a companion who's headed out from Great Falls to spend the weekend at my cabin, which is located up in the mountains approximately 20 miles west of here. As is often the case, I'm a bit early for our rendezvous. Blame it on unbridled anticipation or a latent preoccupation with punctuality, but my premature arrival offers me a few stolen moments of enforced inactivity with which I can revel in the sensory fullness of a pleasant, pre-spring afternoon.Out here on the plains, spring seems much nearer at hand than it does back up in the mountains. The air's still cool and the wind still bites, but the warm afternoon sun embraces me and unlocks a host of smells long-held in winter's freeze: earthy mud puddles, sweet horse manure, damp hay. [End Page 8]While waiting, I wander over to the nearby corral to greet three gentle, mud-splattered horses. As I absently rub their chins and stroke their long, slender noses, I gaze out beyond the horses, out beyond the soupy corral, beyond the expanse of wrinkled, sere, brown plains. My eyes focus on the blue-shadowed wall of mountains from which I've just emerged: Montana's Rocky Mountain Front. From this vantage point, the Front presents itself as a horizon-filling tidal wave of rock—fluid, walking mountains that, over the course of their long march through time, have been thrust skyward and pushed eastward to where their easternmost reefs and ridges now hang precipitously over the wide expanse of the northern Great Plains.Dead center in my line of vision stands the tilted summit of Crown Mountain—the univocal, eloquent peak that towers about the narrow mountain valley where I live, provides me with the ultimate spatial reference point for my life, and fills my days with the gracious bounty of its abiding presence. From here, however, Crown Mountain presents itself to me not so much as a soloist, but rather as one voice in a chorus of mountain song. Working southward from this orienting center, I encounter Crown Mountain's nameless twin and the rocky ridge line descending to Welcome Pass, above the notch of which rises the deceptively unassuming head of the Scapegoat Massif. Much nearer at hand and dominating the foreground stands the dark cone of Haystack Butte—an intrusive igneous island in a sea of sedimentary mountains. Further south runs the high ridge guarding the headwaters of the Dearborn River, with Steamboat Mountain rising above the rugged country drained by Elk Creek, Blubber Creek, Falls Creek, Cuniff Creek.Working northward from the crown, the mountains are no less spectacular, no less evocative: the slanting summit of Fairview Mountain, the jagged gray wall of Sawtooth Ridge, the low gap of Sun Canyon (where the united Sun River flows out onto the plains and benches of central Montana), the flattened rock face of Castle Reef, and, framing the northern edge of my vista, the rising bulk of Ear Mountain. Of course, standing here in Augusta I'm well aware that what I can see from this spot is less than half of the Front, so my imagination continues north to Blackleaf Canyon, the Birch Creek country, the Badger-Two Medicine, the east slopes of Glacier National Park, and that holy border sentinel, Chief Mountain.I first saw this glorious stretch of country on a blustery November day 16 years ago, and I have yet to encounter another place that speaks to me with such force and beauty, such overwhelming, undeniable eloquence. [End Page 9] And, on this soul-stirring March afternoon, the... (shrink)

In today’s postmodern world with the latest and top notch internet technologies in the market, if it has become easy and accessible for everyone to communicate with others sitting at the other corner of the world, it has also given rise to the cybercrimes including cyber terro rism which has not only provided grave threats to the whole world but also posed a question of whether with the manipulation of cyber space, cyber terrorists can damage or destroy the physical (...) infrastructure of its target. Owing to easy access to everyone and strong damage done as compared to traditional terrorism, today terrorists are relying on cyber terrorism as well. The Islamic State has emerged as one of the brutal and violent terrorist organization s which hired cyber experts and manipulated cyber space to the extent that today they are most active and professional cyber users’ terrorist organization of the world. The main focus of the paper is to highlight the basic definition of cyber terrorism, how often it is different from traditional terrorism, use of cyber terrorism, how cyber terrorism can be manipulated through various latest tools and techniques and how Islamic State is using cyber space to spread its message. (shrink)

Cultural characteristics in relation to educational technology acceptance (ETA) aims at analyzing the effect of cultural factors that include norms of the society, values, and practices which shape the perception and usage of technology by the individual as incorporated in his/her education. This concept illustrates that cultural factor increases that perception of helpfulness, ease of implementation, and total satisfaction with technology by a significant notch. Understanding these cultural factors is critical to the development and implementation of pedagogical technologies that (...) are aligned with specific target audiences. A number of people in the study was 2100, out of which 1115 were from Mumbai, India and 985 others were from other areas. The sample included people with various education levels, occupations and ages, which gives a comprehensive idea of the variety of users’ perceptions of educational technology. Employing the data based on the collected set of factors, descriptive analysis, factor analysis, and correlation matrixes were used in a process of distinguishing key patterns and relations between particular variables. This cross-sectional research has relied on multiple regression analysis to assess the significant predictor factors that include perceived ease of integration and expected performance of the technology by the users on the two outcomes: user engagement and technology satisfaction. As earlier stated, SPSS was used in this research study to conduct statistical tests. The comparative analysis revealed that there were significant regional differences concerning the social impact expectations, EE and PC but there was no impact of regions as per PEI and TS. The research thus brings out the importance of cultural differences in the explanation of ETA. This just underline the need for a strategic and specific approach that takes into account regional and cultural factors to improve the reception of technologies as well as to improve the user satisfaction even if it is a diverse population. The paper provides important view on rather engaging culturally competent educational technology systems. (shrink)

Get the science facts, not science fiction, on the cutting-edge developments that are already changing the course of our future. Every day, scientists conduct pioneering experiments with the potential to transform how we live. Yet it isn’t every day you hear from the scientists themselves! Now, award–winning author Jim Al–Khalili and his team of top-notch experts explain how today’s earthshaking discoveries will shape our world tomorrow—and beyond. Pull back the curtain on: genomics robotics AI the “Internet of Things” synthetic (...) biology transhumanism interstellar travel colonization of the solar system teleportation and much more And find insight into big–picture questions such as: Will we find a cure to all diseases? The answer to climate change? And will bionics one day turn us into superheroes? The scientists in these pages are interested only in the truth—reality-based and speculation-free. The future they conjure is by turns tantalizing and sobering: There’s plenty to look forward to, but also plenty to dread. And undoubtedly the best way to for us to face tomorrow’s greatest challenges is to learn what the future looks like—today. Praise for What the Future Looks Like “A collection of mind-boggling essays that are just the thing for firing up your brain cells.” —Saga Magazine “The predictions and impacts are global... [and] the book contains far more fascinating information than can be covered in this review.” —Choice “This book is filled with essays from experts offering their informed opinions on what the science and technology of today will look like in the future, from smart materials to artificial intelligence to genetic editing.” —Popular Science “Fun is an understatement. This is a great collection to get the summer book season started.” —Forbes.com “The focus on sincere, factual presentation of current and future possibilities by leading experts is particularly welcome in this era of fake news and anti-science rhetoric.” —Library Journal. (shrink)

In 1995, the eyeless (ey) gene was dubbed the “master‐regulator” of eye development in Drosophila. Not only is ey required for eye development, but its misexpression can convert many other tissues into eye, including legs, wings and antennae.(1) ey is remarkable for its ability to drive coordinate differentiation of the multiple cell types that have to differentiate in a very precise pattern to construct the fly eye, and for its power to override the previous differentiation programs of many other diverse (...) tissues. Even more remarkable, the ey homolog Pax6 and homologs of other eye determination genes from Drosophila are also required for eye development in vertebrates,(2,3) prompting reassessment of the evolution of vision throughout the animal kingdom.(4,5) Now Kumar and Moses have published a study that throws a new light on ey function in Drosophila.(6) According to their work, ey becomes a master regulator of eye development much later than previously thought, and is regulated by signalling through the Notch and EGFR signaling pathways. BioEssays 23:763–766, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Possible effects of interaction (cross-talk) between signaling pathways is studied in a system of Reaction–Diffusion (RD) equations. Furthermore, the relevance of spontaneous neurite symmetry breaking and Turing instability has been examined through numerical simulations. The interaction between Retinoic Acid (RA) and Notch signaling pathways is considered as a perturbation to RD system of axon-forming potential for N2a neuroblastoma cells. The present work suggests that large increases to the level of RA–Notch interaction can possibly have substantial impacts on neurite (...) outgrowth and on the process of axon formation. This can be observed by the numerical study of the homogeneous system showing that in the absence of RA–Notch interaction the unperturbed homogeneous system may exhibit different saddle-node bifurcations that are robust under small perturbations by low levels of RA–Notch interactions, while large increases in the level of RA–Notch interaction result in a number of transitions of saddle-node bifurcations into Hopf bifurcations. It is speculated that near a Hopf bifurcation, the regulations between the positive and negative feedbacks change in such a way that spontaneous symmetry breaking takes place only when transport of activated Notch protein takes place at a faster rate. (shrink)

The mechanisms responsible for the fine tuning of development, where the wildtype phenotype is reproduced with high fidelity, are not well understood. The difficulty in approaching this problem is the identification of mutant phenotypes indicative of a defect in these fine‐tuning control mechanisms. Evolutionary biologists have used asymmetry as a measure of developmental homeostasis. The rationale for this was that, since the same genome controls the development of the left and right sides of a bilaterally symmetrical organism, departures from symmetry (...) can be used to measure genetic or environmental perturbations. This paper examines the relationship between asymmtry and resistance to organophosphorous insecticides in the Australian sheep blowfly, Lucilia cuprina. A resistance gene, Rop‐1, which encodes a carboxylesterase enzyme, also confers a significant increase in asymmetry. Continued exposure of resistant populations to insecticide has selected a dominant suppressor of the asymmetry phenotype. Genetic evidence indicates that the modifier is the L. cuprina Notch homologue. (shrink)

This book features a group of top-notch philosophers tackling some of the biggest questions in higher education: What role should the liberal arts have in a college education? Should colleges orient themselves to the educational demands of the business sector? What is the role of highly selective colleges in the public sphere? To what extent should they be subsidized directly, or indirectly, by the public? Should they simply teach students skills and academic knowledge, or should they play a role (...) in shaping character, and if so to what end? Should highly selective colleges admissions practices give an edge to racial minorities, or legacies, or poor students? How much should the public purse subsidize disadvantaged students attending such institutions? These questions are fundamentally about moral and political valuesquestions of distributive justice and of what constitutes valuable education. Philosophers are trained to identify value considerations in great detailindeed, often with more precision than is ever needed for practical purposes!but most disagreements about policy and practice proceed with minimal attention to the values assumed on either side, and all sides can benefit from more clarity about exactly what moral values are at play. The philosophers here, then, address some of the fundamental questions underlying debates about higher educationand in ways that are interesting and accessible to others.". (shrink)

Comparison across formal languages is an essential part of formal linguistics. The study of closely-related varieties has proven extremely useful in comparing differences that might otherwise appear unrealted, and has helped to identify the core principles of Universal Grammar. This comprehensive handbook serves two functions. It will provide a general and theoretical introduction to comparative syntax, its methodology, and its relation to other domains of linguistic inquiry; and it will provide a systematic selection of the best comparative work being done (...) today on those language groups and families where substantial progress has been achieved. With top-notch editors and contributors from around the world, this volume will be an essential resource for scholars and students in formal linguistics. (shrink)

This paper examines the middle ear of fossil living animals in terms of the homologies which have been drawn between its parts in different vertebrate groups. Seven homologies are considered: 1, the middle ear cavity/spiracular pouch; 2, the stapes/hyomandibula; 3, the stapedial/hyomandibular processes; 4 the tympanic membrane; 5, the otic notch; 6, the fenestra ovalis; 7, and the stapedial/hyomandibular foramen. The reasons leading to assessments of homology are reviewed. Homologies 1 and 2, based largely on embryological evidence, are fairly (...) robust, though there are arguments about the details. Homologies 3, 4 and 5 stem from ideas about early tetrapod evolution, and were influenced by contingent factors including the order and time of discovery of early fossil taxa, and perceptions of their phylogeny which resulted from this. They were also influenced by ideas of the evolution of terrestriality among tetrapods. Most of the conceptions have been overturned in recent years by new fossil discoveries and new ways of looking at old data. Homology 6 has been little considered. One possible hypothesis, placed in a strictly archetypal theoretical framework has been ignored but deserves consideration on other grounds. Homology 7 depends on how tetrapods are characterised, not a question which has posed difficulties until recently, but which is likely to with the discovery of intermediate fossil forms. (shrink)

During somitogenesis an oscillatory mechanism termed the “segmentation” clock generates periodic waves of gene expression, which translate into the periodic spatial pattern manifest as somites. The dynamic expression of the clock genes shares the same periodicity as somitogenesis. Notch signaling is believed to play a role in the segmentation clock mechanism. The paper by Hirata et al.(1) identifies a biological clock in cultured cells that is dependent upon the Notch target gene Hes1, and which shows a periodicity similar (...) to that of the segmentation clock. This finding opens the possibility that the same oscillator mechanism might also operate in other tissues or cell types. BioEssays 25:200–203, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

This book represents conversations between philosophers and theologians on several issues of current theological interest. God, the church, theological authority, atonement, the Holy Spirit, religious ethics, the problem of evil, and other topics are debated by top-notch theologians and philosophers of various theological and philosophical persuasions. Since contemporary philosophers and theologians seldom communicate professionally, this book represents a fascinating and highly unusual cross-disciplinary conversation.