We had a fantastic night!!

A powerful geomagnetic storm creates extreme auroras in the skies above Abisko National Park in Sweden. This video was shot in three hours by Lights Over Lapland photographer Chad Blakley, and shows 8 photographers participating in Lights Over Lapland's aurora borealis photo expedition.
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Tubulin acetyltransferase discovered: Ciliary role in the ancestral eukaryote expanded to neurons in metazoans

Published online before print December 6, 2010, doi: 10.1073/pnas.1016396108

PNAS December 14, 2010 vol. 107 no. 50 21238-21239

---Michel R. Leroux1---
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada V5A 1S6

The emergence of α- and β-tubulins from an FtsZ-like prokaryotic homolog represented a defining event in eukaryogenesis. It permitted, together with actin and molecular motors, the establishment of a cytoskeleton able to support dynamic events such as cell division and trafficking of vesicles and proteins. It also served as the foundation for the microtubule-based cilium, an organelle with motility and sensory functions that replaced the less versatile prokaryotic flagellum (1). As it turns out, a mechanism to stabilize the ciliary axoneme, involving acetylation of α-tubulin, evolved in the ancestral eukaryote (2–4). This reversible modification situated inside the microtubule lumen still operates in extant ciliated protists and is exploited by metazoans to support ancillary microtubule functions, particularly in neurons (5). The concurrent discovery of an α-tubulin acetyltransferase by two separate groups, published in PNAS (3) and in Nature (4), now paves the way for a detailed understanding of the cellular and physiological roles conferred by tubulin acetylation.

Discovery

Tubulin acetylation was first detected on the microtubule axonemes of Chlamydomonas motile cilia in 1985 (6). It would take nearly 20 y before the activity responsible for tubulin deacetylation, afforded by histone deacetylase 6 (HDAC6) and SIRT2, would be discovered (2, 5). Surprisingly, the factor(s) responsible for adding an acetyl moiety to the ε-amino group of K40 on α-tubulin have remained enigmatic until now (2, 5). The codiscovery of a bona fide tubulin acetyltransferase followed notably different paths.
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Using a biochemical approach, Shida and colleagues (3) from the Nachury and Goodman laboratories copurified an uncharacterized protein (C6orf134) with the BBSome, a ciliary trafficking complex implicated in Bardet–Biedl syndrome. C6orf134 has one telltale feature, namely a cryptic Gcn5-related N-acetyltransferase (GNAT) domain found in histone acetyltransferases (HATs). In addition, the researchers had isolated a BBSome-interacting protein, BBIP10, that was important for tubulin acetylation, but unlikely to be the prime catalyst for this modification (7). Their suspicion that C6orf134 is the sought-after tubulin acetyltransferase is confirmed by demonstrating the ability of the human protein to acetylate α-tubulin in vitro, as well as in vivo, through siRNA knockdown studies. Hence, C6orf134 is assigned the name α-tubulin K40 acetyltransferase (αTAT) (Fig. 1).



Fig. 1.

Acetylation of α-tubulin by the tubulin acetyltransferase αTAT/MEC-17 emerged in the ancestral eukaryote, likely to promote cilium formation and stability. Additional functions evolved in metazoans, including neuronal roles in touch sensation. Tubulin acetylation is countered by the deacetylases HDAC6 and SIRT2.



On the basis of a predicted GNAT domain in the Caenorhabditis elegans MEC-17 protein, previously implicated to function in cells harboring acetylated tubulin (touch receptor neurons or TRNs), Akella and coworkers (4) investigated the potential role of diverse orthologs as tubulin acetyltransferases. In vitro studies with murine MEC-17 corroborated such an activity, and disruption of MEC-17 in Tetrahymena, human cells, and zebrafish revealed their requirement for tubulin acetylation in vivo.

Further substantiation of a conserved role for αTAT/MEC-17 in tubulin acetylation is sought by both groups, using C. elegans as a model system. Each realize that αTAT/MEC-17, encoded by a single-copy gene in most organisms, is joined by a paralog, W06B11.1 (atat-2), in the nematode. Indeed, the mec-17 and atat-2 C. elegans genes are shown to function redundantly in acetylating the sole α-tubulin bearing a K40 residue, MEC-12; whereas individual mec-17 or atat-2 mutants have reduced levels of acetylated tubulin (3), the double mutant resembles mec-12 insofar as having none (3, 4).

Of note, the Elongator complex, which contains a subunit (ELP3) with HAT activity, is purported to function as a major tubulin acetyltransferase (8). However, several studies, including those mentioned above, find evidence to the contrary (3, 4, 9). Its potential role in tubulin homeostasis thus necessitates further investigation.

Acetyltransferase Specific for α-Tubulin?

αTAT/MEC-17 consists mainly of a HAT domain, and the tubulin deacetylase HDAC6 includes histones as potential substrates. To address the substrate specificity of αTAT/MEC-17, Shida et al. (3) query its capacity to act on histones. Acetylation assays using purified components reveal that it effectively acetylates tubulin but not histone H3/H4 or a mixture of core histones; in contrast, a histone acetyltransferase, HAT1, does not modify tubulin. Satisfyingly, αTAT/MEC-17 increases axonemal microtubule stability (4), as expected, likely by preferentially acetylating polymerized α-tubulin over free α/β-tubulin heterodimers (3).

Although these data support the notion that αTAT/MEC-17 is a lysine acetyltransferase for tubulin and not histones, its substrate repertoire might encompass additional proteins. This possibility was suggested by Akella and coworkers (4), albeit with a caveat. Specifically, the group reported that loss of C. elegans αTAT activity in the mec-17;atat-2 double mutant affects TRN mechanosensation to a greater extent than having a nonacetylatable MEC-12(K40R) form of tubulin in the organism—implying additional role(s) for the acetyltransferase independent of tubulin acetylation. However, Shida et al. (3) a priori perform the same experiment but obtain the inverse result. In addition, loss of acetyltransferase activity phenocopied the mec-12 mutant in one study (4) but exhibits a less severe phenotype in the other (3). Further scrutiny of αTAT/MEC-17 in C. elegans and other species should resolve these discrepancies and potentially expose novel substrates.

Phylogenetic Distribution Suggests Ancestral Ciliary Role

The distribution of αTAT/MEC-17 across all eukaryotic clades (3) reveals that it was present in the last eukaryotic common ancestor, which was ciliated (1). Perhaps more revealing, the absence of this protein from organisms that secondarily lost cilia (3) suggests that its primeval and ongoing cellular function is linked to cilium biogenesis, function, and/or maintenance. Indeed, αTAT/MEC-17—but not several other ostensibly key ciliogenic proteins, including intraflagellar transport (IFT) components required for ciliary trafficking—is absolutely conserved in ciliated eukaryotes (3).
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Conserved…Yet Nonessential Ciliary Function?

The prevalent population of acetylated microtubules in protists and nonneuronal cells occurs within the ciliary axoneme (2–5). Through guilt by association, a ciliary function for αTAT/MEC-17 is therefore expected, but what is the current evidence for such a role? Based on the available data, an essential ciliogenic role for the acetyltransferase seems unlikely. Although disrupting MEC17 in Tetrahymena abolished tubulin acetylation, no overt defect in cilium formation or motility was noted (4). Similarly, cilia are still present in zebrafish and mammalian cells subjected to morpholino- or siRNA-mediated knockdown of αTAT/MEC-17, respectively (3, 4). Interestingly, however, a timecourse experiment reveals a delay in cilium formation for cultured human cells depleted of αTAT/MEC-17 (3), a phenotype whose cellular or physiological consequence is unclear but deserves further attention.

Intriguingly, most C. elegans-ciliated sensory neurons lack detectable acetylated tubulin. Because MEC-12 is present in TRNs and other (ciliated) neurons (8, 10), this situation could arise because of restricted expression of the acetyltransferases in ciliated neurons. Shida et al. (3) now demonstrate that although mec-17 expression is limited to TRNs; its paralog atat-2 is also expressed in some ciliated neurons (including CEP and OLQ). Indeed, ATAT-2 is needed for acetylating tubulin in dendritic processes and cilia in those neurons (3). Understanding the differential requirement for acetylating distinct axonemal microtubules could prove to be informative.
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Neuronal Functions

Adding to our understanding of αTAT/MEC-17 function, Shida et al. (3) and Akella et al. (4) demonstrate distinct neuronal roles for the nematode and zebrafish proteins. First, C. elegans MEC-17 and ATAT-2 are required for body touch sensation, which depends on the nonciliated, acetylated tubulin-containing TRNs (3, 4). ATAT-2 is also needed for nose touch avoidance and wild-type locomotion in the absence of food, behaviors modulated by mechanosensory-ciliated neurons (OLQ, CEP) containing acetylated tubulin that express atat-2 but not mec-17 (3). Second, knockdown of zebrafish MEC-17 causes various developmental phenotypes, some potentially linked to ciliary dysfunction (e.g., curved body shape, hydrocephalus, and small eyes) and another that may not be—a neuromuscular defect that impairs touch sensation (4). Thus, tubulin acetylation supports the function of at least some nonciliated neurons, highlighting an expanded role for αTAT/MEC-17 in metazoans.

Outlook

In the absence of unequivocal ciliary phenotypes following disruption of αTAT/MEC-17 in protists and metazoan cells, the challenge will be to uncover more subtle effects conferred by acetylation of axonemes. Given that the motility of at least one molecular motor (Kinesin-1) depends on tubulin modifications (including acetylation) in neurites (11), the search for a ciliary function could include probing for defects in kinesin-/dynein-driven IFT or, perhaps, transport of components to the base of (growing) cilia; dysfunction of either could potentially explain the slower ciliary growth rate observed upon abrograting αTAT/MEC-17 (3). The functional link between αTAT/MEC-17 and BBSome, and BBIP10, should also prove revealing. Notably, the finding of a ciliary transport-tubulin acetylation connection may parallel the recent discovery of a core IFT protein (DYF-1) associated with polyglutamylation activity—another tubulin modification that confers microtubule stability (12).

The most important discoveries bring with them many more questions than they answer. The unveiling of the tubulin acetyltransferase, coupled with the awareness of two reverse enzymes, HDAC6 and SIRT2, promises to clarify the cellular functions of this ancient modification pathway. For one, tubulin acetylation can now be better understood along with other tubulin modifications, including glutamylation, glycylation, and detyrosination (2, 5). Also, whereas HDAC6 has multiple substrates and binding partners, and acts in a broad range of cellular processes—e.g., cilium disassembly, malignant transformation, and misfolded protein degradation (13)—abrogation of αTAT/MEC-17 may reveal a more limited range of phenotypes uniquely associated with tubulin acetylation. In brief, the discovery of a conserved tubulin acetyltransferase will play an important role in understanding key aspects of the eukaryotic microtubule cytoskeleton.

Endogenous Myc maintains the tumor microenvironment

artikel teknis yang berhubungan:

# Genes expressed in human tumor endothelium.

#Tumor angiogenesis involves an intricate interplay between the tumor and supportive cell(tumor-associated
endothelial cells, pericytes, smooth muscle cells,
fibroblasts, and macrophages) i.e recruits migrating
endothelial cells and pericytes, and forms new blood vessels
through vascular remodeling and maturation.

#Canonical Wnt signaling is involved in switching from cell proliferation to myogenic differentiation of mouse myoblast cells

Abstract

The ubiquitous deregulation of Myc in human cancers makes it an intriguing therapeutic target, a notion supported by recent studies in Ras-driven lung tumors showing that inhibiting endogenous Myc triggers ubiquitous tumor regression. However, neither the therapeutic mechanism nor the applicability of Myc inhibition to other tumor types driven by other oncogenic mechanisms is established. Here, we show that inhibition of endogenous Myc also triggers ubiquitous regression of tumors in a simian virus 40 (SV40)-driven pancreatic islet tumor model. Such regression is presaged by collapse of the tumor microenvironment and involution of tumor vasculature. Hence, in addition to its diverse intracellular roles, endogenous Myc serves an essential and nonredundant role in coupling diverse intracellular oncogenic pathways to the tumor microenvironment, further bolstering its credentials as a pharmacological target.
Keywords

Myc inhibition,pancreas,tumor microenvironment
therapeutics

Tumors are dysfunctional tissues wherein cancer cells reside in an interdependent association with a somatic microenvironment comprised of diverse stromal, vascular, and inflammatory cell types. Evidence has amassed that the various normal somatic cells that make up the tumor microenvironment are essential for various aspects of macroscopic tumor growth, maintenance, invasion, and angiogenesis, and profoundly influence initial responses to therapy, tumor recurrence, and the evolution of drug resistance. Unfortunately, in established tumors, cancer cells and their adjacent stroma are so reciprocally intertwined that the cause-and-effect relationships linking them have proven very difficult to disentangle: It remains unclear to what extent tumor cells instruct their microenvironment versus the microenvironment instructs the tumor cells, or the extent to which each is dependent on the other for its maintenanc
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Nonetheless, the obligate role in tumor growth and maintenance played by the tumor microenvironment has prompted a variety of novel therapeutic approaches aimed at neutralizing tumor cell-nonautonomous components of the tumor mass, most notably tumor vasculature and inflammation. These approaches seek to capitalize on the attractive notion that, by aiming at the normal stromal compartment of tumors rather than genetically unstable cancer clones, evolution of drug resistance should be greatly reduced. Unfortunately, by and large, such therapies have not proven especially effective. In great part, this is because the extracellular programs that craft and maintain tissues are inherently degenerate and robust, as befits processes whose imperative is to build and maintain consistent tissue architectures even when the precise signals driving such processes are both varied and variable (Coussens et al. 2002; Fingleton 2003; Miller et al. 2005; Bergers and Hanahan 2008). Effective and durable therapies aimed at the tumor microenvironment will require the identification and specific targeting of pathway effectors that are both nondegenerate and obligate.

Myc is a basic helix–loop–helix leucine zipper transcription factor whose activity is deregulated in most human cancers. Acute ectopic activation of Myc is sufficient in many tissues to engage and maintain the diverse intracellular programs (cell growth, cell cycle progression, biosynthetic metabolism, ribogenesis, and translation) (Meyer and Penn 2008) and extracellular programs (release of cytokines and chemokines, recruitment of inflammatory cells, extensive stromal remodeling, invasion, and angiogenesis) that normal and neoplastic somatic cells need for their expansion (Pelengaris et al. 1999, 2002; Shchors et al. 2006; Soucek et al. 2007). This pleiotropic role hints that Myc inhibition might be an especially efficacious therapeutic strategy, since it could concomitantly incapacitate both intracellular and extracellular oncogenic pathways. Consistent with this, we recently used a dominant-negative approach to inhibit Myc systemically in vivo to show that endogenous Myc is essential for maintenance of oncogenic KRas-induced tumors of the lung (Soucek et al. 2008). However, key questions remain:

Most notably, is the dependence on Myc for tumor maintenance a tumor cell-autonomous or tumor cell-nonautonomous process, and how general is the requirement for Myc in other tumor types driven in other tissues by other oncogenic mechanisms?

The well-characterized rat insulin promoter 1 (RIP1)-Tag2 mouse model of multistage pancreatic β-cell carcinogenesis is a workhorse for studying how the microenvironment modulates tumor growth (Christofori and Hanahan 1994; Bergers and Hanahan 2008). RIP1-Tag2 tumorigenesis is driven by transgenic expression of simian virus 40 (SV40) large T and small t antigens from the RIP (Hanahan 1985). All RIP1-Tag2 animals develop hyperplastic/dysplastic islets at ∼5–7 wk of age (Hanahan 1985), and, at ∼9 wk of age, some of these lesions transition to a highly angiogenic phenotype that exhibits histological features of high-grade dysplasia (Folkman et al. 1989). Thereafter, a subset of these angiogenic lesions evolves into solid tumors. RIP1-Tag2 mice typically die from tumor burden and associated hyperinsulinemia at ∼14 wk (Christofori and Hanahan 1994). The protracted, stepwise, and sporadic kinetics of tumor evolution in RIP1-Tag2 mice intimate that SV40 T/t antigens are insufficient to pilot tumorigenesis through various evolutionary bottlenecks without the cooperation of additional mutations. Furthermore, at least some of these crucial bottlenecks are thought to reflect inadequacies in the capacity of the normal somatic microenvironment to support vigorous tumor expansion. Most notable of these is the angiogenic switch, a complex and functionally degenerate tissue transition involving recruitment of inflammatory cells, release of proteolytic and angiogenic effector molecules, extensive stromal remodeling, and vascular elaboration. The root cause of this dramatic shift in tissue dynamics and local microenvironment remains unknown; in particular, to what extent is tumor angiogenesis dependent on tumor cell-specific signals as opposed to tumor cell-extrinsic signals that originate within the host stroma?

To address these questions directly, we combined the RIP1-Tag2 pancreatic β-cell mouse tumor model with our TRE-Omomyc;CMVrtTA mouse, in which the dominant-negative Myc inhibitor Omomyc (Soucek et al. 1998, 2002, 2004) may be reversibly induced systemically in vivo (Soucek et al. 2008). Omomyc competitively blocks Myc/Max heterodimerization and binding to the E-box, thus inhibiting the capacity of Myc proteins to transactivate target genes (Soucek et al. 1998, 2002). Tumorigenesis in the RIP1-Tag2 model is driven by a completely different oncogenic mechanism from the KRasG12D lung tumor model, in a very different tissue type in which the tumor microenvironment plays a critical part in tumor progression and maintenance. We used this model to establish the role that endogenous Myc within tumor cells plays in maintenance of β-cell tumors and their peculiar microenvironment.
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Results
Endogenous Myc is required for progression and maintenance of RIP1-Tag2 islet tumors

Expression of the dominant inhibitory Myc dimerization domain mutant Omomyc in TRE-Omomyc;CMVrtTA mice is driven from a tetracycline-responsive promoter element (TRE) whose activity is reliant on a reverse tetracycline-dependent transactivator, rtTA (Tet-On system), expressed off the CMV promoter (Soucek et al. 2008). The CMV promoter is highly active in most adult mouse tissue types (Furth et al. 1991; Kothary et al. 1991; Baskar et al. 1996; Soucek et al. 2008), and administration of doxycycline to TRE-Omomyc;CMVrtTA mice elicits widespread inhibition of endogenous Myc trans-activation, including exocrine and endocrine pancreas (Soucek et al. 2008). TRE-Omomyc;CMVrtTA mice were crossed into the RIP1-Tag2 mouse model of pancreatic β-cell cancer (Hanahan 1985). In the absence of doxycycline, TRE-Omomyc;CMVrtTA;RIP1-Tag2 triple-transgenic mice developed tumors with incidence, multiplicity, and kinetics of tumor progression indistinguishable from their RIP1-Tag2 littermates (Supplemental Fig. 1).
All of the tumors examined were well or moderately differentiated neuroendocrine tumors, based on clinical and pathological criteria, and appeared to be circumscribed, nodular masses with noninfiltrative borders (Fig. 1).

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To ascertain the role of endogenous Myc function in the pathogenesis of SV40 T/t–driven islet cancer in RIP1-Tag2 mice, we first asked whether inhibition of Myc prevents expansion and progression of RIP1-Tag2-driven tumors. Systemic Omomyc expression was induced in 7-wk-old TRE-Omomyc;CMVrtTA;RIP1-Tag2 mice by addition of doxycycline to their drinking water for seven subsequent weeks, then the animals were sacrificed and their pancreata were harvested and assessed immunohistochemically. As expected, at 14 wk of age, RIP1-Tag2 mice exhibited the predicted distribution of islet tumor sizes and grades as described in Christofori and Hanahan (1994). In contrast, no overt islet tumors were present in Omomyc-expressing animals (TRE-Omomyc;CMVrtTA;RIP1-Tag2 mice treated with doxycycline). Indeed, both islet size and distribution remained similar to that of control littermates not expressing RIP1-Tag2 (Fig. 1A; low-power-magnification images are also provided as Supplemental Fig. 2). Hence, Myc inhibition prevents formation of RIP1-Tag2 β-cell tumors.

To assess the impact of inhibiting endogenous Myc on established RIP1-Tag2 islet tumors, we induced Omomyc expression in 11-wk-old TRE-Omomyc;CMVrtTA;RIP1-Tag2 mice—which at this age harbor hyperplastic lesions, angiogenic tumors, and carcinomas (Supplemental Fig. 3)—and maintained Omomyc expression for three further weeks. Pancreata were then harvested, and tumor status was assessed histologically. Strikingly, whereas the 14-wk-old RIP1-Tag2 Omomyc-negative control group exhibited multiple, large, angiogenic, and aggressive islet tumors, Omomyc-expressing animals (TRE-Omomyc;CMVrtTA;RIP1-Tag2 mice treated with doxycycline) lacked any such lesions (Fig. 1B; low-power-magnification images are also provided as Supplemental Fig. 2). To exclude the formal possibility that Omomyc suppresses expression of SV40 T antigens driven from the insulin promoter in RIP1-Tag2 islets, we directly assayed expression of SV40 large T immunohistochemically. Omomyc induction had no impact on T-antigen expression in RIP1-Tag2 β cells (Supplemental Fig. 4).

To investigate the mechanism of islet tumor regression in RIP1-Tag2 mice following Myc inhibition, we induced Omomyc expression for 1 wk in 13-wk-old TRE-Omomyc;CMVrtTA;RIP1-Tag2 mice and assayed both proliferation and apoptosis. Although overall tumor size is not significantly reduced after only 1 wk of Omomyc expression, Omomyc expression elicited both a profound suppression of tumor cell proliferation and a significant increase in apoptosis (Fig. 2A), irrespective of tumor grade or stage (Supplemental Fig. 5). Hence, Myc inhibition is both cytostatic and cytotoxic in RIP1-Tag2 tumors. Nonetheless, the β cells in the regressed islet tumors of Omomyc-expressing TRE-Omomyc;CMVrtTA;RIP1-Tag2 mice retained the classic aberrant cytologic features of transformed β cells (Fig. 2B), indicating that Myc inhibition does not block SV40 T/t-oncogenic function per se, only the propagation and expansion of such transformed cells. Of note, the regressed islet tumors retained strong peripheral glucagon expression, and, in general, the ratio of glucagon-positive α cells to insulin-positive β cells in Omomyc-regressed tumors was comparable with that in normal islets (Fig. 2C).

+++++++++++++++

Endogenous Myc is required for maintenance of the RIP1-Tag2 islet tumor microenvironment

Inactivation of ectopic Myc in Myc-driven β-cell tumors triggers rapid degeneration of the tumor microenvironment, marked by collapse of tumor vasculature (Pelengaris et al. 2002; Shchors et al. 2006; Soucek et al. 2007). However, whether endogenous Myc plays an analogous role in driving and maintaining the microenvironment in tumors driven by other oncogenes is unknown. Since the switch to an angiogenic phenotype is a prerequisite for expansion, invasion, and metastasis of RIP1-Tag2 tumors (Bergers et al. 2000), we next examined the impact of Myc inhibition on the microenvironment supporting established RIP1-Tag2 islet tumors. First, Omomyc was induced in 13-wk-old RIP1-Tag2 mice for 1 wk, and tumor hypoxia was assessed. Hypoxia was absent from all normal islets in control mice and was only occasionally evident in some regions of the many large (but extensively vascularized) β-cell tumors of RIP1-Tag2 mice (19% ± 3.8% of tumors). In contrast, hypoxia was widespread among islet tumors from Omomyc-expressing TRE-Omomyc;CMVrtTA;RIP1-Tag2 mice (68.75% ± 9.5% of tumors) (Fig. 3A). Such regions of hypoxia coincided with regions of significant endothelial cell death (27% ± 3.2% of all dying cells in angiogenic lesions and overt tumors of Omomyc-expressing TRE-Omomyc;CMVrtTA;RIP1-Tag2 mice are endothelial), suggesting that hypoxia arises from attrition of tumor vasculature (Fig. 3B). Detailed kinetic analysis of such phenomenon by double staining for Meca32 and active Caspase 3 clearly showed that, at 3 d after doxycycline treatment, the great majority of apoptotic cells in the TRE-Omomyc;CMVrtTA;RIP1-Tag2 mice are endothelial, not tumor (Fig. 4). Onset of tumor cell death follows rapidly thereafter, and, by 7 d of Myc inhibition, the majority of cells dying are tumor β cells. Hence, vasculature collapse precedes tumor death and is not a secondary consequence of tumor regression. Concomitant analysis of pericytes by immunohistochemistry with NG2 antibody revealed only occasional cell deaths at either 3 or 7 d of Myc inhibition (Supplemental Fig. 6).


The principle proximal mediator of angiogenesis in RIP1-Tag2 tumors is VEGF, which is constitutively present in normal pancreatic islets but is sequestered in an inactive state by the extracellular matrix. The onset of islet tumor angiogenesis in RIP1-Tag2 mice is precipitated by proteolytic release of ECM-bound VEGF and ligation to its principal receptor, VEGF-R2/Flk-1 (Bergers et al. 2000). Since Myc inhibition triggers rapid vascular attrition, we ascertained whether Myc inhibition abrogates VEGF:VEGF-R2 ligation by staining pancreas sections from Omomyc-expressing TRE-Omomyc;CMVrtTA;RIP1-Tag2 mice with the GVM39 monoclonal antibody that specifically recognizes VEGF:VEGFR2 (Flk1)-ligated conjugates (Brekken et al. 1998). Omomyc expression blocked all detectable interaction between VEGF and its receptor (Fig. 5), offering a compelling proximal mechanism for attrition of islet tumor vasculature following Myc inhibition.

The immediate proximal trigger for release of ECM-bound VEGF that drives and maintains RIP1-Tag2 islet tumor angiogenesis is activation of matrix metalloprotease type 9 (MMP9) (Bergers et al. 2000). MMP9 is produced by two principal inflammatory cell types in RIP1-Tag2 islets (macrophages and neutrophils) (Nozawa et al. 2006) that home to incipient tumors in response to release of various chemoattractants (Shojaei et al. 2008). Given their crucial role in the angiogenic step of RIP1-Tag2 islets, we ascertained whether both the location and number of these inflammatory cells are modulated by Myc inhibition. We verified that macrophages accumulate along the peripheries of RIP1-Tag2 tumors, where they are thought to orchestrate interactions with surrounding stroma, while neutrophils accumulate in the tumor interior, as described by Nozawa et al. (2006) (Fig. 6). In contrast, both macrophages and neutrophils were completely absent from tumors of TRE-Omomyc;CMVrtTA;RIP1-Tag2 mice expressing Omomyc for only 3 d (Fig. 6), indicating that sustained expression of endogenous Myc is required for both recruitment and retention of inflammatory cells by established RIP1-Tag2 tumors.

To identify possible mediators of the Myc-dependent cross-talk between tumor and microenvironment, we used an unbiased approach to identify inflammatory and vascular modulators that are directly and rapidly influenced by Myc inhibition. Laser-captured tumor islets were isolated from the pancreata of 13-wk-old TRE-Omomyc;CMVrtTA;RIP1-Tag2 mice treated with either doxycyline or sucrose for 2 d, and gene expression was profiled and compared. Our analysis focused on cytokine, chemokine, and inflammatory response genes described in the PCR arrays from SAbiosciences (http://www.sabiosciences.com/Cytokines_Inflammation.php). We then identified only those genes that showed a fold change of at least 0.2 between Omomyc-treated and untreated states. We found that multiple genes implicated in inflammation and inflammocyte recruitment were rapidly modulated by Myc inhibition (Fig. 7). Some of the genes down-regulated upon Myc inhibition—such as IL8rb, Il19, Il3, LTb4r2, Il11, Ccl7, Ccl8, and Ccl12—have well-characterized roles in chemotaxis, proliferation, and maturation of various inflammatory cells; others—such as Il1r and Ccr4—are known to influence tumor angiogenesis and invasion. Hif1a was also significantly up-regulated, consistent with the rapid onset of tissue hypoxia observed upon Myc inhibition. Among the genes up-regulated following Myc inhibition were Il12b, ccl5, and Tlr2, all known to stimulate macrophage and NK activation.

Systemic expression of Omomyc in TRE-Omomyc;CMVrtTA;RIP1-Tag2 mice models a Myc inhibitory drug by blocking Myc function in both SV40 T/t-antigen-transformed β cells themselves and all other cell types in the RIP1-Tag2 tumors. Hence, it is not possible to determine the extent to which the tumoricidal effects of Myc inhibition are due to its effect on the tumor cells themselves versus the tumor microenvironment. To ascertain whether the dramatic collapse of the RIP1-Tag2 tumor microenvironment triggered by Myc inhibition is mediated through the tumor or the stromal compartments, we crossed our TRE-Omomyc;RIP1-Tag2 model into the RIP-rtTA mouse so that doxycycline-inducible Omomyc is expressed exclusively in the β-cell compartment of each tumor. Inhibition of endogenous Myc only in the β-cell compartment of established RIP1-Tag2 tumors triggered rapid and widespread death of tumor endothelial cells (Fig. 8A) and tumor regression that was indistinguishable from that elicited by systemic Myc inhibition (Fig. 8B). Hence, maintenance of the vascular and inflammatory somatic microenvironment required to support SV40 T/t-antigen-driven RIP1-Tag2 tumors is absolutely

One notional therapeutic advantage of targeting Myc function in cancers is its lack of functional redundancy, thus constraining opportunities for evolution of resistance. Since Myc inhibition is so effective at restraining RIP1-Tag2 tumor expansion, we reasoned that it must potently select for mechanisms by which tumor clones escape its grip, and, indeed, we did observe occasional individual islet tumors in TRE-Omomyc;CMVrtTA;RIP1-Tag2 mice (∼0.4% of all tumors) that failed to regress following doxycycline treatment (Fig. 9A). To determine the mechanism of their apparent resistance, we immunohistochemically assayed these rogue tumors for expression of Omomyc. In every instance (n = 7), the nonresponsive tumors were devoid of detectable Omomyc expression (Fig. 9B), while surrounding exocrine tissues clearly retained doxycycline-inducible Omomyc immunoreactivity, as did all those tumors that regressed in response to doxycycline. Hence, the only mechanism we observe by which RIP1-Tag2 tumors acquire refractoriness to doxycycline is through loss of the Omomyc transgene. Of note, such Omomyc-negative tumors exhibited both VEGF:VEGFR2 ligate distribution and immune cell recruitment identical to that of control RIP1-Tag2 tumors (Fig. 9C,D). Taken together, these data support the notion that Myc is an essential and nonredundant target whose function is absolutely required for RIP1-Tag2 tumor maintenance.


Discussion

We previously used a systemic, switchable dominant-negative approach to show that lung tumors driven by oncogenic KRas in vivo are continuously dependent on endogenous Myc function for their maintenance at all stages of their evolution (Soucek et al. 2008). However, neither the mechanism by which Myc inhibition triggers tumor regression nor the general applicability of Myc inhibition to other tumor types driven by other oncogenic mechanisms was known. Here, we show that inhibition of endogenous Myc also triggers regression of pancreatic islet tumors driven by SV40 large T and small t antigens in RIP1-Tag2 mice. Just as with KRasG12D-driven lung tumors, Myc inhibition elicits rapid and widespread onset of tumor cell arrest and apoptosis, culminating in universal regression of all tumors, irrespective of tumor grade or stage. Hence, endogenous Myc function is an obligate requirement for RIP1-Tag2 tumor maintenance. Extensive studies have delineated the mechanisms by which SV40-encoded large T antigen and small t antigen drive tumorigenesis. Large T antigen, SV40's principal oncoprotein, simultaneously incapacitates Rb and p53, the two principal tumor suppressors that restrain promiscuous proliferation. In parallel, small t modulates the pleiotropic impact of the PP2A Ser/Thr phosphatase that modulates multiple kinases downstream from Ras (Ahuja et al. 2005; Sablina and Hahn 2008). Any role played by endogenous Myc in SV40 transformation and tumorigenesis remains ill-defined. At no stage of RIP1-Tag2 islet tumor evolution do we observe any overt up-regulation of c-Myc protein (Supplemental Fig. 7), suggesting that oncogenically activated Myc is never the oncogenic “driver” of these tumors, but, instead, is a downstream effector of the SV40 T/t oncoproteins. Indeed, t antigen has been shown to enhance c-Myc activity by suppressing c-Myc dephosphorylation at Ser 62 and stabilizing the protein. Moreover, a stabilized c-Myc mutant can substitute for t-antigen expression in cell culture transformation assays (Sablina and Hahn 2008), again suggesting that endogenous Myc is a bona fide downstream effector of small t.

Large T's association with p300 is also thought to promote c-Myc activity and potentiate large T-mediated cell cycle entry and cell transformation (Singhal et al. 2008). Of note, the β cells within the regressed islet tumors in Omomyc-expressing TRE-Omomyc;CMVrtTA;RIP1-Tag2 mice remain clearly transformed even when Myc is inhibited. Hence, while growth and maintenance of macroscopic β-cell tumors driven by SV40 T/t require endogenous Myc, at least some cell-intrinsic aspects of SV40 T/t cellular transformation do not. It is also intriguing that, despite their transformed cytological features, the regressed islet tumors in Omomyc-expressing RIP1-Tag2 mice exhibit size, distribution, and α-cell to β-cell ratios similar to islets in normal littermates. Since the α-cell compartment does not expand alongside that of β cells during RIP1-Tag2 tumorigenesis, it would appear that the tumors regress back to both the size and site of their origins.

Tumor cells, like their normal counterparts, are completely dependent on their local microenvironment for provision of oxygen, nutrients, survival factors, and supporting stroma. Moreover, tumor growth, just like regeneration of normal tissues, requires a complex interplay between the expanding tissue and various accessory cells—most notably inflammatory cells, endothelial cells, and fibroblasts. However, the reciprocal interaction between tumor cells and stroma is complicated because it evolves over time, making it difficult to address the most important therapeutic question: Which driving processes within a tumor are causally responsible for maintaining the tumor microenvironment, and do those processes originate in the tumor cells themselves or within the multifarious stromal compartment? While multiple studies indicate that ectopic Myc drives and maintains multiple aspects of the tumor microenvironment in transgenic Myc-driven tumors (Pelengaris et al. 1999, 2002; Shchors et al. 2006; Soucek et al. 2007), the role played by endogenous Myc in tumors driven by other oncogenic mechanisms in other tissue types has remained unclear. Our data unequivocally show that short-term systemic Myc inhibition in TRE-Omomyc;CMVrtTA;RIP1-Tag2 β-cell tumors is sufficient to trigger collapse of the tumor microenvironment, with concomitant death of endothelial cells, attenuation of inflammatory cells, vascular collapse, and hypoxia.

Importantly, collapse of the tumor microenvironment temporally precedes detectable regression of tumors, implicating it as a potential cause, and certainly not just a consequence, of tumor regression. Moreover, since tumor regression occurs with identical kinetics and gross pathology when endogenous Myc is inhibited solely in the β-cell compartment, this confirms that it is endogenous Myc within the tumor cells themselves that is responsible for instating and sustaining the signal cross-talk between tumor and microenvironment. Of course, we cannot exclude the possibility that endogenous Myc may also play a tumor maintenance role in cells within the stromal compartment, a role that could further augment the therapeutic impact of any systemic Myc inhibitory therapy. Of note, our data support the notion that targeting Myc, a nonredundant obligate effector lying upstream of the plethora of signals that maintain the tumor microenvironment, may sidestep the adaptive compensation that bedevils existing anti-angiogenic and anti-inflammatory cancer therapies. These same obligate and nonredundant attributes also have the potential to minimize the other principal reason for failure of targeted therapies in cancer treatment; namely, the evolution within tumors of de novo mechanisms that circumvent the tumor cells' initial requirement for that target. In this regard, it is interesting that, out of several hundred individual β-cell tumors, each comprised of many thousands of tumor cells in which both Rb and p53 had been concomitantly incapacitated, the only occasional tumors in TRE-Omomyc;CMVrtTA;RIP1-Tag2 mice that were refractory to doxycycline had all lost expression of the Omomyc transgene, consistent with the idea that Myc inhibition per se cannot be circumvented by compensatory or evolutionary mechanisms. This, together with the remarkable mildness of side effects that systemic Myc inhibition elicits (Soucek et al. 2008), reinforces the notion that inhibiting Myc is an exceptionally promising and generic strategy for treating diverse cancers.

Geron To End Embryonic Stem Cell Research!(to focus research in either promising agent:oncology drug)

3 days ago,


IRA FLATOW, HOST:

This is SCIENCE FRIDAY. I'm Ira Flatow.

For the rest of the hour, we'll look at the state of embryonic stem cell research. Earlier this week, the Geron Corporation announced it was abandoning its research into using embryonic stem cells to treat spinal cord injury. Geron was the first company to get the green light from the FDA to conduct clinical trials using embryonic stem cells. That was way back in 2009. And now, citing, quote, "capital scarcity and uncertain economic conditions," the company is looking to sell off that part of its business and focus on other work.

Joining me now to talk about the announcement, what it means for other research using embryonic stem cells is Leonard Zon. He is an investigator at the Howard Hughes Medical Institute and also director of the stem cell program at Children's Hospital Boston and professor of pediatrics at Harvard Med School. Welcome to SCIENCE FRIDAY. Welcome back.

DR. LEONARD ZON: Oh, thank you, Ira. It's a pleasure to be here.

FLATOW: Is this a real blow to stem cell, the embryonic stem cell research?

ZON: Well, we're certainly saddened by the decision to stop the trial in its midst, and it is, you know, upsetting that something would get this far along and have an issue. I think there's a lot going on in the field, and we still are very excited about the promise of stem cell research. But I think, as this illustrates, funding that research and looking for the ultimate therapies is going to take some time.

FLATOW: It's sort of a purely business decision then?

ZON: From my understanding, that's what happened here. So the company Geron had two paths: one was an oncology drug that seemed rather promising, was in phase two trial, and the other was to continue its stem cell research. It was clear that they had put a lot of money into stem cell research, and so they thought that would be a good path. But having to choose one or the other, they then chose the oncology drug path.

Now, we don't know everything about those decisions, and obviously there were some patients who were treated. So we don't know if all the decision was made as a business decision. But that's what I've been told informally.
Baca Lagi(klik judul)......


FLATOW: So as you say, there were four patients who were under treatment, and they had hoped to treat 10 patients?

ZON: That's right. That's right. This is a very interesting trial. The idea was that there are embryonic stem cells which can make all the cells of your body, and these cells could be turned into supportive cells for neurons, for the brain cells and also for the spinal cord cells. And so the idea was once these cells were made, these supportive cells, they could be introduced into a patient who had a spinal cord injury, and they would start supporting the cells, and the repair of the neurons would be better if they were treated with the cell product. So, you know, we have four patients who are treated, and I guess they wanted to treat 10, and we'll have to follow those patients and see how they do.

FLATOW: 1-800-989-8255 is our number if you'd like to talk about this. You can also tweet us at scifri. These were early stage trial, right, just phase one?

ZON: That's right. So the idea was, really, a safety trial. If you were to take patients who are obviously devastated from having a spinal cord injury and then put in these supportive cells, we would want to make sure that they wouldn't cause any damage. And at least from the, you know, texts that we've had and other messages, it seems that there wasn't any major problem in terms of safety with the four patients who were treated.

A safety trial is only done for safety purposes. It's not to necessarily evaluate efficacy, how well it works. So I think we need to still see how the patients do, but again, it was to find out is the drug or these cells safe if you put them into a patient who's had a spinal cord injury.

FLATOW: By this company pulling out of actual testing of embryonic stem cell treatments, doesn't that cut drastically the number of companies left who are actually making those tests?

ZON: Yes, it's a very small list of companies. So actually, there's only one other company that's doing embryonic stem cell research, and that's a company called ACT. And they're trying to turn these embryonic stem cells into a cell that's in the eye. It's called a retinal pigment epithelial cell. But there are patients who have a genetic disease where those cells are defective, and they end up becoming blind. And the also more common disease, macular degeneration, also affects that cell population.

So that company hopes to use the embryonic stem cells to inject them into the eye and try to rescue the blindness or prevent the blindness that occurs in this particular genetic disease called Stargardt's disease. So short of that, there aren't other companies who are using embryonic stem cells, but there's a growing number of companies that are switching and trying to use reprogrammed skin cells.

When we talked last time a few years ago, we discussed how this new technology could take a skin cell and reprogram it to think it's an embryonic stem cell. And these cells, in many ways, have great abilities to be matched for the patient, let's say for their immune system. So there's a number of companies now who are trying to make those cells functional, and then trying to use them to do transplantation to fix a disease.

Those cells also end up being very interesting because you can make disease-specific cells. So you can take a disease and actually study it in a dish, a disease in a dish, and then try to find drugs that would be used to treat those diseases. And this is something that we're even seeing pharmaceutical companies get involved in, using stem cell technology.

FLATOW: What about the shortage now? As Geron backs out, don't they have a whole population of cells to use, and what's going to happen to that cell line or those cell lines that they have?

ZON: Absolutely. It's a very interesting discussion. We have to know that Geron has the largest number of cell lines that we know of for embryonic stem cells, and we would like to know what's going to happen to those stem cell lines. Obviously it's a business, and they probably will want, in their partnering opportunities, to sell it to another business. But it does create an issue for the stem cell field what will happen to those lines and how the - how will they be used in the future.

FLATOW: And would somebody take over continuing those lines, or do they just throw them out?

ZON: Well, that would be a very significant shame. I think that, you know, those lines are incredibly valuable, and we'd like to see them used for both biology as well as for medicine. And so, hopefully, they'll be placed in the care of a good company and they'll use them.

And, you know, I think what's interesting now when we look at this clinical trial is how it will - the results of the clinical trial actually get reported. You have four patients treated, and, you know, will they be followed? Will they be reported in the scientific literature? Those are also important things for the company to decide.

And if they're trying to partner that opportunity, how will their new partner or new - or when they sell the business, how will that company actually deal with that information? So both the lines as well as the dealing with the clinical trial that obviously these patients are already transplanted and will be followed, that's going to require some insight from the new company.

FLATOW: And if I recall, it was a huge regulatory hurdle for the company to overcome, all kinds of paperwork and documentation and expenses that way?

ZON: That's right. It's a - yeah. Absolutely. There was an amazing amount of paperwork that went into this. As you might expect when a totally new therapy comes about, the FDA is going to be involved in a very responsible way, ask for a number of experiments to be done, pre-clinical experiments that would allow them to ultimately do the trial. This took many, many years and many millions of dollars.

So, in a significant way, Geron has played an important role by forging this pathway of regulatory hurdles. So I think for future companies that come in, the FDA will know how to deal with this, to some degree, and I think that new therapies won't have to do as much work as has been done for Geron.

FLATOW: All right. Let's go to the phones, 1-800-989-8255. Let's go to Jerry(ph) in Cookeville, New Jersey. Hi, Jerry.

JERRY: Oh, that's Cookeville, Tennessee.

FLATOW: I'm sorry. Cookeville...

JERRY: That's OK.

FLATOW: That's close by, right?

JERRY: Yeah, but very interesting conversation with the - what the gentleman was just talking about with the human stem cells and all the promise that that's really showing. And as far as embryonic stem cells go, I really don't think that it's really done a whole lot, you know, considering all the different treatments. They use human stem cells. I mean, before long that will be like wanting to keep building wagons when the car is the wave of the future.

ZON: Well, I think it's interesting that the embryonic stem cell field really started in 1998 when the first human embryonic stem cells were derived. And you have a need to study those cells for many years before they can become interesting for biology, but also interesting as new therapies.

I often discuss - if you look at the history of organ transplant, for instance, bone marrow transplantation, a procedure that's done every day - even here at Children's Hospital we do hundreds every year - what happens is is that, in 1961, there was the discovery of the stem cell, and it didn't become a standard of therapy until about the late 1970s. So there's a large gap between the initial discoveries and then ultimately being successful.

And I do think that what this illustrates from Geron is it took a long time for the company to actually get this therapy into a patient, and that was very costly to deal with all the regulatory hurdles. And so that timeline is just not appetizing for venture capital companies as well as for large pharma. And so the timeline is long, and I think that makes people think, as the caller just said, that it's taking a long time before embryonic stem cells could be therapeutically useful.

FLATOW: Isn't that the weakness of the system, of allowing pharma to do this kind of research instead of having it, let's say, federally funded at NIH or someplace to develop this therapy? Because if they don't do it, if they drop it, it's not going to be developed.

ZON: Well, as you know, the entire field of organ transplantation was done completely academically initially. And then once it was clear that it was successful - and I would argue as soon as there's a success for embryonic stem cells or these new reprogrammed skin stem cells - then there will be an entire industry around being able to make it better.

I do think we were held up tremendously by NIH funding, which was not available in the 1990s through a presidential policy. But then, over time, that's been loosened up, and there is more money for embryonic stem cell research, and also for these skin reprogrammed cells that the NIH is investing in that particular area. So hopefully this will continue and that we'll see, over time, and, you know, over coming years, that this will be interesting therapeutically.

FLATOW: Mm-hmm. And where do we - let's talk about these stem cells, not the embryonic ones, but the other kinds that people can actually use their own cells and reprogram them. Is there any one disease to you, looking, surveying the field, that seems most promising at this point?

ZON: Well, I mean, at Children's Hospital, we're trying to use these to turn those cells into blood stem cells and being able to use those for patients who don't have a donor for marrow transplantation. I think that there's a lot of research going on in these skin cells - they're called iPS cells - and these skin cells, again, could be made from patients who have a particular disease. So we are making hundreds of lines of different genetic diseases.

We just made lines from a very rare blood disease - there's only 100 patients in the world who have that particular disease - so that we can study it and understand it. We make it from very common diseases, diabetes and Parkinson's disease also. So pretty much stem cell research could help the many diseases, but they're going to require significant investigation to study each of those diseases and their organs that are affected.

FLATOW: I'm Ira Flatow. This is SCIENCE FRIDAY from NPR. Talking with Leonard Zon, investigator at the Howard Hughes Medical Institute. Our number: 1-800-989-8255. Let's go to Richard in Penngrove, California. Hi.

RICHARD: Hi, Ira. Just love the show. And, Dr. Zon, I wondered if you were aware - I'm sure you are - of the story, which I only heard about on NPR in the last couple of days. And you'll forgive me. I've forgotten - I don't even think it was in the United States, and probably not because of the unfortunate backward policies that have caused some delay in our research. But the young - the very young, actually, baby - I guess it was in the first five days - was born and - either obtained or born with a virus which destroyed its - the young person's liver.

They were - they had done some clearance work before in research, before and had approval to go ahead, and this was the first case, apparently, that it was appropriate, injecting a liver stem cell into the young person - injecting or placing, I don't know how it was - with a coating from an algae, which allowed the membrane of the algae to provide a protective coating against the virus but permeable still so that it could actually take over and support liver functions until the young person's liver is healthy enough to restore him to normal health. And I believe he's several months old. Are you aware of this, sir?

ZON: Well, I'm, you know, I don't know that particular case. I heard a little bit about it, but not that much about it. It does illustrate how you can use a variety of cells and do transplantation and really affect things, affect organ function. And so we're just at the beginning of seeing how cell therapy can actually work, and so we see a number of studies to try to fix different heart disease and also, as you're illustrating, liver disease. I think that it's important that the people who are listening realize that some of these therapies are rational and have a scientific basis and should be done, and I believe what you're talking about was done in the correct - in a reputable institution.

I also just want to say that we are very concerned about stem cell tourism, so you do need to worry about some company, let's say, that is telling you they'll fix any type of disease through a particular cell population. And very frequently, we find that that group of companies is trying to make money rather than actually trying to help people. Having said that, I don't know this particular instance, so it sounds very fascinating.

FLATOW: But what you're saying is that as soon as someone, some company has a breakthrough in this and creates a real product, everybody else will want to join in on the bandwagon and starts investing more money and research in it.

ZON: I think that's true. I mean, we go back to - if you think about IVF, and at a certain point in time, there was a large debate about whether this was ethical as well as whether it should be done at all. And then as soon as there was a baby, I think that entire debate went away. I think if you look at organ transplants in the early - in the '60s and '70s, there were a number of patients who did extremely poorly from organ transplants and a number of the doctors were heavily criticized by trying to do these types of procedures as, you know, it would never work. But then as soon as there was a success, the entire field became much more invigorated, and we were able to see how it could become an industry as well as it could become a standard of therapy.

FLATOW: Dr. Zon, thank you for taking time to be with us today.

ZON: Well, thank you, Ira. It's a pleasure.

FLATOW: Happy holidays to you. Leonard Zon is a professor of pediatrics at Harvard Med School and also director of the Stem Cell Program at Children's Hospital in Boston.

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transendensi satu(and the sihr beyond...)

matematika memang bukan pelajaran favoritku.sungguh...jadi harus diperjelas dulu disini bahwa ini cuma sekedar tulisan iseng saja.tidak bermaksud sok tahu.
berbicara tentang angka,angka satu memang sepertinya memiliki keunikannya.keunikan yang tampak nyata sekali ketika kita melihat pada pertidaksamaan diatas,atau disebut juga dengan Liouville constant.
bukan teori ini yang kubicarakan karena terus terang saja aku juga masih bingung sama penjelasan yang diberikan oleh wikipedia tentang konstanta ini.
tapi aku ingin berbicara tentang angka satu,misterinya,...transendensinya...

Baca Lagi(klik judul)......
Hari ini,tepatnya tanggal 11-11-11.banyak orang gembira dihari ini.di televisi disiarkan berita tentang pasangan yang menikah dihari ini.begitu banyak sekali..sampai ada yang menikah dengan 2 orang perempuan sekaligus ckckck.
memangnya ada apa dengan hari ini?dan apa sih istimewa hari ini?
kalau aku boleh menduga mungkin karena tanggal ini adalah kombinasi yang sempurna dari angka satu.seluruh angka yang muncul dihari ini adalah satu.perasaan juga hari raya idul adha sudah berlalu seminggu tapi.masih tetap terasa meriahnya mungkin juga karena hari ini.hari yang unik..

oke..kembali ke angka satu dan transendentalitasnya.
banyak sekali contoh-contoh yang menunjukkan istimewanya angka ini.dengan sedikit menafikan angka nol untuk ketidaksuksesan errorr.angka satu sepertinya adalah sebuah solusi yang praktis dan efisien.
mungkin pernah ditulis diblog ini tentang penemuan kapal nabi Nuh yang 99,99persen akurat.entah aku harus percaya atau tidak dengan berita ini,tetapi kalau dipikir-pikir masih ada kemungkinan 0.000000000....1 ketidakakuratan dalam cerita ini.ketidakakuratan yang berkarat dalam dongeng yang terlarang untuk dibaca..

lalu ada contoh ekstrim lain,seperti misalnya fakta bahwa massa atom 99,95persen berada dan terpusat pada inti atom.hal ini selain menawarkan pada kita tentang probabilitas bahwa pasti tersedia cukup massa pada pusat galaksi yang menjaga agar galaksi tetap utuh juga menawarkan probabilitas lain bahwa massa atom TIDAK semuanya berada pada inti atom.hanya oleh koreksi kecil saja probabilitas telah menjadi tersebar dan nampak menjadi variable didepan mata kita.

mungkin itulah sedikit ke-istimewaan dari angka satu.juga ada sedikit cerita diblog ini juga tentang seekor siput yang berjalan keluar dari sumur dengan perjalanan sehari ini yang sama dengan modulus dua dari perjalanannya esok.siput akan sampai dibibir sumur tepat pada 0.01 cm dari bibir sumur.ini sepertinya probabilitas kedua yang menawarkan solusi yang tak terdebatkan.

kembali kepada keunikan hari ini.sepertinya juga banyak bayi-bayi yang lahir dihari ini.walaupun banyak diantara meraka yang dicesar tetapi terlahir pada tanggal 11-11-11.sebuah kombinasi angka yang luar biasa mantap dan adalah juga sebuah keistimewaan tersendiri..hehe

posting gambar buat blog

Baca Lagi(klik judul)......

Humberto Maturana.Prof

"Living systems are cognitive systems, and living as a process is a process of cognition. This statement is valid for all organisms, with or without a nervous system."

sistem hidup adalah sistem kognisi,dan kehidupan dalam proses-proses adalah kognisi.pernyataan ini menjelma di seluruh organisme,dengan atau tanpa sistem syaraf.
ini adalah sebait pernyataan atau lebih tepatnya sebuah hipotesa yang ditawarkan oleh Maturana.
Humberto Maturana ilmuwan kelahiran Santiago,Chile dan berdiam disana(bekerja sebagai neurosaintis di pusat riset "Biologia del Conocer") namun perkembangan pendidikannya banyak dihabiskan di Amerika.Disana Prof.Maturana bertemu dengan banyak sekali jenius-jenius lain yang memberinya sebuah pertanyaan,bagaimanakah?apakah?darimanakah?dan mampukah sebuah sistem mempertahankan dirinya didalam kubangan kompleksitas-kompleksitas.

Yang oleh Alexander Bogdanov,seorang ilmuwan yang lain lagi dari Rusia,diberi nama Tektology.

Mampukah sebuah sistem mempertahankan diri dalam artian jauh dari keseimbangan.sebuah sistem apakah,yang terbuka secara energi namun tertutup secara organisasional selain dari organisme hidup yang tidak hanya mempertahankan kehidupan tetapi juga mengembangkan proses-prosesnya didalam sebuah sistem yang "stabil jauh dari keseimbangan".

Baca Lagi(klik judul)......


Humberto Maturana
From Wikipedia, the free encyclopedia...

Humberto Maturana (born September 14, 1928, in Santiago, Chile) is a Chilean biologist and philosopher. He is considered a member of the second wave of cybernetics, known for developing a theory of autopoiesis about the nature of reflexive feedback control in living systems.

Biography

After completing secondary school at the Liceo Manuel de Salas in 1947, Maturana enrolled at the University of Chile, studying first medicine then biology. In 1954, he obtained a scholarship from the Rockefeller Foundation to study anatomy and neurophysiology at University College London. He obtained a PhD in biology from Harvard University in 1958.

He works in neuroscience at the University of Chile, in the research center "Biología del Conocer" (Biology of Knowledge). Maturana's work has been developed and integrated into the work on Ontological coaching done by Fernando Flores and Julio Olalla.

As of the year 2000, professor Maturana established his own reflection and research center: the Instituto de Formación Matriztica.

Work

Maturana's work extends to philosophy and cognitive science and even to family therapy. He was early inspired by the work of the biologist Jakob von Uexküll.

Constructivist epistemology

Maturana and his student Francisco Varela were the first to define and employ the concept of autopoiesis. Aside from making important contributions to the field of evolution, Maturana is also a founder of constructivist epistemology or radical constructivism, an epistemology built upon empirical findings of neurobiology.

Maturana and Varela wrote in their Santiago Theory of Cognition: "Living systems are cognitive systems, and living as a process is a process of cognition. This statement is valid for all organisms, with or without a nervous system."[2]

Cultural biology

At the Instituto de Formación Matríztica Maturana has contributed extensively to the Biology of knowledge and the biology of loving. At this point, Maturana has formulated new perspectives about human life and continues to do so. Psychology, the use of language, experience, and the general impulse to understand serve as explanatory bases for the depiction of human ways of life. In this way, they are proposing the notion of "Cultural biology" as the intertwinement and dynamic of the biology of knowledge and the biology of loving as a manner to present both cultural and biological bases of human existence.