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Extracellular Signal-Regulated Kinases 1 and 2 Regulate the Balance Between Eccentric and Concentric Cardiac GrowthNovelty and Significance
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Rationale: An increase in cardiac afterload typically produces concentric hypertrophy characterized by an increase in cardiomyocyte width, whereas volume overload or exercise results in eccentric growth characterized by cellular elongation and addition of sarcomeres in series. The signaling pathways that control eccentric versus concentric heart growth are not well understood.
Objective: To determine the role of extracellular signal-regulated kinase 1 and 2 (ERK1/2) in regulating the cardiac hypertrophic response.
Methods and Results: Here, we used mice lacking all ERK1/2 protein in the heart (Erk1−/− Erk2fl/fl-Cre) and mice expressing activated mitogen-activated protein kinase kinase (Mek)1 in the heart to induce ERK1/2 signaling, as well as mechanistic experiments in cultured myocytes to assess cellular growth characteristics associated with this signaling pathway. Although genetic deletion of all ERK1/2 from the mouse heart did not block the cardiac hypertrophic response per se, meaning that the heart still increased in weight with both aging and pathological stress stimulation, it did dramatically alter how the heart grew. For example, adult myocytes from hearts of Erk1−/− Erk2fl/fl-Cre mice showed preferential eccentric growth (lengthening), whereas myocytes from Mek1 transgenic hearts showed concentric growth (width increase). Isolated adult myocytes acutely inhibited for ERK1/2 signaling by adenoviral gene transfer showed spontaneous lengthening, whereas infection with an activated Mek1 adenovirus promoted constitutive ERK1/2 signaling and increased myocyte thickness. A similar effect was observed in engineered heart tissue under cyclic stretching, where ERK1/2 inhibition led to preferential lengthening.
Conclusions: Taken together, these data demonstrate that the ERK1/2 signaling pathway uniquely regulates the balance between eccentric and concentric growth of the heart.
The myocardium undergoes cellular and ventricular chamber remodeling and/or hypertrophy as a means of augmenting or maintaining cardiac output in response to increased workload or pathological insults. Cardiac hypertrophy is an independent risk factor for heart failure, arrhythmias, sudden cardiac death, and cardiovascular morbidity and mortality.1,2 The fundamental response of the myocardium to an increase in afterload is termed concentric hypertrophy, which consists of an increase in ventricular wall thickness without chamber enlargement.3 In contrast, conditions that increase preload, including significant valvular regurgitation and volume overload, promote chamber dilatation with no increase or even a decrease in left ventricular wall thickness, a process involving eccentric hypertrophy.
The concentric and eccentric hypertrophy of the entire myocardium is mainly the result of different modes of cardiomyocyte cell growth.4 In eccentric hypertrophy, there is preferential assembly of contractile protein units in series, leading to a relatively greater increase in the length than the width of myocytes. Concentric hypertrophy results from an assembly of contractile protein units in parallel with a relative increase in the width of individual cardiac myocytes.5,6 Concentric and eccentric growth likely result from orchestrated activation of specific intracellular signaling pathways, although the identity and mechanisms whereby these signaling pathways differentially regulate myocyte growth are not currently known.
The mitogen-activated protein kinases (MAPKs) have been implicated as focal mediators of cardiac hypertrophy in both cell culture and genetically modified mouse models.7 For example, the extracellular signal-regulated kinases 1 and 2 (ERK1/2) branch of the greater MAPK signaling cascade appears to induce a unique form of concentric cardiac hypertrophy in transgenic mice caused by expression of activated MAPK kinase (Mek)1.8 Moreover, dozens of studies conducted in cultured cardiac myocytes have suggested that ERK1/2 signaling is necessary for promoting hypertrophic growth.9 Signaling through the ERK1/2 cascade is classically initiated at the cell membrane by activation of the small G protein Ras that then recruits the MAP3K Raf-1 to the plasma membrane, where it is activated.10 ERK1/2 also become activated in cardiac myocytes in response to many stimuli, such as G protein–coupled receptor agonists, receptor tyrosine kinase agonists, cytokines, reactive oxygen species, and stretch.7 These various stimuli initiate MAP3Ks, which then phosphorylate and activate the dual-specificity kinases MEK1 and MEK2 (MAP2Ks) that serve as dedicated kinases for ERK1/2 phosphorylation and activation.11
Interestingly, although transgenic mice overexpressing an activated form of Mek1 develop concentric hypertrophy, inhibition of ERK1/2 by overexpression of dual-specificity phosphatase (DUSP)6, which inactivates ERK1/2 in the heart, did not reduce cardiac hypertrophy following multiple pathological stimuli.12 These results suggest that although activation of MEK1-ERK1/2 signaling can program cardiac hypertrophy, ERK1/2 signaling may not be needed for cardiac hypertrophy induced by pathological stimuli. These seemingly contradictory findings may be attributable to the type of cardiac growth that results from ERK1/2 activation or inactivation, such as concentric versus eccentric cardiac growth. Indeed, here, we show that ERK1/2 activation specifically leads to concentric cardiac growth at the level of the cardiac myocyte, whereas inhibition of ERK1/2 preferentially permits eccentric growth. Through the combined use of Erk1- and Erk2-null mice, activated Mek1-expressing transgenic mice, and adult cardiomyocytes in culture, we show that ERK1/2 regulate the ability of myocytes to grow either in width (concentric) or in length (eccentric). Thus, the MEK1-ERK1/2 pathway may be the first identified signaling pathway capable of specifically directing the mode of cardiomyocyte hypertrophy.
An expanded Methods section is available in the Online Data Supplement at http://circres.ahajournals.org.
Animal Models
Erk1−/− animals have been described previously.13 Erk2-loxP (fl) mice were described recently.14 The Nkx2.5-Cre knock-in mice,15 as well as transgenic mice in which a nuclear-localizing Cre cDNA was placed under the control of the mouse α-myosin heavy chain (αMHC) promoter, have also been described previously.16 Echocardiography for assessment of ventricular size and function was performed in 2% isoflurane-anesthetized mice.16
Western Blotting
Generation of protein samples from tissue, along with Western blotting and chemifluorescent detection, have been described previously.8 All antibodies were obtained from Cell Signaling Biotechnology (Beverly, Mass).
Histology and Staining
Hearts were collected at the indicated times, fixed in 10% formalin-containing PBS, and embedded in paraffin. Serial 5-μm heart sections were cut and stained with hematoxylin/eosin or Masson trichrome.
Invasive Hemodynamic Studies
Invasive hemodynamics in the closed-chest mouse was performed with a 1.4F Millar catheter (Millar Instruments, Houston, Tex) as described previously.17
Loss of ERK1/2 From the Heart Induces Hypertrophy and Early Adult Lethality
Previous studies have shown that Erk1-null mice have normal cardiac structure and function,12 although it was not possible to examine Erk2-null mice because of embryonic lethality.14,20 To circumvent this problem and to unequivocally determine the necessary function of both ERK1/2 in the heart as hypertrophic mediators, we crossed Erk1−/− mice with Erk2fl/fl targeted mice and a cardiac Cre-recombinase–expressing mouse line. We used both Nkx2.5-Cre knock-in mice and transgenic mice expressing Cre under the control of the mouse αMHC promoter.16 Western blotting showed absence of ERK1 protein (upper band) and very efficient depletion of ERK2 protein (lower band) in the same mutant hearts with either the Nkx2.5-Cre or αMHC-Cre lines (Figure 1A). No other changes were observed in ERK5, p38, or c-Jun N-terminal kinase protein levels or phosphorylation, although MEK1/2 were hyperphosphorylated with ablation of Erk1/2, highlighting a negative-feedback mechanism (Figure 1A).21
Whereas mice of the genotype Cre, Erk1−/− Cre, Erk2fl/fl Cre, and Erk1−/− Erk2fl/fl had normal lifespans, Erk1−/− Erk2fl/fl-Cre (both αMHC-Cre and Nkx2.5-Cre) began dying after 60 days of age and none survived beyond 7 months (Figure 1B and data not shown). Interestingly, surviving Erk1−/− Erk2fl/fl-Cre mice showed spontaneous cardiac hypertrophy as defined by an increase in heart weight normalized to body weight (Figure 1C and 1D). This increase in heart weight also correlated with induction of the hypertrophic gene program, such as increased mRNA for Nppa, Nppb, Acta1, and Myh7 (Figure 1E). Histological analysis of these hearts showed ventricular dilation by 60 to 90 days of age with areas of mild fibrosis, as assessed with Masson trichrome staining (Figure 1F and 1G; Online Figure I, B and D). However, analysis of cardiac histological sections and isolated cardiomyocytes did not show changes in myofiber organization or sarcomeric structure (Online Figure I, E and F). Analysis of apoptosis by TUNEL staining in these null hearts did not show increased cell death at baseline in 60- to 90-day-old mice (Online Figure I, A and C). Thus, loss of Erk1/2 from the heart induces pathology and a form of hypertrophy without increased cell death.
Careful assessment of cardiac ventricular chamber dimensions showed dilation beginning even at 30 days of age in Erk1−/− Erk2fl/fl-Nkx-Cre mice, which became more pronounced by 60 and 90 days with both Cre lines (Figure 2A). Corresponding with ventricular dilation, cardiac ventricular performance, as measured by echocardiography, was significantly and progressively reduced at 30, 60, and 90 days of age in Erk1−/− Erk2fl/fl-Cre mice (both Nkx2.5-Cre and αMHC-Cre lines) (Figure 2B). Analysis of cardiac contractility with a Millar catheter also showed a severe reduction in function in Erk1−/− Erk2fl/fl-Nkx-Cre mice at 60 days of age at baseline and with increasing dosages of dobutamine (Figure 2C). However, Erk1−/− Erk2fl/fl-Nkx-Cre mice were not in overt heart failure at the age of 60 days because left ventricular end diastolic filling pressures were not elevated, nor was lung edema observed (Figure 2D and data not shown). Myocytes isolated from hearts of Erk1−/− Erk2fl/fl-Nkx-Cre mice even showed enhanced contractility when compared to control cardiomyocytes (Online Figure II). However, with just 30 more days of age (90 days) double-null mice developed overt failure with significantly reduced cardiac function and pulmonary edema, as demonstrated by increased lung weight/body weight ratio (Figure 2E). Although resting ECG recordings were normal in the Erk1−/− Erk2fl/fl-Nkx-Cre mice (data not shown), there may be some contribution of arrhythmia to the lethality as these mice aged and dilatory growth became extreme. Thus, we believe that overt heart failure is the primary cause of lethality in Erk1−/− Erk2fl/fl-Cre mice, as also evidenced by panting and reduced mobility with aging (Online Movie).
Loss of ERK1/2 From the Heart Does Not Reduce Stress-Induced Hypertrophy
Although Erk1−/− Erk2fl/fl-Cre mice showed spontaneous cardiac hypertrophy with aging, it was still formally possible that loss of ERK1/2 from the heart might attenuate stress-induced cardiac hypertrophy, given the countless studies that have suggested a necessary role for this signaling pathway in transducing growth of cultured cardiomyocytes. To address this issue, we first subjected 45-day-old Erk1−/− Erk2fl/fl-Nkx-Cre mice to 14 days of angiotensin II/phenylephrine (Ang II/PE) infusion to induce pathological hypertrophy. Erk1−/− Erk2fl/fl control mice showed a significant increase in cardiac hypertrophy after 14 days of infusion, which was similar to the percent increase in heart weight observed in Erk1−/− Erk2fl/fl-Nkx-Cre mice after infusion (Figure 3A). However, Erk1−/− Erk2fl/fl-Nkx-Cre mice showed a greater increase in left ventricular end diastolic dimension (LVEDD) and a greater decrease in fractional shortening (FS) compared with control mice after 14 days of Ang II/PE infusion (Figure 3B and 3C).
We also attempted to perform transverse aortic constriction (TAC) on Erk1−/− Erk2fl/fl-Nkx-Cre mice to assess their hypertrophic potential with this more potent stimulus but were unsuccessful because all succumbed to rapid lethality given their compromised state. However, we were able to perform TAC on Erk1−/−αMHC-Cre mice, Erk2fl/fl-αMHC-Cre mice, and αMHC-Cre control mice for 2 weeks beginning at 60 days of age. Western blotting confirmed deletion of ERK1 protein in Erk1−/−αMHC-Cre mice and ERK2 protein in Erk2fl/fl-αMHC-Cre mice (Online Figure III, A). Although all groups showed the same heart weights, ventricular chamber dimensions and FS under sham conditions, Erk2fl/fl-αMHC-Cre mice showed significantly more cardiac hypertrophy after TAC and a greater reduction in FS but no change in LVEDD (Figure 3D through 3F; Online Figure III, B through D). These results again suggest that ERK1/2 are not required for cardiac hypertrophy, and, if anything, a loss of ERK1/2 from the heart produced slightly more growth with pathological stimulation.
The loss of ERK1/2 also did not prevent physiological exercise–induced hypertrophy (Online Figure IV, A through C), a stimulus that itself tends to induce eccentric heart growth. Indeed, Erk1−/− Erk2fl/fl-Nkx-Cre mice actually developed significantly more cardiac hypertrophy with swimming exercise compared with controls, which was associated with greater chamber dilation and an even greater increase in myocyte length without an increase in myocyte thickness (Online Figure IV, A through D).
Loss of ERK1/2 Induces Preferential Eccentric Cardiomyocyte Growth
Hearts from Erk1−/− Erk2fl/fl-Cre mice showed robust dilation and loss of whole-organ function, even though isolated myocytes from these hearts were not functionally compromised. This suggested that loss of ERK1/2 from the heart induced failure resulting from extreme ventricular remodeling, dilation, and increased wall tension but not caused by myocyte dysfunction, as is typically observed in most other forms of heart failure. To further understand the cellular mechanism underlying these observations, we first isolated adult myocytes from hearts of Erk1−/− Erk2fl/fl-Nkx-Cre mice and compared them with myocytes from transgenic mice expressing activated (a) MEK1 (greater ERK1/2 activation). Remarkably, adult myocytes from hearts of Erk1−/− Erk2fl/fl-Nkx-Cre mice were significantly longer, whereas aMEK1 myocytes were wider and shorter (Figure 4A and 4B). Indeed, the length/width ratios between these 2 genotypes was even more pronounced, suggesting that ERK1/2 activation promotes concentric myocyte growth, whereas loss of ERK1/2 results in a default program of eccentric growth (Figure 4C). This growth relationship was even more pronounced after Ang II/PE stimulation, where myocytes from hearts of Erk1−/− Erk2fl/fl-Nkx-Cre mice showed an even greater increase in cell length, although some increase in width was observed (Figure 4D and 4E). Similarly, as discussed above, swimming exercise caused significantly greater elongation of Erk1−/− Erk2fl/fl-Nkx-Cre cardiomyocytes compared with controls, without an increase in width (Online Figure IV, D).
To investigate the mechanism of cellular growth associated with ERK1/2 activity in adult myocytes, we performed 2 additional assays. First, we isolated adult rat cardiomyocytes and infected them with recombinant adenoviruses encoding β-galactosidase (control) or dominant-negative (dn) Mek1 and Dusp6 together to achieve complete inhibition of ERK1/2 signaling over 3 days in serum-free cultures (Figure 5A). Reciprocally, we infected myocytes with a recombinant adenovirus encoding aMEK1 to induce constitutive ERK1/2 signaling over 3 days (Figure 5A). Myocytes were then immunostained for α-actinin and measured for length and width (Figure 5B). Remarkably, inhibition of ERK1/2 produced longer myocytes, whereas activation of ERK1/2 produced wider myocytes, with even greater differences in length-width ratios (Figure 5C and 5D). Although this was a static cell culture–based model system, it nonetheless again suggested that ERK1/2 were regulating the intrinsic growth response of the myocyte to discriminate between length and width. As a control, coinfection of Ad-Dusp6 with Ad-aMEK1 fully inhibited ERK1/2 phosphorylation, showing that Dusp6 dominates over aMek1 (Online Figure V, A). More importantly, Ad-aMek1-induced cardiomyocyte concentric growth was fully blocked by Ad-Dusp6 coinfection, conclusively indicating that aMek1 only functions through ERK1/2 in programming growth and that aMek1 has no function on its own apart from ERK1/2 (Online Figure V, B and C).
As a second, potentially more "physiological" assay, we used engineered heart tissues (EHTs) wherein neonatal rat cardiomyocytes are reconstituted in an anisotropic myocardial syncytium under defined mechanical load.22 After 7 days in culture, EHTs were infected with a combination of adenoviral vectors encoding dnMek1 and Dusp6 to inhibit ERK1/2 signaling or a control green fluorescent protein (GFP)-encoding virus (Figure 5E). The EHTs were subsequently transferred to a stretch device and submitted to unidirectional cyclic stretch for an additional 5 days. Unlike the in vivo situation, EHTs are not affected by confounding compensatory mechanisms such as neurohumoral stimulation. In addition, mechanical load on the cardiomyocytes in EHTs are similar between groups, and any alteration in morphology is only associated with an intrinsic change in the cardiomyocyte growth program. On culture day 12, EHTs were dispersed with a collagenase mixture, and cells were fixed and stained with sarcomeric α-actinin to assess cell dimensions (Figure 5F). In accordance with our observations in vivo, the ex vivo inhibition of ERK1/2 signaling in the EHT system also resulted in a significant increase in cell length and a significant reduction in cell width (Figure 5F and 5G). These results again demonstrate the ability of the ERK signaling cascade to directly modulate cell size, independently of effects on contractility.
Our results suggest a model whereby ERK1/2 signaling is necessary to prevent eccentric cardiomyocyte growth. Indeed, Erk1/2 double-null ventricular myocytes lengthen and become slightly thinner with aging and pathological stimulation to cause whole-organ eccentric growth. Antithetically, activation of ERK1/2 with aMek1 preferentially programmed concentric cardiac growth, while, at the same time, partially inhibiting eccentric growth. These results suggest a refined hypothesis whereby ERK1/2 are not technically necessary for whole-organ hypertrophy, as measured by heart weight normalized to body weight, but are necessary for promoting a properly coordinated growth response that also allows myocyte thickening and addition of sarcomeres at the periphery (Figure 6). Thus, ERK1/2 signaling is necessary for facilitating a select type of cardiac growth in vivo, concentric hypertrophy, while, at the same time, preventing eccentric growth and addition of sarcomeres in series (Figure 6).
The model of growth proposed above is also consistent with previous work in which we inhibited the ERK1/2 pathway in vivo using a transgene to overexpress Dusp6 in the heart.12 Dusp6 transgenic mice showed complete loss of ERK1/2 phosphorylation and activity, although the cardiac hypertrophic response was not reduced following TAC or agonist infusion.12 In fact, Dusp6 transgenic mice subjected to long-term TAC showed even larger increases in heart weights compared with control mice, an increase that was associated with chamber dilation, suggesting greater eccentric growth. Thus, although we had not previously measured cellular lengths and widths in Dusp6 transgenic hearts, their increased propensity toward dilation with pathological stimulation suggests a similar mechanism in play, whereby loss of ERK1/2 signaling promotes cardiomyocyte lengthening.
To our knowledge the MEK1-ERK1/2 signaling pathway appears to be unique in its ability to regulate both the length and width decision of a myocyte with aging or stress stimulation. Previously, activation of the MEK5-ERK5 signaling pathway was reported to produce eccentric cardiac hypertrophy by lengthening myocytes, although the reciprocal relationship of increased width was not examined in Mek5 or Erk5 gene-deleted mice.23 Moreover, many transgenic mouse models of cardiomyopathy and heart failure lead to spontaneous dilation with myocyte lengthening, such as with myocyte enhancer factor-2 overexpression.24,–,26 The data we present with the MEK1-ERK1/2 pathway are unique because activation of this pathway leads to myocyte thickening, whereas loss leads to myocyte lengthening without cellular dysfunction, suggesting it is a primary effect. Moreover, growth of adult myocytes in culture over 3 days showed the exact same relationship, and even myocytes from beating and cyclically stretched EHTs showed the same effect. Because nearly all other transgenic models of heart failure appear to cause secondary dilation, we believe that the MEK1 effect in driving concentric hypertrophy is highly unique and suggestive of a true biological signaling pathway whose role is to program myocyte thickening.
Ventricular dilation can result from either myocardial cell elongation through an addition of contractile protein units in series or myocyte slippage and changes in wall architecture.27 Either event, or a mixture therein, changes the geometry of the ventricle by increasing the internal radius and thinning of the free wall, resulting in greater wall tension and secondary neuroendocrine stress signaling.28 In fact, according to Laplace's law, our echocardiographic measurements in hearts from Erk1−/− Erk2fl/fl-Cre mice suggest an almost doubled load at the end of diastole as compared with control mice. This significantly increased load could explain the reduced FS observed in hearts from Erk1−/− Erk2fl/fl-Cre mice, leading to secondary induction of hypertrophic marker gene expression, fibrosis, and mild desensitization to β-adrenergic receptor agonists. Indeed, volume overload–induced eccentric hypertrophy caused by mitral regurgitation can also lead to mechanical dysfunction.29 However, this reduction in whole-organ function and secondary disease manifestations are unlikely the result of a primary defect in myocyte contractility in the absence of ERK1/2, because adult myocytes from these hearts showed even better functional performance in isolation. Such results from Erk1/2-deleted adult myocytes are in stark contrast to the observed slowing of contraction in unloaded myocytes from other models of heart failure.30 Such a dramatic increase in series sarcomeres without matching concentric growth of sarcomeres on the periphery of the fibers likely promotes whole-organ dysfunction through dilation and dramatically increased wall tension with less myocyte–myocyte connectivity.
Concentric hypertrophy usually results from pressure overload, whereas eccentric hypertrophy usually results from situations of volume overload or forms of exercise. However, almost all hypertrophic stimuli appear to activate and induce phosphorylation of ERK1/2.7 Together, these observations may suggest 2 divergent points of view. The more simplistic view suggests that the ERK pathway is activated in all types of hypertrophy to program concentric growth of myocytes. Therefore, in pressure overload, the MEK1-ERK1/2 pathway would work with other signaling pathways to add sarcomeres in parallel and increase the width of the cells, whereas in volume-overload situations, the ERK pathway would work against the machinery that drives the cell toward elongation. Alternatively, it is possible that volume overload does not lead to continual recruitment and activation of ERK1/2 in the myocyte or, more provocatively, could even lead to mild inhibition of ERK1/2 to permit preferential addition of sarcomeres in series. Unfortunately, the relationship between types of cardiac growth (concentric versus eccentric) and the associated profile of ERK1/2 activation has not been carefully mapped in vivo at multiple time points, although Toischer et al recently reported ERK1/2 activation at 24 hours of pressure-overload hypertrophy (with concentric myocyte growth) but not with an eccentric hypertrophy–promoting shunting procedure.31
The precise intracellular targets that are phosphorylated by ERK1/2 to mediate concentric growth and suppress eccentric growth have not been identified. In theory, ERK1/2 might phosphorylate one or more regulatory proteins that control sarcomeric assembly, such that ERK1/2 activation inhibits the construction of series units, whereas assembly of sarcomeres in parallel is enhanced. In addition to affecting assembly of sarcomeres, ERK1/2 might regulate the site of new protein synthesis within the sarcomeres, either at the periphery of a fiber area or within the middle of a fiber to produce lengthening (Figure 6). In addition to acute regulation of sarcomerogenesis, ERK1/2 activation might affect the type of hypertrophy through a transcriptional mechanism that secondarily affects how myocytes grow. ERK1/2 might also impact other signaling pathways that control other aspects of cardiomyocyte growth, although analysis of AKT, GSK3β, JAK/STAT, and calcineurin did not reveal differences among control, Mek1 transgenic, or Erk1−/− Erk2fl/fl-Cre mice (Online Figure VI).
Interestingly, autophosphorylation of ERK1/2 on Thr188, which directs ERK1/2 to phosphorylate nuclear targets, did not affect the growth response,32 suggesting that MEK1-ERK1/2 signaling within the cytoplasm may be more germane in controlling the type of growth that occurs. Indeed, ERK1/2 are known to directly phosphorylate the cytoplasmic ribosomal proteins p90 ribosomal S6 kinase (p90RSK) and p70S6K that could control protein synthesis.33 Clearly, additional studies are needed to identify the ERK1/2 effectors in hypertrophy and study them through gain- and loss-of-function approaches in vivo to assess their roles in concentric and eccentric hypertrophic growth.
Sources of Funding
This work was supported by grants from the NIH (to J.D.M.), the Fondation Leducq (Heart failure network grant to J.D.M), and the Howard Hughes Medical Institute (to J.D.M.). I.K. was supported by a long-term fellowship from the Human Frontiers Science Program. W.H.Z. is supported by the German Research Foundation (DFG ZI708/7-1, 8-1, 10-1) and the Federal Ministry of Education and Research (BMBF).
In October 2010, the average time from submission to first decision for all original research papers submitted to Circulation Research was 13.9 days.
Non-standard Abbreviations and Acronyms
- a
- activated
- Ad
- adenovirus
- Ang II
- angiotensin II
- dual-specificity phosphatase
- dn
- dominant negative
- engineered heart tissue
- extracellular signal regulated kinase
- fl
- loxP site
- fractional shortening
- green fluorescent protein
- left ventricular end diastolic dimension
- mitogen-activated protein kinase
- mitogen-activated protein kinase kinase
- myosin heavy chain
- phenylephrine
- transverse aortic constriction
- Received August 30, 2010.
- Revision received November 11, 2010.
- Accepted November 23, 2010.
- © 2011 American Heart Association, Inc.
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- Bueno OF,
- Molkentin JD
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- York A,
- Saba-El-Leil MK,
- Meloche S,
- Robbins J,
- Molkentin JD
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- 18.↵
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- Toischer K,
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Novelty and Significance
What Is Known?
An increase in afterload or preload induces cardiac concentric and eccentric hypertrophy, respectively.
The extracellular signal-regulated kinases (ERK) pathway is activated by stimuli inducing concentric hypertrophy.
Constitutive activation of the ERK pathway in the heart results in concentric hypertrophy.
What New Information Does This Article Contribute?
Increases in MEK1-ERK1/2 signaling directly programs myocyte thickening in vitro and in vivo.
Decreased or absent ERK1/2 signaling induces myocyte lengthening and eccentric hypertrophic growth.
Mice lacking ERK1/2 from the heart show eccentric cardiac growth at baseline and with stimulation.
We studied mice lacking all ERK1/2 protein in the heart and mice expressing activated Mek1 in the heart to evaluate the role of the ERK 1/2 signaling cascade in regulating the cardiac hypertrophic response. Whereas activation of the ERK pathway induced concentric hypertrophy, inhibition of this pathway resulted in eccentric hypertrophy. Using cardiomyocytes isolated from these mouse models, and using ex vivo culture models we show that these effects were mediated directly by ERK signaling. Greater ERK1/2 signaling directly programmed myocyte thickening, whereas inhibition of ERK1/2 signaling promoted myocyte lengthening. Thus, this study sheds light on the molecular mechanisms that are partially responsible for the differential hypertrophic response of the heart to an increase in preload versus afterload.
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- Extracellular Signal-Regulated Kinases 1 and 2 Regulate the Balance Between Eccentric and Concentric Cardiac GrowthNovelty and SignificanceIzhak Kehat, Jennifer Davis, Malte Tiburcy, Federica Accornero, Marc K. Saba-El-Leil, Marjorie Maillet, Allen J. York, John N. Lorenz, Wolfram H. Zimmermann, Sylvain Meloche and Jeffery D. MolkentinCirculation Research. 2011;108:176-183, originally published January 20, 2011https://doi.org/10.1161/CIRCRESAHA.110.231514
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- Extracellular Signal-Regulated Kinases 1 and 2 Regulate the Balance Between Eccentric and Concentric Cardiac GrowthNovelty and SignificanceIzhak Kehat, Jennifer Davis, Malte Tiburcy, Federica Accornero, Marc K. Saba-El-Leil, Marjorie Maillet, Allen J. York, John N. Lorenz, Wolfram H. Zimmermann, Sylvain Meloche and Jeffery D. MolkentinCirculation Research. 2011;108:176-183, originally published January 20, 2011https://doi.org/10.1161/CIRCRESAHA.110.231514


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The State Office Building dominates the scene in this photo taken in the summer of 1979. The building on the lower left hand corner next to the SOB parking lot housed Thibodeau's Cash and Carry, Thibodeau's Market and Sally's Kitchen. The building at the bottom left corner was the Alaska Native Brotherhood Hall. Across the street from the hall were the Channel Apartments. All three buildings were demolished in the 1980s.
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April 20, 2008
The following is the text of Mayor Bloomberg's weekly radio address as prepared for delivery on 1010 WINS News Radio for Sunday, April 20, 2008
"Good Morning. This is Mayor Mike Bloomberg.
"Last Wednesday marked the one-year anniversary of the Virginia Tech shootings, the terrible day when one student killed 32 people and then himself. The pain and shock of that tragedy echoed throughout our entire nation. But the saddest truth is, across the country about 34 Americans are murdered with guns every single day - and most of those guns were purchased illegally. Illegal guns are raising the level of violence in our cities, and more and more Americans are starting to ask: Why is it so easy for criminals to get their hands on guns? That's certainly not what our forefathers had in mind when they drafted the Second Amendment.
"Despite these grim realities, we have reason to feel hope. The Mayors Against Illegal Guns coalition that I founded with Boston Mayor Tom Menino two years ago is gaining momentum. Our membership has expanded to include more than 320 mayors who represent more than 55 million Americans. Last week, we met in Washington D.C. for our second national summit. It was a productive conference, capped by a groundbreaking agreement with Wal-Mart, the largest seller of firearms in the nation.
"Wal-Mart has joined with our coalition of mayors to create "The Responsible Firearms Retailer Partnership": a 10-point code to help ensure that guns don't fall into the wrong hands. This pioneering set of guidelines includes running background checks for employees to make sure that the people selling guns aren't criminals, videotaping sales to deter illegal purchases, and creating logs to alert salespeople of customers with suspicious sales histories. As the biggest private employer in the world and the biggest gun-seller in America, Wal-Mart has set a new standard for gun retailers across the country. We want all law-abiding citizens who purchase guns to ask: Does this dealer follow the responsible firearm standard? And if not, why not?
"Although we still have a ways to go in the fight against illegal guns, this agreement was a big win for safe streets and for our democracy. It showed that we don't have to wait for Congress to act to affect real change. In the absence of national leadership, private businesses are teaming up with local law enforcement to give the American people what we want: stronger protections, safer streets, and the freedom to send our kids off to school without fearing for their security.
"This is my vision for cities like New York. It's one shared by many Americans - and I hope by our three presidential candidates, too. This week we unveiled a TV commercial - now airing nationwide - that features past statements from all three candidates in support of closing the "gun show loophole." This loophole allows people to sell guns at shows without performing background checks. The candidates all say they want to close the loophole- and you can see that for yourselves by watching the commercial on our website at www.mayorsagainstillegalguns.org.
"Now we need our leaders to back up their words with actions, because the gun show sales are just part of the problem. We also need a law that prohibits anyone on the terrorist watch list from purchasing a gun. This should be a no-brainer! But in Washington, it isn't. That's why, in the weeks and months ahead our coalition will continue pushing Congress to act.
"As New Yorkers, even though we live in the safest big city in the nation, we understand the tragic consequences of gun violence. We shared the grief felt by the Virginia Tech community last year, and they'll be in our prayers again this weekend, during what is a very sacred time for our city. Right now, tens of thousands of New Yorkers are gathered in Yankee Stadium for an historic mass led by Pope Benedict. At the same time, nearly two million Jewish New Yorkers are observing the festival of Passover. This is a perfect occasion to celebrate our religious freedoms, count our blessings, and rededicate ourselves to making New York an even better, safer, and more tolerant city.
"This is Mayor Mike Bloomberg. Thanks for listening."
John Gallagher (212) 788-2958
Listen to the radio address


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Great news in the federal budget for anyone looking to purchase a home. The Department of Finance expressed their commitment to increasing the competition of mortgage lenders rather than freezing rates.
I have generally found using a mortgage broker may result in getting a lower rate and saving money because mortgage brokers have wider access to mortgage lenders where as you may not get as good a deal with your bank. So dealing with a professional mortgage broker for your mortgage certainly deserves looking into.
If you are considering purchasing a home or renewing your mortgage, please give me a call, I know some great mortgage brokers that can not only give you more choice and better rates but great advice.
Earning the right to be your Trusted Advisor for life,
Stephen Hall
Century21 Seller's Choice Inc.


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U.S. Fish and Wildlife Service biologist Charles "Charlie" Herbert was awarded the Department of the Interior's Meritorious Service Award on Wednesday, just before announcing his retirement from 33 years of federal service.
Meant to recognize Service employees who support the agency's mission through their exceptional contributions, the Meritorious Service Award is the second highest honor a Service employee can receive.
"Charlie is a dedicated professional who has made outstanding contributions to the Fish and Wildlife Service and the Department of the Interior," said Robyn Thorson, Director of the Service's Pacific Region. "His accomplishments truly embody what it means to be a public servant."
Hebert was one of the Service's key leaders of the agency's on-the-ground response following the 2010 Deepwater Horizon oil spill in the Gulf of Mexico. He was deployed for six months to Houma and New Orleans, Louisiana, where he was instrumental in coordinating and advocating for fish and wildlife response actions. His negotiation skills ensured that fish and wildlife needs were adequately addressed by senior Coast Guard officials, who were balancing a wide range of actions. Hebert also played a key role in advocating for wildlife following Hurricane Katrina in 2005.
Hebert's career began as a National Wildlife Refuge biologist in Baton Rouge, Louisiana, in 1978. Throughout his career with the Service, he served as a National Wildlife Refuge Manager and Contaminant Specialist. He gained an outstanding reputation as one of the Service's premier oil and hazardous substance spill responders. Employed at refuges in Louisiana, North Carolina, and Rhode Island, Charlie was actively involved in biological, law enforcement, and management issues, and coordinated closely with the public, other agencies and local Congressional offices.
In 1996, Hebert led the Service's efforts in response to the North Cape Oil Spill that affected habitat at the Ninigret National Wildlife Refuge in Rhode Island. As a result of this experience, Charlie was selected to lead the Service's pre-spill readiness and response efforts. He was based in the Pacific Regional Office in Portland, Oregon.
As the Service's only full-time spill coordinator, he played a pivotal role in preparing the agency for and responding to major oil spills in coordination with field offices, the Coast Guard, the Environmental Protection Agency, and non-governmental organizations. He has been instrumental in coordinating spill and natural resource damage assessment with the Pacific states and the oil industry through the first Joint
Assessment Team established in the United States. In recognition of his expertise in contaminant-related issues, the Canadian government asked for Hebert to assist with large-scale disaster response efforts.
Image courtesy U.S. Fish and Wildlife Service


text:
American Essay in the American Century : Chicago and Revivalism, 1880-1920
Ned Stuckey-French
The American Essay in the American Century is a compelling, highly readable book that illuminates the history of a secretly beloved literary genre. A work that will appeal to fiction readers, scholars, and students alike, this book offers fundamental insight into modern American literary history and the intersections of literature, culture, and class through the personal essay. This thoroughly researched volume dismisses, once and for all, the death of the essay, proving that the essay will remain relevant for a very long time to come.
Captains Emergency Reference W
Por Que Lloras?
Kali` Jewels
The Political Writings of the 1790s: Loyalism: Responses to Paine, 1792-93 Volume 6 : French Revolution Debate in Britain
2000 Import and Export Market for Vegetables and Fruit in South Korea
Christ and the Cherubim : Or, the Ark of the Covenant a Type of Christ Our Saviour
Justice Served
Allison` Happy Summer


text:
Marilyn Manson: "Talking"
Every generation needs an outlaw, and as a new millennium began, Marilyn Manson was America s Most Wanted. Like a computer game come to life, he s playing a role and inviting us to join his fantasy world. This is his story, in his own words.
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Desktop Guerrilla Tactics: a Portable Thin Client Approach
We based our thin client boot floppy on BusyBox (www.busybox.net), which provides a complete bootable system on a floppy disk. It originally was created by Bruce Perens and currently is maintained by Erik Andersen. For a full explanation of each step, however, we would refer you to the three articles written by Bruce Perens and published in LJ, as well as the documentation from the BusyBox Web site (see www.linuxjournal.com/article/4335, www.linuxjournal.com/article/4395 and www.linuxjournal.com/article/4528).
Below, we outline the most elaborate part of our thin client approach. If you want to go straight to setting up your thin client network, skip this section and use the floppy image available on our Web site (cng.ateneo.net/cng/wyu/software). You have to modify only the network.cnf and libvga.config files to suit the circumstances of your network.
Step 1: we first created a filesystem with the appropriate nodes and configuration files for our system. We did this first on a Linux workstation. To simplify and automate the process, we wrote a script called genfilesys.sh. You can download this script from cng.ateneo.net/cng/wyu/software. We adapted this script from Bruce Perens' script (also available from the LJ FTP site at ftp.linuxjournal.com/pub/lj/listings/issueXXX/7109.tgz) and added configuration files for SVGALIB and UDHPC:
mkdir svilinux-filesystem ./genfilesys.sh ./svilinux-filesystem
In genfilesys.sh, we also set parameters for the video mode and mouse types, defined in libvga.config. You may want to modify this to suit your environment.
Step 2: build uClibc. uClibc is a C library with supplementary routines that we needed in order to run our VNC viewer. We downloaded the source package uClibc-0.9.20.tar.bz2 from www.uclibc.org and compiled it into our preparatory filesystem:
tar xvjf src/uClibc-0.9.20.tar.bz2 cd uClibc-0.9.20 make make install make PREFIX=../svilinux-filesystem install_target export PATH=/usr/i386-linux-uclibc/bin:$PATH cd ..
Step 3: build BusyBox. We downloaded the BusyBox source package, busybox-1.00-pre2.tar.gz, from www.busybox.net and built it in our workstation:
tar xvzf src/busybox-1.00-pre2.tar.gz cd busybox-1.00-pre2 make config make dep make make PREFIX=../svilinux-filesystem install cd ..
For the configuration, we chose to enable CONFIG_AWK, CONFIG_TELNET, CONFIG_UDHCPC and CONFIG_FEATURE_INITRD; we disabled CONFIG_SYSLOGD.
Step 4: configure SVGALIB. Because we were using VNC, at the very least we needed to incorporate SVGA support into our small distribution. To do this, we downloaded SVGALIB from www.svgalib.org and compiled it:
tar xvzf src/svgalib-1.4.3.tar.gz cd svgalib-1.4.3 vi Makefile.cfg (defaults are okay) make install make prefix=../svilinux-filesystem installsharedlib ln -s libvgagl.so.1.4.3 \ ../svilinux-filesystem/lib/libvgagl.so.1 ln -s libvga.so.1.4.3 \ ../svilinux-filesystem/lib/libvga.so.1
Do not use the experimental version of SVGALIB, as it uses a kernel helper for the frame buffer. Using this would mean recompiling the kernel to include this support, further bloating the kernel.
Step 5: configure the SVGA VNC viewer. We needed to configure our own VNC viewer that would work with SVGA, so we downloaded sources from www.tightvnc.com and packages.qa.debian.org/s/svncviewer.html. This VNC viewer still works with the stock VNC server from Red Hat.
tar xvjf src/tightvnc-1.2.9_unixsrc.tar.bz2 cd vnc_unixsrc xmkmf cd libvncauth xmkmf make cd ../.. tar xvzf src/svncviewer-0.1.1.tar.gz gzip -dc src/svncviewer_0.1.1-5.diff.gz | \ patch -p0 cd svncviewer-0.1.1 vi Imakefile
(Add -I/usr/local/include to INCLUDES and -L/usr/local/lib -L../vnc_unixsrc/libvncauth to SVGALIB.)
rm makefile xmkmf make strip -s -x -X svncviewer install svncviewer ../svilinux-filesystem/bin
Step 6: generate a ROM filesystem. We generated a ROM filesystem could load onto our boot floppy:
genromfs -f initrd -d ./svilinux-filesystem gzip -9 initrd
Step 7: build a small kernel. To minimize the size of our kernel, we decided to build a statically linked bzImage-style kernel. We removed all unnecessary items, such as unneeded drivers and features. The features we need to include are:
RAM disk support (in the Block Devices menu).
Initial RAM disk (initrd) support (also in the block devices menu).
ROM filesystem support (in the File Systems menu).
DOS FAT filesystem (in the File Systems menu).
VFAT (Windows 95) filesystem (in the File Systems menu).
We configured and compiled the kernel by invoking in our kernel source directory:
make menuconfig make dep clean bzImage
Step 8: create a bootable floppy with SYSLINUX. SYSLINUX is a bootloader for Linux that operates off MS-DOS floppies. It is part of a standard Red Hat 9 install. Thus, with our prepared floppy in the drive, we invoked:
syslinux /dev/fd0
This altered the boot sector of our floppy and also copied the second-stage bootstrap ldlinux.sys file to it.
We then copied our RAM disk initrd.gz and the compiled kernel bzImage to the floppy:
mount -t msdos /dev/fd0 /mnt cp initrd.gz /mnt/initrd.gz cp /usr/src/linux/arch/i386/boot/bzImage /mnt/linux
Step 9: create a SYSLINUX configuration file. We created a file called syslinux.cfg in our floppy that contains the following lines:
TIMEOUT 20 DEFAULT linux LABEL linux KERNEL linux APPEND root=/dev/ram0 initrd=initrd.gz
Client hardware underutilized
It seems like an interesting solution. Issues I have with it, VNC does not encrypt it's traffic. Solution to that, SSH tunneling - hard part would be setting up the session (each user has to log in with a password and username first?). The next issue is the fact the thin clients hardware is entirely unused, this seems like a waste and pushes more load onto the server. Why not use something like Xubuntu on the clients (designed to be thin) and handle the home directories on the fat server? I am sure you can get the client to ask for updates if needed, although this does require the use of a hard drive.
At the very least I would add the SSH tunneling to ensure some measure of security.
At SSH would be great. After
At SSH would be great. After all these years, developers of vnce could have added at least some basic form of encryption. It's understood that it's a free project althiough they do have a purchase version now. But the software would reach even more widespread use if there was at least some encryption. Maybe they were saving this for the paid version and never added it to the free version on purpose. There are other flavors of vnce avaialable that do have encryption but I hear the data stream slows down greatly though. It's a trade-off.
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
Diskettes ? Are you kidding ?
Try a real thin client: http://pxes.sf.net
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
actually, there is nothing stopping us from installing this system on a bootable CDROM or flash storage device.
another solution would be to save the image in the server and configure systems with bootable PXE LAN cards. we just configure the PXE server to serve both the kernel and the filesystem (ramdisk) separately.
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
We at our installation are trying to use Openoffice solution over thin clients running off RedHat 9 servers (low end/midrange). We are using xdcmp and find speeds terribly slow. After reading about your VNC experiment I have some queries :
a) Through VNC how can separate user logins be handled ? VNC only allows using the console X Screen isnt it. So wont there be a situation wherein every user views each other's work ?
Kindly reply. If not difficult email to email@example.com
Thanks in advance..
- Mohan
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
that's the thing about this solution. it does support multiple session logins. this is done by using a combination of xdm/gdm/kdm , vnc and xinetd. try it out. good luck!
Important aspect: Sound
Although there is generally not a business case for having sound on a workstation, how was sound addressed? I don't just mean the odd beep here and there, I mean full multimedia and such.
Re: Important aspect: Sound
The MuNAS solves the problem that the X Window system does not support the transformation of audio data. It makes the thin-client/server computing model in Linux be capable of executing multimedia applications. The audio data generated by Open Sound System (OSS/Free ) compatible audio applications which are executed in the terminal server can be transferred to X-terminals. The MuNAS is designed and developed for the thin-client system. With MuNAS installed, you can execute multimedia applications in the terminal server and listen for the sound from your X-terminal. Otherwise, these applications must be executed mutely in the thin-client architecture of Unix.
you can get more information on this web site
Innovation Group
Advanced Thin-client Technology Inc.
Re: Important aspect: Sound
At first blush, I find it hard to trust any Linux software whose extremely ugly web page was written under Windows -- with Frontpage, no less!
Re: Important aspect: Sound
Maybe you can check again ,We have change that~@@
Re: Important aspect: Sound
in this version, no sound. just your usual beeps.
a possible solution would be to grab what LTSP does for sound. that would be a good start. but, a topic for another article ;-)
Re: Important aspect: Sound
There are sound packages that stream the sound to the clients. Look at the LTSP site for some info.
Re: Desktop Guerrilla Tactics:Bandwidth requirements
You would be shocked at how little bandwidth is required to do such a thing. For efficiency disable all screen savers and set the desktop background to a neutral wallpaper with no fancy stuff. I run on machine with 120 users on it and the bandwidth used is about 200k average. X is incredibly efficient as long as you can keep the necessary screen refresh rates down by not running too much eye candy.
I do something similar for test rollouts and even production
When setting up a thin client environment I generally use a straight x setup running xdmp. I do not run the LTSP package but I do use their sound utilities. The problem with LTSP I feel is the complexity and the lack of configuration flexibility. I also cannot have 200 people logging into a box and pulling a kernel across the network all
at the same time in the morning.That being said one thing I use alot is a slax cd distro that I did one little hack to. I added a line at the bottom of rc.local that uses wget to grab a shell script
from a internal web server and execute it. The wget command passes the mac address of the nic eth0 to a php page on the internal web server. This php page either will pass a default shell script that contains the flollowing.
/usr/X11R6/bin --query linuxserver.mydomain.com
Or it can pass any other configuration based on the mac address that it needs to. The beauty in it is that you never have to remaster a cd yet you have full control over of the client configurations. Say a month from now you wish to move some clients to a new server. I just point the script the get from the web server to a different server and bingo they are instantly migrated. Or If your server gets to loaded you can you can just push half of the clients to a new server. It also allows you to do
automated network mounts, printer configs, network settings,sound etc. I am willing to bet that using this method I can bring up a 500 workstation enterprise in a single day. It is also safe that if for some reason I wish to revert back I just remove the client cd.
Re: I do something similar for test rollouts and even production
actually, that is not such a bad idea. the current version of the floppy system does contain wget. it shouldn't be very hard to grab the VNC server settings from a web server within the network.
this is will definitely try out. thanks for the idea.
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
If you want a simple thin-client system, try pilotlinux. (www.pillotlinux.nl). It is a Morphix based cd that transforms the pc into a thinclient.
- Download the iso
- Burn it to cd
- boot PC from cd
- Connect to a server
The current beta (version 2.0 beta3) supports RDP (microsoft Terminal Server). The next beta (available at the end of the week) also supports VNC and X.
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
cool. what does this CDROM distro contain aside from the RDP client (rdesktop, i suppose)? it is meant for regular end-users like knoppix or is it for high performance computing dudes?
as a matter of fact, i have a single floppy system that does RDP too. you can complile rdesktop with svgalib too. as a matter of fact, it can still fit on the vnc floppy in this article. email me if you are interested.
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
It's meant for ease of use :-)
Currently we are running PilotLinux on a Pentium 166 with 64 MB ram (no HDD, just a cdrom-drive).
PilotLinux contains:
- the knoppix hardware detection software
- A complete X-windows system
- Special software to make it possible to connect to the server without user intervention
- Special GUI software to make the cd easy to use
A new beta is being tested and almost ready for upload. It contains also support for VNC (4.0) and the X-protocol.
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
oh and one more benefit.... CDROMs last longer than floppies!
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
True. But remember, the article states that not all of the clients have CD drives.
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
true. but, don't you think we should start worrying about the day when floppy drives will be phased out? ;-)
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
I have a very very ancient PowerPC which runs MacOS 8.x and cannot be upgraded to MacOS X :-( ... so I wanted to know if I can make a floppy such as described in the article for it? Or am I just trying to raise the dead?
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
yup. can you install Linux PPC on that mac and install the necessary software. but, i would not be able to do much.
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
to the Mac user: probably not, as there would be extra steps involved in recompiling a PowerPC-based Linux kernel. An easier approach may be to re-partition the Mac hard drive to give yourself a little room for a PowerPC-based Linux-distribution, such as YellowDog Linux. Properly set up, you could use yellowdog as a "slightly-thicker" client to access the main Linux server.
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
We've used Quantian (a Knoppix-based bootable CD distro) to very quickly set up such a fat-server, thin-client environment. It's incredibly easy because Quantian comes with both LTSP and openMosix (for clustering). The steps are trivial:
1. Download Quantian.
2. Burn ISO to CD.
3. Determine NIC types on thin clients.
4. Go to BusyBox and create boot floppies.
5. Boot Quantian on fat-server.
6. Start terminal server and clustering apps.
7. Input IP address range for clients.
8. Boot clients from floppies.
Our server wasn't particularly fat (1GHz AMD Duron with 1GB RAM on a 100MBPS ethernet) and we only went up to 3 clients, but there was no drag on the server with that set up. The "downside" to Quantian is that it is a math/stats distro and lacks OpenOffice (uses Koffice by default).
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
More recent versions of Quantian include OpenOffice.
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
I believe Quantian has put back OpenOffice, so it may have it now.
There is also ClusterKnoppix as well. And don't forget that once installed to disk, the lack of OpenOffice or any other app is easily solved with Apt-get. The client-server setup makes it easier to install to disk, since you are only installing the server, the clients still boot from the floppy or cd (or ethernet card).
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
thanks for pointing this out. as a matter of fact, the Knoppix people have already placed in "terminal server" functionality into the base knoppix distribution.
quantian does add the novelty of being about to "farm" out processes to other machines in the quantian cluster. i presume using openmosix. very nice!
i am just curious what does quantian and knoppix use for its terminal server functionality? i haven't actually tried it myself yet. it is vanilla X-windows or VNC?
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
It's X. The thin-client looks just like you've booted the Knoppix CD.
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
shucks. now that would be bandwidth heavy. well, can't have everything. hahaha.
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
There's an option to VNC that places a lower burden on the server: run X on all the workstations with a display manager (gdm or xdm) running on the server. Performance is quite good over 10MHz ethernet.
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
This is an interesting approach, I am dubious about the responsiveness of a straight vnc client server approach based on personal experience with vnc.
Does anyone have any other first hand experience with vnc?
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
if you are using a LAN the performance is spectacular. the sluggishness typically noticable in thin client solutions is hardly noticable.
for a low bandwidth links like VPN over unrealiable internet or a 28.8kbps dial-up which we used in our tests, there is some sluggishness.
generally, our users find the performance acceptable in both scenarios. in the LAN scenario, they hardly notice it is a thin client. i would like to note that we are using tightVNC for this with the low-bandwidth optimized tight encoding.
however, in our setup, the resources limits were configured on a per user basis effectively limiting the amount of RSS and CPU time per user. this prevents the scenario were one user hogs the resources.
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
this was actually one of the original proposal. however, the goal of the project was to have a "bandwidth"-friendly system.
currently, the system uses tightVNC and works pretty well on a 28.8kbps dial-up line. i have not tested it on anything lower since i do not have a slower modem lying around.
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
Its good to know that you got good results from your approach. I have tested VNC before on a 100Mbps LAN but I thought it was not that good. I encountered some minor screen redraw problems but I admt it was a usable system. Maybe its time to revisit VNC again (using tightVNC).
I downloaded your disk image and will try it out myself.
Good luck to your project. Maybe we can share user expereinces as I also have a project here in Davao where I helped an NGO migrate to an LTSP system. It has been running since December 2003.
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
Yes, the compression on TightVNC is much better. I use it regularly to
move my desktop (applications humming along intact) from work, to
my home office, to the coffee shop and from machine to machine at work.
Those are all lan or broadband class connections, but i run a graphics rich
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
thanks for show of support.
you know how to contact me if you need some tips. i currently have one production system (mainly for mainframe support, lotus notes and web browsing) and a new one being deployed.
we are having wine/SMP problems on the newer system. grrr.
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
I think that forgot some details about the test. For example, server configuracion (memory, processor speed, hardisk, etc), network topology, how many clients connected to the server, network performance, etc. Without that information, the test have little value for a third party.
Re: Desktop Guerrilla Tactics: a Portable Thin Client Approach
I think the article was more focused on the human user side of the project. with some technical details thrown in.
Machine Specifications [was Re: Desktop Guerrilla ...]
i apologize for leaving out the details on the machine specification. as somebody already mentioned, this is mainly focusing on the "human" aspect of the project. but i understand the need.
the "fat" server is actually a Intel Pentium III 733MHz with 512MB RAM. it is not quite as beefy as i would like it to be. during the tests i was able to cram 10 users into the system mainly using their web browsers, x3270 emulators and Lotus Notes (on Wine). however, running openoffice will not allow me to run that many users.
the "thin" clients tests were are low as a Pentium classic 75Mhz with 8MB RAM. i suppose we can even go lower.
hope this helps.
Machine Specifications [was Re: Desktop Guerrilla ...]
Thanks for the additional info.
That sounds like a reasonable setup, fitting the intended budget here. Judging by your tests, what would you consider the bottleneck? CPU load, hard disk performance or memory usage?
Thanks again,
Machine Specifications [was Re: Desktop Guerrilla ...]
the main bottleneck is memory. the only cases were my CPU maxes out are cases when there is not enough memory and the system starts to page. however, particular applications need more CPU than others.
another note is that i use system limits per user on my system. this way each user is limited to a particular number of processes, RSS and CPU time.
Machine Specifications [was Re: Desktop Guerrilla ...]
Can you provide a little more infoon the system limits per user? How is this done? What utilities should I study to enable this type of control? I'm aware of disk quotas, but can you provide a few utility names/tips for the others, processes, RSS, CPU time?
Machine Specifications [was Re: Desktop Guerrilla ...]
system limits are configured in limits.conf. just make sure that you /etc/pam.d/system-auth has the pam_limits.so session module loaded.
Machine Specifications [was Re: Desktop Guerrilla ...]
From real world experience I can tell you that the bottleneck you are most likely to hit is memory. I run a similar setup with about 200 clients connected to it, the server is a dual zeon 1.4 ghz machine which is not that much processor but the machine does have 4 GIG of ram and if I could put in more I would.
Numbers, numbers, numbers ...
Nonetheless, it would be really interesting to get some numbers.
I'm considering a similar solution for a small CyberCafe (10 - 20 stations), but small here also means extremely cash strapped. So any information on how "fat" such a server actually needs to be (and thus how expensive) would be most appreciated.
Anyway, thanks for the article.
Re: Numbers, numbers, numbers ...
Although not the same setup as this, the article at http://linux.dbw.org/articles/linux_nt_what_the_tests_prove.html might give you some ideas on how to come up with the answer your self.
Re: Numbers, numbers, numbers ...
> http://linux.dbw.org/articles/linux_nt_what_the_tests_prove.html
Seems unreachable at the moment but I'll try again. Thanks anyway!


text:
|UK Pectus Excavatum and Pectus
Information Site
|What is Pectus Excavatum/ Carinatum?
|Living with a Pectus Anomaly
|Non-surgical Treatment
|Surgical Treatment
|Photo Illustrations
|Referral Information
|Other Links
|Access Forum
|Contacts & Feedback
What is Pectus Anomaly?
|Pectus anomaly describes a deformity with the sternum (breastbone).
There are two main types of anomaly:
Pectus Excavatum
Pectus Carinatum
|(PE, or "funnel chest"/"sunken chest") in which the sternum is depressed, and so the chest looks hollow
|(PC, or "pigeon chest") in which the sternum is raised and so the chest pushed out
Pectus Arcuatum
|This is a rare third type of anomaly. This is where there is a ridge high across the upper part of the sternum and so the rest of the chest falls away to a flatter shape. Pectus anomalies occur in approximately 4 people in every 1,000 and are more common in men. Anomalies vary from mild to very marked.
What causes pectus excavatum/carinatum?
|Pectus anomalies are thought to be caused by poorly coordinated
and possibly excessive growth of the costal (rib) cartilages. The
anomaly occurs at the junction of the ribs and sternum (breast bone)
where the growing part of each rib – the cartilage – is located.
Overgrowth of the cartilage causes the ribs and cartilages to
"buckle" and pushes the sternum either inwards (pectus excavatum)
or outwards (pectus carinatum).
Certain conditions are associated with pectus anomaly, including scoliosis (where the spine curves and becomes deformed), Marfan's syndrome (an inherited disorder of the connective tissue) and Poland's syndrome (a rare inherited condition which involves the absence or underdevelopment of the chest muscles on one side of the body).
A pectus anomaly is often seen at birth but usually becomes more obvious during early adolescence when growth is rapid. Once growth is complete the anomaly remains the same.
Pectus Excavatum
Pectus Carinatum


text:
Agatha Raisin and the Vicious Vet (Agatha Raisin Mysteries, No. 2)
"A glorious cross between Miss Marple, Auntie Mame and Lucille Ball with a tad of pit bull tossed in. She's wonderful." St. Petersburg TimesFeisty Agatha Raisin, until recently a public-relations executive in London, has retired to peaceful Cotswold, where a romance is budding with the attractive new village vet, Dr. Paul Bladen. But Bladen accidentally kills himself while attending to Lord Pendlebury's horse, and Agatha must turn to her distinguished neighbor, the retired military man James Lacey, for comfort. Together, the odd couple begin to investigate Dr. Bladen's death . . . and the curious lack of sorrow shown by his divorced wife. But will they succeed in unmasking a killer before suffering an "accident" of their own?
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text: Hi, Recently I land into a web page that was selling agarose electrophoresis tanks (combs and all) for a mere $10. Now that my class has ballooned out to 65, I'm scurrying back to my cache, bookmarks, web search engines and Sherlock to look for it. To my horror none could find it. can anyone recall the webpage? if so, please mail me the url. I manage to find a review of gel equipment. Again the page that i want is not there. Thanks in anticipation. Yours sincerely razip -------------------------------------------------------------------------------- Dr. Mohd Razip Samian E-mail: razip at usa.net School of Biological Sciences Universiti Sains Malaysia Tel: 60-04-860 4007 Penang 11800 : 04-657 7888 x-4007 Malaysia Fax: 60-04-656 5125 ===============================================================================


text:
Obama 'Micro Targeting' Swing Voters in Virginia Foray
President Barack Obama courted the voters who fueled his victory in Virginia four years ago as he tries to hold the once-solidly Republican state in November.
Obama, with a refreshed populist message on taxes, focused on military families and the economy in the first stop on a two- day swing through the state's so-called golden crescent: the Washington suburbs of northern Virginia south through Richmond and Hampton Roads, where most of the population is concentrated.
"When we win Virginia we're going to have won the election," Obama told the overflow crowd at Green Run High School in Virginia Beach, where he went after meeting with the spouses of service members at a local café.
Obama was the first Democratic presidential candidate to win Virginia since Lyndon Johnson did it in 1964, and capturing the state's 13 Electoral College votes in November is part of the victory map for both Obama and Republican Mitt Romney.
While Obama took the state by six percentage points in 2008, both campaigns are forecasting a close contest this year. Obama held a three percentage point lead over Romney in an average of six polls taken since mid-May, as compiled by the website Real Clear Politics.
Virginia Visits
Obama has been to Virginia 15 times since announcing his run for re-election in April 2011, and Romney has visited six times since announcing his candidacy in June 2011.
"The Obama campaign is doing in Virginia what they're doing in other battleground states," said Quentin Kidd, a political science professor at Christopher Newport University in Newport News, Virginia. "They're micro-targeting African Americans in Hampton Roads, and in particular African Americans in the military. They're micro-targeting Latinos in northern Virginia, and they're micro-targeting areas with a younger population like Richmond and Virginia Beach."
Among the states, Virginia's economy is the most dependent on federal defense spending through its contractors and military bases, collecting $56.9 billion in 2009, according to a Bloomberg Government study. It was followed by California and Texas.
General Dynamics Corp. (GD) and Northrop Grumman Corp. (NOC) are based there; Lockheed Martin Corp. (LMT), the world's largest defense contractor, based in Bethesda, Maryland, employs approximately 7,700 people in Virginia, or 6 percent of its global workforce.
Virginia Economy
That has helped cushion the effects of the recession. Virginia's unemployment rate was 5.6 percent in May, down from a high of 7.3 percent in January 2010. By comparison, the rate nationally was 8.2 percent and hit 10 percent in October 2009.
Still, Virginia was among four electoral battleground states that showed declining economic health in the first three months of the year, according to the Bloomberg Economic Evaluation of States. The index is based on the performance of local-company shares, tax collections, home prices, mortgage delinquencies, job growth and personal income.
Romney's campaign criticized Obama over cuts in defense spending even before Obama arrived in the state. The Republican candidate released an open letter to Obama, accusing him of supporting budget cuts that would shutter factories and shipyards.
Defense Cuts
"Your insistence on slashing our military to pay the tab for your irresponsible spending could see over 200,000 troops forced from service," Romney said in the statement. That "will overwhelm overburdened state offices like the Virginia Department of Veterans Services. It will impose suffering and hardship on so many military families."
Obama repeated the populist themes he's been using on the campaign trail, saying he is working to keep the promise of the American dream that "even if you weren't born into wealth" people can provide a good home for their family and an education for their children.
He said the ideas being put forward by Romney and Republicans in Congress "basically involve taking the country backward," including providing tax cuts to the wealthy, "even if it starts cutting into benefits that we're providing to our veterans."
Obama is calling on Congress to pass a yearlong extension of Bush-era tax cuts for families making less than $250,000 a year while letting rates rise for higher earners.
Portraying Romney
The message is intended to highlight his differences on economic policy with Romney, co-founder of Boston-based Bain Capital LLC. Obama has accused Romney and congressional Republicans of pursuing "top-down economics" that favor the wealthy. His campaign also is focusing on Romney's work at Bain, a private equity firm, accusing him of profiting from the loss of jobs in the U.S. to overseas competitors.
Bain yesterday said Romney remained its sole stockholder and continued to be listed as the sole stockholder and in various executive positions in Securities and Exchange Commission filings even after leaving in 1999 to run the Winter Olympics. The company statement was released after a Boston Globe report raised questions about when the presumptive Republican presidential nominee left the firm.
The timing has become an issue because his campaign responded to reports of Bain-owned companies laying off employees by saying the former Massachusetts governor wasn't responsible for actions after his departure.
Bain Targeted
Dave "Mudcat" Saunders, a longtime Virginia political strategist who is working on Democrat Wayne Powell's House race against Majority Leader Eric Cantor, a Republican, said the president's populist message is working.
"Obama should stick with Bain Capital attacks," he said. "Everybody in small-town Virginia feels like they've been taken advantage of."
Vicki Johnson, a 57 year-old secretary who lives in Virginia Beach and attended the event at the high school, said that while she supports the president she's not sure if he can win Virginia again.
When asked if she was at all disappointed in his first terms she said, "I wasn't sure he was going to turn things around in four years anyway."
Most of the places Obama is visiting voted for Democrat John Kerry in 2004 and came out in even bigger numbers for Obama in 2008. In Hampton Roads, where Obama will hold his second campaign event today, Obama beat Republican Senator John McCain 69 percent to 30 percent. Obama won Roanoke City 61 percent to McCain's 38 percent, and he won Fairfax County, where he will go tomorrow, 60 percent to 39 percent. He will also go to Richmond, where he got 79 percent of the vote, and Glen Allen, outside of the capital.
Virginia Beach is the only one of the cities Obama is visiting that voted for McCain in 2008, giving him a narrow victory of 49.8 percent to Obama's 49.1 percent.
To contact the reporter on this story: Kate Andersen Brower in Washington at firstname.lastname@example.com
To contact the editor responsible for this story: Steven Komarow at email@example.com


text:
Snarling Dogs
The Super Bawl Fire Bawl is the Fire Bawl with two additional features:
Hormone Control™ this enables you to switch between a clean or dirty wah sound.
Twinductor Beef Boost™... Activates a second inductor, causing the wah to sound especially thick!
myFXDB user reviews
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You can post questions, reviews, etc. in the main forum or data and pictures in the data dump forum.
- manual (Snarling Dogs)


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