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Rikon London is delighted to offer this Aston Martin Rapide S for sale, presented in Obsidian Black over Winter Wheat.
Servicing has been kept strictly with the main dealer since new, with last visit to AM Manchester on the 6th of July 2018 at 13,684 miles.
This example also benefits from extended manufactures warranty which expires on the 9th of July 2019.
Paint Protection Film has been applied to areas susceptible to stone chips.
Tilt-telescoping steering wheel, Bi-xenon headlamps and LED taillamps, Electric Front Seats with Memory; all 4 Seats offer Cooling and Heating, Bluetooth, FM/AM, USB and iPod Connectivity, Bang & Olufsen 16 speaker sound system with two tweeters that rise from the dashboard on activation of the system.
Ivory Alcantara Headling, Black Brake callipers, Garage Door Opener, Reversing Camera, Piano Black Facia Trim, Obsidian Black Carpet. Seat Inner Stitching to match, 20-inch 10 Spoke Black Diamond Cut Alloy Wheels, Sports seats, Seatbelts in Flint, Rear Entertainment System.


Formerly known as ♥Vascular Ease Lotion♥ New name and new look, same amazing formula!
Soothing lotion - perfect skin care after a long day on your feet. This herbal formulation is made with rich levels of Horse Chestnut, Butcher's Broom and Gotu Kola to keep your legs skin snappy, happy and nourished.
We added cups and cups of essential oils of Geranium, Peppermint and Lemon.
Directions: Gently massage on legs and feet twice a day.


PRINCETON, NJ -- Despite the great attention paid to the importance of the women's vote in the 2012 election, there has been a larger change in men's than in women's preferences compared with 2008. Barack Obama's support is down seven percentage points among men versus three points among women. In Gallup's latest 21-day rolling average of likely voter preferences, based on interviewing conducted Oct. 1-21, Romney leads Obama by 14 points among men, whereas Obama and John McCain were tied among men in Gallup's final pre-election estimate in 2008. Obama currently leads Romney by eight percentage points among women, whereas he led McCain by 14 among women in 2008.
Overall, the gender gap in support for the two candidates is somewhat wider than Gallup's estimate of where it was just before the 2008 election - at 22 points, compared with 14 points. Obama has lost support among both gender groups compared with 2008, when he won the popular vote by seven points over McCain, but the results show that he has lost more among men than among women.
Romney More in Tune With Men's Issues?
Gallup's recent analysis shows that there are no highly specific "men's" issues when men in swing states were asked "What do you consider the most important issue for men in this election?" The top five responses were jobs, the economy, the deficit, healthcare, and taxes. These are the types of issues on which Romney does best on a relative basis vis à vis Obama. Romney does particularly well, as one example, on the deficit. Thus, Romney's stronger position among men may result from his perceived strength on issues that are specifically most important to men.
The same swing-state survey asked American women to name most important women's issues in this election, and the results showed "abortion" and "equal rights" to be in the top five, along with jobs, healthcare, and the economy. These results give some indication of why Obama has been able to hold on, proportionately, to the women's vote. Recent national polling among registered voters indicates that Obama is given the clear edge, 53% to 37%, on government policies relating to birth control, and polling in late September shows that he led Romney on "social issues such as gay marriage and abortion" by 26 points.
Still, an analysis of women's responses to a separate question asking about the most important problem facing the nation -- without specific mention of "women's issues" -- shows that women's responses do not differ substantively from men's in most instances. Women are, however, less likely to mention the deficit, a Romney strength, and more likely to mention healthcare, a relative Obama strength, but the differences are not large.
At this point, Romney's slight edge in the overall likely voter preferences reflects the fact that he leads among men by a wider margin than Obama leads among women. Obama's support among women is down from the support he received from them in 2008, but not to the same extent as the increase in men's support for Romney compared with men's support for John McCain in 2008. This growing gender gap may reflect Romney's relative strength on issues relating to the economy, jobs, and the deficit. Of course, voter preferences, both overall and within gender groups, may change significantly between now and Election Day, Nov. 6.
Results are based on telephone interviews conducted as part of Gallup Daily tracking Oct. 1-21, 2012, with a random sample of 8,203 likely voters, aged 18 and older, living in all 50 U.S. states and the District of Columbia.
For results based on voters, one can say with 95% confidence that the maximum margin of sampling error is ±1 percentage point.
Gallup's U.S. Economic Confidence Index declined slightly to -19 for the week ending Oct. 21, from -17 the week prior. An 85-point gap separates the opinions held by Democrats and Republicans.
A review of Gallup data touching on foreign policy reveals that Barack Obama is relatively well rated on the issue, even as his economy ratings lag. As of early September, Americans also had more confidence in Obama than Mitt Romney to handle foreign policy.
More than one in three Americans (37%) name the "economy in general" as the most important problem facing the country. Seventy-two percent cite at least one economic issue -- on par with the 69% prior to the 2008 election.


• Parking on streets within the city is not allowed between 3 and 6 a.m. To submit a request for an exception, call the Midland Police Department at 989-631-5716.
• Parking on the curb, sidewalk, area between the sidewalk and curb, or in front of private or public driveways is not allowed.
• Vehicles cannot block or obstruct public sidewalks or paved pathways.
• Do not double-park in the city.
• Drivers may not park within 20 feet of a crosswalk, within 15 feet of an intersection, or on city park property.
• Parking on lawns or grassy surfaces is not allowed.
• To park in a handicapped space, you must have a Secretary of State-issued tag or license plate that is visible on your vehicle.
• You may not park in a manner that obstructs travel lanes and fire hydrants.


Help AG, a leading information security services and solutions provider in the Middle East, today announced its participation in the inaugural edition of Gulf Information Security Expo & Conference (GISEC) which will be held at the Dubai World Trade Centre from 3-5 June 2013. The security expert, a gold sponsor of the event, will be showcasing Help AG information security services and solutions from five of its vendor partners- Juniper Networks, Blue Coat Systems, F5 Networks, Symantec and RSA.
Establishing a secure online presence is a fast becoming vital to conducting business. Research by Visa Middle East in collaboration with the GCC projects revenues from online commerce in the region to reach USD15 billion by 2015. Nicolai Solling, Director of Technology Services at Help AG will deliver an informative and in-depth presentation titled 'Attack Deception: More Than Just Website Security' wherein he will elaborate upon the best methods for companies to protect their websites from attacks.
Help AG identifies and selects its vendors partners by conducting regular analysis of security trends in the region. Of its extensive portfolio, the company has decided to highlight solutions from five of its vendor partners. These include network security from Juniper Networks, web security and WAN optimization from Blue Coat Systems, software and hardware solutions for application layer protection from F5 Networks, Data Loss Prevention (DLP) and endpoint encryption and protection from Symantec and e-GRC solution from RSA.
Help AG boasts a level of technical expertise that is rare for systems integrators and resellers in the region. This allows the security specialist to offer its customers vulnerability assessment, penetration testing, architecture and platform reviews, source code reviews, anti-defacement services, cloud based threat mitigation and password and access audit services. The company has even recently established a dedicated division for its security analysis services and this will be headed by Khaled Al Hawasli. Help AG intends to use GISEC as a platform to generate awareness about its many service offerings.
Stephan Berner, Managing Director at Help AG said, "We have decided to participate as a gold sponsor of GISEC because we strongly believe that IT & Information security deserves a dedicated platform given the scale to which the market has grown. Being present at this event allows us to demonstrate both our solutions and services and this exposure is key to our goal of establish ourselves as the leading Trusted Advisor for Information Security in the Middle East.
An offshoot of the hugely popular GITEX Technology Week, GISEC will focus on the latest information security trends, cyber security legislation in the Middle East and cyber security solutions in addition to knowledge exchange via a strong conference line-up, which brings together information security experts from Government & Military, Finance, Oil & Gas, Telecoms and large scale enterprise sectors. Help AG can be found at stand C6-20.


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Back to Women's Basketball coverage
Kansas defeats Tulsa, 82-78
2 p.m., Dec. 22, 2013
Allen Fieldhouse, Lawrence, KS
Media & Analysis
Holiday giving: CeCe Harper's 13 assists spark KU women past Tulsa
By Matt Tait
Photo by John Young
Kansas reserves Caelynn Manning-Allen, left, and Bunny Williams cheer from the bench late in the second half of their game against Tulsa, Sunday afternoon at Allen Fieldhouse. The Jayhawks won, 82-78, and will next face Yale on Dec. 29. 2013 in Lawrence.
Kansas Women's Basketball vs. Tulsa
KU-Tulsa women's box
CeCe Harper insists it had nothing to do with the holidays, but the Kansas University senior guard sure was in a giving mood during Sunday's 82-78 victory over Tulsa at Allen Fieldhouse.
Harper, who still is adjusting to the demands of playing point guard for this young Kansas squad, recorded her first career double-double, highlighted by a career-best 13 assists.
"I think I'm just starting to get into the point-guard mentality more," said Harper, who added 15 points and five rebounds and said heading home to her mom and dad for the holidays was the best gift she has ever given. "I'm really trying to get shots for others rather than myself."
That concept, which is absolutely crucial for Kansas, is nothing new for Harper, who played point guard exclusively during her high school career. But it is new in a sense, given that Harper spent the past few years watching Angel Goodrich work her magic as the Jayhawks' point guard.
Sunday, Harper looked Goodrich-esque in the way she set up teammates for easy buckets and helped hold off a scrappy Tulsa team that refused to be knocked out.
The Jayhawks (6-5) opened with a 9-0 spurt and started the second half with an 8-2 run, but neither enticed Tulsa to fold. KU never trailed but had to fight like mad to maintain a three-to-seven-point cushion down the stretch.
Things looked momentarily bleak after Tulsa's Ashley Clark cashed two free throws with 1:01 to play to pull the Golden Hurricane within 78-76. Moments later, when KU's Asia Boyd (game-high 22 points on 7-of-11 shooting) fired up a wild shot with 35 seconds to play, Tulsa raced down the floor looking to tie or take the lead.
But a scrum in the paint near the Tulsa basket allowed Harper to come out with the ball, and she raced up the floor with the game clock ticking down to 20 seconds and KU up by two.
From the bench, KU coach Bonnie Henrickson was begging Harper to slow it up. But with Boyd on her left, the senior pushed the pace and dished her final assist of the day. There were a few free throws that followed, but the aggressive play essentially iced the victory.
"When it was happening, I didn't hear her," Harper said of Henrickson's pleas. "But it was kind of my mentality to push, so ... "
As it turned out, Henrickson had no problem with it.
"I was trying to do the best stop sign I could there," Henrickson said. "I'd rather her dribble around for eight more seconds and make 'em chase you a little bit, but, honestly, (being aggressive is) in most players' nature."
Harper was one of four Jayhawks to reach double figures, and, as it turned out, KU needed just about every point it got to hold off the Golden Hurricane (4-4).
Junior forward Chelsea Gardner (18 points, eight rebounds) controlled the paint for Kansas, which shot 53 percent (including 5-of-14 from three-point land) and outrebounded Tulsa 35-30.
Boyd also continued her hot play of late, leading the Jayhawks in scoring and also adding five rebounds, five assists, a block and a steal.
Despite the productive and balanced offensive showing — junior guard Natalie Knight scored 11 points, and freshman Keyla Morgan chipped in nine — Henrickson was more concerned about her team's defensive issues, given that just one game remains — 2 p.m. Sunday vs. Yale — before the Jayhawks jump into Big 12 play.
"For them to come in here and score 78 points is alarming to me," Henrickson said. "If we're gonna score 82, I'd like to win. Yes, we did it tonight, but I'm not sure that's gonna bode very well for us if we don't (address) defensively where we broke down so bad."
More like this story on KUsports.com
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KU women's basketball balanced in exhibition rout of Fort Hays State
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KU women's basketball vs. Oklahoma State
KU Sports Hour New KU AD Jeff Long makes strong first impression July 12, 2018
Press Conferences & Post-Game Interviews Bonnie Henrickson and KU players talk after ORU win November 10, 2013
Press Conferences & Post-Game Interviews Bonnie Henrickson talks at KU women's media day October 9, 2012
Press Conferences & Post-Game Interviews Bonnie Henrickson on Lew Perkins' retirement June 10, 2010

redpajama_set_name: RedPajamaCommonCrawl


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Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production
Enxuan Jing, Brice Emanuelli, Matthew D. Hirschey, Jeremie Boucher, Kevin Y. Lee, David Lombard, Eric M. Verdin, and C. Ronald Kahn
PNAS August 30, 2011 108 (35) 14608-14613; https://doi.org/10.1073/pnas.1111308108
Enxuan Jing
Brice Emanuelli
Matthew D. Hirschey
Jeremie Boucher
Kevin Y. Lee
David Lombard
Eric M. Verdin
C. Ronald Kahn
For correspondence: c.ronald.kahn@joslin.harvard.edu
Contributed by C. Ronald Kahn, July 20, 2011 (sent for review April 14, 2011)
Sirt3 is a member of the sirtuin family of protein deacetylases that is localized in mitochondria and regulates mitochondrial function. Sirt3 expression in skeletal muscle is decreased in models of type 1 and type 2 diabetes and regulated by feeding, fasting, and caloric restriction. Sirt3 knockout mice exhibit decreased oxygen consumption and develop oxidative stress in skeletal muscle, leading to JNK activation and impaired insulin signaling. This effect is mimicked by knockdown of Sirt3 in cultured myoblasts, which exhibit reduced mitochondrial oxidation, increased reactive oxygen species, activation of JNK, increased serine and decreased tyrosine phosphorylation of IRS-1, and decreased insulin signaling. Thus, Sirt3 plays an important role in diabetes through regulation of mitochondrial oxidation, reactive oxygen species production, and insulin resistance in skeletal muscle.
mitochondrial metabolism
protein acetylation
Insulin resistance in skeletal muscle is a major and early feature in the pathogenesis of type 2 diabetes (1, 2). This pathological condition has been shown to involve decreased activity of the insulin signaling network with reduced tyrosine phosphorylation of the insulin receptor and its substrates, decreased activation of phosphatidylinositol 3-kinase (PI 3-kinase), and decreased activation of Akt/PKB (protein kinase B), leading to reduced glucose uptake and other metabolic abnormalities (3–5). Another early feature of type 2 diabetes is altered mitochondrial function in muscle. Reduced expression of multiple nuclear-encoded genes involved in mitochondrial oxidative phosphorylation and alterations in mitochondrial morphology have been observed in skeletal muscle of both rodent models of diabetes and humans with type 2 diabetes (6–8). Impaired mitochondrial lipid oxidation and glycolytic capacity have also been observed in individuals with diabetes and obesity, whereas enhanced mitochondrial lipid oxidation capacity has been associated with improved insulin resistance (9, 10). This reduced expression and/or activity of mitochondrial proteins has been closely associated with altered skeletal muscle physiology and metabolism. Some, but not all, studies have found similar alterations in skeletal muscle of individuals with a family history positive for type 2 diabetes (8, 11). Reduced oxidative capacity and reduced ATP synthesis rates have also been shown in individuals with type 2 diabetes and in some nondiabetic individuals with a family history for diabetes (12).
In addition to its role in substrate metabolism, the mitochondrion is the major production site of reactive oxygen species (ROS). When ROS level is excessive or there is impaired ROS clearance, the oxidative stress response can activate serine/threonine kinases such as protein kinase C, S6 kinase, and Jun N-terminal kinase (JNK), which can phosphorylate the insulin receptor (IR) and/or insulin receptor substrate (IRS) proteins (13–15), leading to a decrease in their tyrosine phosphorylation, decreased activation of PI 3-kinase and Akt, and resistance to the metabolic actions of insulin. Collectively, these data suggest that altered mitochondrial oxidative phosphorylation may be an early, or even primary, contributor to development of skeletal muscle insulin resistance and type 2 diabetes.
In recent years, the sirtuin family of NAD+-dependent deacetylases has emerged as important regulators of metabolism. Among seven members of the sirtuin family, Sirt3 is of particular interest with regard to mitochondrial function because it is localized primarily in mitochondria (16). Sirt3 has been shown to deacetylate and thereby regulate several mitochondrial targets, including acetyl-CoA synthase 2 and glutamate dehydrogenase (17, 18). It has been suggested that Sirt3 is also closely involved in energy homeostasis and regulation of ATP production in various tissues (19). Recently, we have shown that Sirt3 plays an important role in hepatic lipid metabolism (20). Through these and other effects, Sirt3 has been shown to be involved in mitochondrial function and is associated with aging (21, 22).
We previously found that Sirt3 expression is significantly decreased in muscle of mice with insulin-deficient diabetes (23), suggesting that decreased Sirt3 activity could contribute to the metabolic abnormalities of diabetes. In the present study, we demonstrate that skeletal muscle Sirt3 expression is altered in models of both type 1 and type 2 diabetes and that alteration in Sirt3 expression regulates mitochondrial metabolism and production of ROS, which in turn alters insulin signaling. These findings suggest a broad-reaching role of Sirt3 in altered muscle metabolism in both normal and diabetic states.
Changes in Sirt3 Expression in Models of Diabetes and Aging.
Quantitative PCR using muscle from streptozotocin (STZ) diabetic mice revealed an ∼50% decrease of Sirt3 mRNA, similar to previous data from microarrays (23), and Western blot analysis confirmed a parallel decrease of Sirt3 protein (Fig. 1A). Likewise, analysis of skeletal muscle from mice made obese by a chronic high-fat diet revealed a >50% decrease of Sirt3 mRNA and protein compared with samples from mice fed a normal chow diet (Fig. 1B). Conversely, caloric restriction of mice for 12 wk resulted in a 2.5-fold increase of Sirt3 mRNA and protein in skeletal muscle (Fig. 1C). By contrast, there was no change in muscle Sirt3 expression level with aging as demonstrated by a comparison of 3- and 24-mo-old mice (Fig. S1).
Sirt3 expression in different states of diabetes and aging. (A) Skeletal muscles from the hind limbs of STZ diabetic mice and controls (8-wk-old C57BL/6) were collected. RNA and protein was extracted and analyzed by either quantitative PCR or Western blotting. (B) Skeletal muscles from the hind limb of obese high fat diet (HFD) and control mice were collected and processed for quantitative PCR and Western blot analysis for Sirt3 expression. (C) Hind-limb skeletal muscle of CR mice along with controls was collected and processed for quantitative PCR and Western blot analysis. (D) Mice were either randomly fed or fasted for 24 h; half of the fasted animals were then refed for 16 h. After each treatment, quadriceps muscles from fed, fasted, and refed groups were collected and processed for detection of Sirt3 expression as above.
Changes in Sirt3 expression can also occur rapidly as illustrated by the effects of fasting and refeeding. After 24 h of fasting, Sirt3 mRNA and protein expression in quadriceps muscle were decreased by ∼50% and were reversed after refeeding for 16 h (Fig. 1D). The other mitochondrial sirtuin, Sirt4, was also down-regulated in ob/ob mice. During fasting, however, STZ-induced diabetes and caloric restriction had no effect on expression of Sirt4 in skeletal muscle (Fig. S2).
Sirt3 Knockout Mice Exhibit Impaired Insulin Signaling and Increased Oxidative Stress in Skeletal Muscle.
To elucidate the metabolic effect of reductions in Sirt3 on metabolism and insulin signaling, we used mice with targeted inactivation of the Sirt3 gene. These mice had been backcrossed onto a C57BL/6 background for eight generations. Dual energy X-ray absortiometry (DXA) scanning of 20-wk-old male WT and Sirt3 KO mice revealed no differences in total, lean, or fat mass (Fig. 2A). Interestingly, despite identical body weight and composition, assessment in Comprehensive Lab Animal Monitoring System (CLAMS) chambers revealed that daily food intake was 20% lower in Sirt3 KO mice than in controls (Fig. 2B). This occurred with no change in activity (Fig. S3), but correlated with an ∼10% decrease in basal oxygen consumption (VO2) in Sirt3 KO mice in both dark and light cycles (P < 0.05) (Fig. 2C). There was also a trend for a reduced respiratory exchange rate (RER) (Fig. 2D), especially during the light cycle, suggesting decreased carbohydrate oxidation.
Sirt3 knockout mice have increased oxidative stress and insulin resistance in skeletal muscle accompanied by decreased respiration. (A) A DXA scan was performed using 16-wk-old male C57BL/6 WT and KO mice (n = 4), body composition was measured, and Student's t test was performed for significance. (B) CLAMS analysis was performed using 16-wk-old male C57BL/6 WT and KO mice. Daily food intake per mouse over 48 h of CLAMS study was calculated and Student's t test was performed for significance. (C) VO2 was recorded over 48 h and normalized for lean body mass calculated from the DXA scan. Dark cycle and light cycle VO2 were analyzed separately and Student's t tests were performed for significance. (D) Dark cycle and light cycle RERs were calculated using the ratio between VCO2 and VO2. (E) Skeletal muscle from hind limbs of 24-wk-old fasted WT and Sirt3 KO mice was collected, and 25 mg of muscle was homogenized (n = 5). TBARS assay was performed with skeletal muscle homogenates using a TBARS assay kit (Calbiochem Inc.). Student's t test was performed for significance. (F) Hind-limb skeletal muscle from fed 24-wk-old male WT and Sirt3 KO mice was collected and processed and then subjected to Western blot analysis for JNK phosphorylation and total protein levels. (G) In vivo insulin stimulations were performed on 24-wk-old male WT and Sirt3 knockout mice via vena cava injection. Hind-limb skeletal muscle was collected, processed, and subjected to Western blot analysis using the indicated antibodies. (H) For GTTs, blood glucose was measured by tail bleeding at 0, 15, 30, 60, and 120 min after injection (n = 5).
To determine if reduction of Sirt3 in skeletal muscle might alter mitochondrial ROS production, we assayed thiobarbituric acid reactive substances (TBARS) in skeletal muscle homogenates of 24-wk-old male WT and Sirt3 KO mice. This revealed a 75% increase in TBARS activity in the Sirt3 KO mice (Fig. 2E), indicating elevated oxidative stress in skeletal muscle of KO mice. In parallel, the phosphorylation of JNK was increased ∼50% in skeletal muscle of KO mice (Fig. 2F), reflecting activation of this stress kinase in Sirt3-deficient muscle.
To determine the effect of increased oxidative stress and JNK activation in Sirt3 KO skeletal muscle on insulin signaling, we assessed insulin signaling in vivo by vena cava injection of insulin (5 mU/g) into overnight fasted WT and Sirt3 KO mice. Under basal and insulin-stimulated conditions, there were no significant differences in autophosphorylation of the skeletal muscle IR between WT and KO mice. By contrast, there was a >70% decrease in insulin-stimulated IRS-1 phosphorylation in Sirt3 KO mice, which was paralleled by an ∼50% reduction in insulin-stimulated Akt and Erk phosphorylation (Fig. 2G). This impaired insulin signaling in skeletal muscle was reflected at the whole-body level on i.p. glucose tolerance testing (GTT) with significantly higher glucose levels in the Sirt3 KO mice at 60 min (Fig. 2H). Taken together, these data indicate that Sirt3 knockout mice display impaired insulin action and a lower rate of oxygen consumption with increased oxidative stress in skeletal muscle.
Sirt3 Knockdown Induces Insulin Resistance and Stress Kinase Activation.
To further mimic the decreased Sirt3 expression in different diabetes models, we used siRNA-mediated knockdown (KD) in cultured C2C12 myoblasts to assess the effects of reduced Sirt3 on signaling. Western blotting revealed an over 90% decrease of Sirt3 protein in the Sirt3 KD cells (Fig. 3A). Stimulation of serum-starved control and KD cells with 0, 10, and 100 nM insulin revealed no change in either basal or insulin-stimulated receptor autophosphorylation or receptor protein levels as assessed by Western blotting (Fig. 3A). However, insulin-stimulated tyrosine phosphorylation of IRS-1 was decreased by ∼60%, with no significant change in the level of IRS-1 protein (Fig. 3A). As a result, downstream signaling events, including insulin-stimulated Akt and Erk phosphorylation, were decreased by 60–70% (Fig. 3A). Thus, the impaired insulin signaling in Sirt3 knockdown C2C12 myoblasts is induced at the level of IRS-1 phosphorylation without affecting insulin receptor autophosphorylation or abundance.
Effects of Sirt3 knockdown on insulin sensitivity and stress kinase activation. (A) C2C12 cells were transiently transfected with siRNA targeting Sirt3 or scrambled control. Two days after transfection, cells were serum-deprived for 4 h and then stimulated by addition of different concentrations of insulin for 5 min. Cell lysate was collected and subjected to Western blotting with different antibodies. Autoradiography of Western blots was quantified with ImageJ software. The Student's t tests were performed for significance using relative units to serum-starved control results (n = 3). (B) Sirt3 knockdown and control cells were grown to 70% confluence with low glucose (100 mg/dL glucose) DMEM containing 10% FBS. Lysates were collected and processed and then subjected to Western blotting for antibodies against phosphorylated IRS-1, JNK, and p38 MAP Kinase, as well as antibodies against total proteins. The autoradiography was quantified by ImageJ software, and a Student's t test was performed for significance using relative units from the quantification (n = 3).
One potential link between reduction of mitochondrial Sirt3 and the insulin-signaling cascade could be oxidative stress created by mitochondrial dysfunction following reduction of Sirt3. Indeed, Western blot analysis of Sirt3 KD cells in the basal state (100 mg/dL glucose in DMEM with 10% FBS) demonstrated two- to threefold increases in the stress-induced kinase p-38 mitogen-activated protein kinase and JNK phosphorylation compared with control (Fig. 3B). JNK has been shown to phosphorylate IRS-1 on serine 307 residue and to negatively regulate insulin signaling by reducing the IRS-1 tyrosine phosphorylation (24). Conversely, deletion of JNK in skeletal muscle has been shown to improve insulin sensitivity and prevent high-fat-diet–induced insulin resistance (14, 25). Consistent with this hypothesis, IRS-1 serine 307 phosphorylation was increased by twofold in Sirt3 knockdown C2C12 myoblasts (Fig. 3B), indicating that Sirt3 knockdown in C2C12 cells led to stress-induced kinase activation.
Sirt3 Knockdown in C2C12 Myoblasts Induces Elevated Intracellular ROS and Oxidative Stress.
To directly assess the effect of Sirt3 knockdown cells on intracellular ROS content, we treated cells with 5 (and 6)-chloromethyl-2′7′-dichlorodihydrofluorescein diacetate acetyl ester (CM-H2DCFDA) that monitors intracellular ROS concentrations. Quantification of mean fluorescence indicated a twofold increase in ROS levels in the Sirt3 KO cells (Fig. 4A, left pair of bars). H2O2 treatment of Sirt3 KD cells further increased ROS levels, maintaining the twofold difference with the control cells under a stressed condition (Fig. 4A, right pair of bars).
Sirt3 knockdown C2C12 cells undergo stress response with elevated intracellular ROS production. (A) ROS levels of Sirt3 knockdown and control cells were determined using CM-H2DCFDA (Molecular Probes). (B) After incubation with media with or without 200 μM H2O2, intracellular ROS levels of both control and Sirt3 knockdown C2C12 cells were detected with 2.5 μM CM-H2DCFDA by flow cytometry. Using mean fluorescence of cells in either control or Sirt3 KD cells under different conditions, Student's t test was performed for significance (n = 4). (C). Both control and Sirt3 KD cells were incubated in low-glucose (100 mg/dL) DMEM containing 10% FBS with or without 200 μM H2O2 for 2 h following the oxidative challenge protocol that was previously described (26). Quantitative PCR was performed for different stress markers (n = 3). (D) Using cell homogenate, catalase activity assays were performed using catalase assay kit (Calbiochem). SOD activity assays were performed with cell homogenates using a SOD assay kit (n = 4; Cayman Chemical Company). Sirt3 knockdown and control cells were incubated with growth media with 1 mM of H2O2 for 6 h. At the end of the incubation period, all floating and attached cells were collected and resuspended in PBS. Aliquots of 20 μL of resuspended cells were stained with 20 μL 2× trypan blue and were subjected to cell counter analysis for trypan blue staining. The death rates of the cells were calculated on the basis of the percentage of trypan blue positive cells over the total cell number (n = 5).
The increased levels of ROS produced by oxidative stress are known to induce expression of multiple genes, including PGC-1α and GADD45 (26, 27). In parallel with the increased level of ROS in Sirt3 KD cells, there were significant increases in expression of these genes in the basal state, and these were further enhanced after H2O2 treatment with no change in Sirt3 mRNA expression (Fig. 4B). Sirt3 KD cells in the basal state also exhibited increased activities of the major ROS clearance enzymes with 25% and 40% increases in the activities of superoxide dismutase (SOD) and catalase (Fig. 4C). Thus, Sirt3 KD cells produce more ROS, have increased levels of stress response genes, and have greater increases in enzyme activities involved in ROS clearance in response to the stress compared with control cells.
The increase in basal and H2O2-stimulated oxidative stress in Sirt3 KD cells was associated with higher rates of cell death (Fig. 4D). When control cells were challenged with 1 mM H2O2 for 6 h, ∼10% of the cells died, as assessed by trypan blue staining and cell counting. A similar challenge to Sirt3 KD cells resulted in an increase to 25% dead cells (Fig. 4D). Treatment of WT C2C12 myoblasts with H2O2 or glucose oxidase also mimicked the effect of Sirt3 KD with increased JNK phosphorylation (Fig. S4). Thus, knockdown of Sirt3 in C2C12 myoblasts increases basal oxidative stress and makes cells more sensitive to oxidative challenges.
Sirt3 Knockdown C2C12 Myoblasts Show Defects in Mitochondrial Respiration Capacity.
To better understand how Sirt3 can affect mitochondrial function, we assessed the respiratory profile using a Seahorse Flux Analyzer of cells with stable knockdown of Sirt3 and controls using an experimental paradigm with successive addition of blockers of different complexes in the mitochondrial electron transport chain. Changes on oxygen consumption rates were recorded, and areas under the curve (AUC) were calculated before and after each drug injection. Basal respiration, assessed as the oxygen consumption rate (OCR), revealed a small, but significant, ∼15% decrease in Sirt3 KD cells compared with control (Fig. 5A). Addition of the mitochondrial uncoupler Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) (1 μM) to control cells increased OCR by three- to fivefold to 517 ± 43 pmol/min, reflecting maximum respiratory capacity, and this was decreased by ∼32% in the Sirt3 KD cells to a maximum OCR of only 341 ± 42 pmol/min (Fig. 5B).
Sirt3 knockdown cells display decreased basal and uncoupled rates OCR. (A) After the Seahorse Bioscience bioenergetic profiling experiment with mitochondrial uncoupler and inhibitors, basal mitochondrial respiration was calculated by subtraction of nonmitochondrial respiration (after rotenone injection) from total basal respiration (before oligomycin injection). (B) Uncoupled respiration stimulated by FCCP was calculated with AUC between the FCCP and rotenone injections. (C) Mitochondria from both WT and Sirt3 KO mice quadriceps muscles were isolated, and lysates were prepared for protein analysis as previously described (41). Western blot using mitochondrial total lysates was performed using anti-AcK antibody and antibodies against complex V subunit α and Sirt3. (D) The same mitochondrial lysates were immunoprecipitated with a polyclonal anti-AcK antibody (Cell Signaling Technology) and then subjected to Western blotting analysis using antibodies against a complex I 39-kDa subunit, a complex III core I subunit, and Hsp60.
These decreases in basal and maximal respiratory capacity in Sirt3 KD myoblasts occurred with no significant change in gene expression of a number of nuclear-encoded mitochondrial genes (Fig. S5). Likewise, there was no change in mitochondrial content as estimated by quantitative PCR of mitochondrial DNA-encoded NADH dehydrogenase 1 versus nuclear DNA-encoded β-globin (Fig. S6).
To identify potential targets of Sirt3 in mitochondria that might alter mitochondrial function in situations when Sirt3 levels are reduced, we assessed total mitochondrial protein acetylation status using lysates from skeletal muscle of either WT or Sirt3 KO mice. Western blots of mitochondrial extracts using an anti–acetyl-lysine (anti-AcK) antibody revealed multiple acetylated mitochondrial proteins, with the most prominent bands at molecular weights of 96, 73, and 56 kDa and minor bands of 60, 50, and 40 kDa. Among these acetylated mitochondrial proteins, several (indicated by arrows in Fig. 5C) showed increased acetylation in skeletal muscle mitochondria lysates from the Sirt3 KO mouse, suggesting that these may be targets of Sirt3 in skeletal muscle.
To begin to identify these candidate targets of Sirt3, we immunoprecipitated proteins from the mitochondrial extract using anti-AcK antibody and subjected the immunoprecipitate to SDS/PAGE and Western blotting with antibodies to specific mitochondrial proteins. Although Western blots of the total mitochondrial proteins extract revealed no differences between muscle of WT and Sirt3 KO muscle in content of different subunits in the mitochondrial electron transporter chain (ETC) or the mitochondrial chaperon protein Hsp60, there were increased levels of the 39-kDa subunit of complex I, the 56-kDa core I subunit of complex III, and the 60-kDa Hsp60 precipitated by anti-AcK antibody from the Sirt3 KO mitochondrial lysates (Fig. 5D). The increased acetylation on these ETC subunits and Hsp60 in Sirt3 KO mitochondria suggests that they are direct substrates of Sirt3 and that changes in their acetylation status contribute to the altered the generation of mitochondrial ROS and response to oxidative stress (28–30).
Mammals and other higher vertebrates express a family of sirtuins with different subcellular localizations and a wide range of substrate specificities. In this regard, Sirt3, Sirt4, and Sirt5 are particularly interesting due to their mitochondrial localization, where they can regulate energy homeostasis and oxidative metabolism, as well as oxidative stress and cellular injury. In the present study, we find that Sirt3 expression in skeletal muscle is significantly decreased in rodent models of type 1 and type 2 diabetes and is regulated by fasting and caloric restriction (CR). This led us to explore the link between skeletal muscle Sirt3 expression and control of mitochondrial function and insulin sensitivity in diabetes. Using Sirt3 knockdown in C2C12 cells and skeletal muscles of Sirt3 KO mice, we show that decreases in Sirt3 expression lead to altered mitochondrial function with increased levels of oxidative stress and activation of JNK, which in turn induces impaired insulin signaling.
Skeletal muscle is the major organ involved in postprandial glucose uptake and metabolism and peripheral insulin sensitivity. Changes in mitochondrial mass and oxidative phosphorylation have been shown to occur in muscle of individuals with diabetes and insulin resistance (31, 32). Mitochondrial dysfunction plays a major role in the onset of skeletal muscle insulin resistance through oxidative stress (33). Increased levels of oxidative stress have been demonstrated in skeletal muscle of type 2 diabetic mice (34) and in patients with diabetes (35). Antioxidant administration has been shown to decrease manifestations of insulin resistance in mice (36), but also to reduce the beneficial effects of exercise on muscle glucose uptake in humans in vivo (37), indicating the biphasic role of reactive oxygen species to both potentiate and inhibit insulin action.
Sirt3 provides a target for regulation of skeletal muscle insulin sensitivity via mitochondrial ROS production. Classically, ROS serve many important functions in cell defense, especially against microbial invasion. In recent years, ROS has also been shown to play important roles in activation of different signaling pathways and in the development of insulin resistance. At low physiological levels, ROS can mimic insulin action and enhance insulin sensitivity (37, 38). However, overproduction of ROS in pathological states can lead to adverse effects, including oxidative stress, inflammation, and insulin resistance. The ROS level in the cell is maintained by a balance between production and clearance. Our study shows that, despite increased catalase and SOD activity, ROS levels remain elevated in Sirt3 KD cells. Thus, the increased level of ROS in knockdown cells is not due to decreased clearance or detoxification, but to overproduction of ROS with reduction of mitochondrial Sirt3 abundance and activity. Moreover, after treating control and Sirt3 KD C2C12 cells with antioxidants such as EU.K.134, which is a ROS scavenger, the difference in insulin-stimulated IRS-1 phosphorylation between control and Sirt3 KD cells was abolished, indicating that increased ROS level in KD cells induced impaired insulin signaling in these cells (Fig. S7).
The exact molecular mechanism by which Sirt3 affects oxidative metabolism in skeletal muscle is still largely unknown. Recent studies have shown that Sirt3 can serve as a broad-ranging mitochondrial deacetylase targeting many different substrates (18). Thus, identifying the specific targets regulated by reversible Sirt3 deacetylation that affect mitochondrial oxidative function and help maintain a normal cellular redox state and energy homeostasis will be challenging. Other recent reports have shown links between Sirt3 and mitochondrial ROS production by targeting HIF-1α and SOD2 under different pathological and physiological conditions (39, 40). By immunoprecipitating mitochondrial lysates from WT and KO muscle with anti–acetyl-lysine antibody, we have found that several proteins involved in the electron transporter chain are hyperacetylated in Sirt3 KO muscle, suggesting that these proteins may also be the direct targets of Sirt3. These include the 39-kDa subunit of complex I, the core I subunit of complex III, and the ATPase subunit α of complex V, as well as the chaperone protein Hsp60. Changes in acetylation of these proteins can potentially alter their activities and functions, leading to the mitochondrial stress response and ROS generation. Similar effects of Sirt3 deletion were also observed in tumor cells; ROS was generated from complex III of ETC which served as a signaling molecule that targeted protein functions in other cellular compartments (40). The acetylation of multiple mitochondrial proteins and their role as Sirt3 substrates also suggest that there are mitochondrial acetyl-transferases that can acetylate the targets of the Sirt3 deacetylase. These are also possible targets for alteration in diabetes.
One remaining question is how Sirt3 function is regulated under different pathological and physiological conditions. Although Sirt3 expression is decreased in fasting, it is elevated in muscle of CR mice, suggesting that short-term and chronic nutrient deprivation have different effects on Sirt3 activation. Furthermore, the global deletion of Sirt3 exhibits many other alterations in metabolism, such as altered oxygen consumption and decreased food intake, indicating that Sirt3 has important functions in other organs involved in metabolic homeostasis. It will be interesting to assess Sirt3's effects on appetite regulation in the hypothalamus, where neuronal signals involved in feeding behavior may be altered by deletion of Sirt3.
In summary, the decreased level of Sirt3 in skeletal muscle in states of diabetes and obesity is an important component of the pathogenesis of type 2 diabetes, which can induce altered mitochondrial function, increase ROS production and oxidative stress, and lead to insulin resistance. Our data also provide direct evidence of the importance of reversible acetylation/deacetylation in the mitochondria and its potential role in development of insulin resistance and metabolic disorders. Agents that increase Sirt3 activity or expression could therefore potentially reverse at least some of the adverse effects of type 2 diabetes. Furthermore, site-specific deacetylation/acetylation of mitochondrial proteins may serve as a therapeutic tool to regulate cellular redox state and energy homeostasis in diabetes and insulin resistance, as well as other mitochondrial diseases.
Cell Culture and Maintenance.
C2C12 cells (ATCC) were cultured in high-glucose (400 mg/dL) DMEM (Invitrogen) containing 10% FBS (Gemini Bioproducts) unless otherwise indicated. Cell media were replaced by low-glucose (100 mg/dL) DMEM containing 10% FBS 24 h prior to the experiments.
All animal studies were performed according to protocols approved by the Institutional Animal Care and Use Committee (Joslin Diabetes Center, Boston). Fed mice were killed at 9:00 AM or transferred to a new cage without food for 24 h and then killed for "fasted" studies. STZ diabetic mice were generated as previously reported (23). To induce obesity, mice were fed a high-fat diet (Teklad; TD.88137; 42% fat by calories) after weaning for 24 wk; low-fat diet controls were fed with a standard chow diet (Picolab Rodent Diet 20 containing 13.2% fat by calories). Studies used WT and Sirt3−/− C57BL/6 male mice, maintained on a standard chow diet, unless otherwise indicated.
Constructs and Generation of Transient/Stable Sirt3 Knockdown Cells.
Sirt3 siRNA with scrambled control was purchased from IDT Technology for signaling and gene expression studies in C2C12 cells. Transient transfection of siRNA was achieved using Mirus Transit TKO transfection reagents. Sirt3 shRNA and shGFP control lentiviral constructs were purchased from Open Biosystems, and stable Sirt3 knockdown cell lines were generated for ROS detection and Seahorse bioenergetics on oxygen consumption (OCR) studies.
Oxygen Consumption Analysis.
Cellular OCR was measured using a Seahorse Bioscience XF24 analyzer. Cells were seeded at 30,000 cells/well 24 h before the analysis. Each experimental condition was analyzed using four to six biological replicates. Before measurement was taken, cells were washed, and 630 μL of sodium carbonate-free pH 7.4 DMEM was added to each well. After 15 min equilibration, three successive 2-min measurements were performed with intermeasurement mixing. A total of 70 μL of oligomycin (10 μM), FCCP (10 μM) or rotenone (10 μM) was injected into each well sequentially, and four to five successive 2-min measurements were performed with 2-min intermeasurement mixing. All OCR values before and after the injections and measurements were recorded, OCR and time curves where generated, and the AUC was calculated before and after each injection. For statistical analysis, Student's t test was performed between shGFP and shSirt3 C2C12 cells.
GTT and in Vivo Insulin Stimulation:
For GTTs, mice were fasted overnight and then injected intraperitoneally with glucose (2 g/kg body weight). Tail-vein blood glucose measurements were performed at 0, 15, 30, 60, and 120 min after injection. For in vivo stimulation of insulin signaling, mice were fasted for 16 h and then anesthetized with an i.p. injection of pentobarbital (100 mg/kg). Insulin was injected (5 mU/g) through the inferior vena cava. After 5 min, skeletal muscles from the hind limbs were harvested. Muscles were homogenized and lysed at 4 °C, and lysates were subjected to Western blotting to assess insulin-stimulated phosphorylation cascades.
DEXAs Scanning and CLAM Testing.
To assess metabolic effects of Sirt3 deletion in mice, body weight and composition were measured. Fat and lean mass was measured by DXA scanning. CLAMS method was used to measure activity level, food intake, volume of O2 consumption, and volume of CO2 production (Oxymax OPTO-M3 system; Columbus Instruments). Mean activity, VO2, and VCO2 of both WT and Sirt3 KO mice were calculated for dark and light cycles, and Student's t test was performed to determine statistical difference between metabolic measurements.
We thank Dr. Marcelo Mori and Dr. Steven Russell for providing CR mice skeletal muscles. We also thank Dr. Stephane Gesta for active discussion and help with the Seahorse Bioscience analysis. The work was supported by research Grants R01DK33201 (to C.R.K) and R24DK085610 (to C.R.K and E.M.V.), a grant from the Ellison Foundation (to C.R.K.), and the Mary K. Iacocca Professorship. This study also received support from the Joslin Diabetes Endocrinology Research Center core laboratories.
↵1Present address: Department of Pathology and Institute of Gerontology, University of Michigan, Ann Arbor, MI 48109.
↵2To whom correspondence should be addressed. E-mail: c.ronald.kahn{at}joslin.harvard.edu.
Author contributions: E.J., E.M.V., and C.R.K. designed research; E.J., B.E., M.D.H., J.B., and K.Y.L. performed research; D.L. contributed new reagents/analytic tools; E.J., B.E., and M.D.H. analyzed data; and E.J. and C.R.K. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1111308108/-/DCSupplemental.
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You are going to email the following Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production
Enxuan Jing, Brice Emanuelli, Matthew D. Hirschey, Jeremie Boucher, Kevin Y. Lee, David Lombard, Eric M. Verdin, C. Ronald Kahn
Proceedings of the National Academy of Sciences Aug 2011, 108 (35) 14608-14613; DOI: 10.1073/pnas.1111308108
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redpajama_set_name: RedPajamaGithub


Description: How To Be Beautiful Computer Network Diagrams Network Diagram Computer Network Diagrams Network Diagram Software Home Area Network Network Diagram Software #6013 from the above 1066x979 resolutions which is part of the "DIY Needed" directory. Download this image for free in HD resolution the choice "Save full resolution" below. If you do not find the exact resolution you are looking for, then go for a native or higher resolution.
Certainly one of one of the most popular electrical wiring queries is regarding how to wire a switch. Whilst working with switches in the home is fairly effortless, wiring just one might not be that quick for everyone. An ON-OFF switch is really quite simple to wire. There are several types of switches, but for this instance, let's say you are installing a single-pole toggle switch, an extremely widespread change (along with the simplest).
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FULTON, NY – This Saturday, August 18 Power Seal Asphalt Sealing & Northeast Racing Products, Auction, Trade Show and Swap Meet will present a night of fast, family, affordable, fun racing at the Fulton Speedway.
Racing on the 'Highbanks' will feature the final race of the Unique eCigs 358 Modified Series, SUNY Canton DIRTcar Sportsman, Billy Whittaker Cars & Trux RUSH Late Models and E&V Energy Novice Sportsman.
Adult grandstand admission is $15 with everyone 18 years old and younger free. Pit is $27 Member, $30 Non-Member. Grandstands will open at 5:00 pm with racing at 7:00 pm.
The Tracey Road Equipment DIRTcar Modifieds will have two-point battles going on Saturday night. The first is to decide the Champion in the Unique eCigs 358 Modified Series. Rookie Ron Davis III and Jordan McCreadie who has called Fulton Speedway his Saturday night race place for the first time are tied at the top of the standings. Never count out former track champion Larry Wight who is just ten points back.
Saturday night's race takes on double importance as it also counts towards track points, with just three races left to decide the 2018 Tracey Road Equipment DIRTcar Modified Track Champion. For others it is a chance to battle for wins and good finishes to carry momentum into the 32nd Annual Outlaw 200 Weekend Friday & Saturday, September 28-29.
August 18 format. No track handicapping, draw at the pit gate, timed hot laps, feature redraw with the feature being 50-laps, $2,000-to-win.
(Unique eCigs 358 Modified Series) – 32R-Ron Davis III (110) 9J-Jordan McCreadie (110) 99L-Larry Wight (108) 20-Jeff McGinnis (94) 42P-Pat Ward (90).
(Tracey Road Equipment DIRTcar Modifieds) – 99L-Larry Wight (649) 32R-Ron Davis III (628) 83X-Tim Sears Jr. (626) 42p-Pat Ward (614) 62s-Tom Sears Jr. (583).
A big thanks goes out to one of the night's sponsors, Sportsman racer Tom Juno and his company Power Seal Driveway Sealer. The top-two in both Sportsman features will race in the Power Seal Challenge. The four drivers will draw for starting spots in a 4-lap dash paying (1) $150 (2) $100 (3) $75 (4) $50.
Tom Juno and Corey Barker will have their Sportsman pit location Saturday in the midway. Fans can get up close to see what happens during a race night for race teams.
(SUNY Canton DIRTcar Sportsman) – 8-Alan Fink (660) 24K-Nick Krause (636) 38-Zach Sobotka (636) 60-Jackson Gill (624) 3-Chris Mackey (620).
(Billy Whittaker Cars & Trux RUSH Late Models) – 38-Jason Parkhurst (1,384) 3X-Kevan Cook (1,380) 81-Bret Belden (1,368) 93-Sean Beardsley (1,346) 10-Chris Fleming (1,328).
The Fulton Speedway would like to welcome Power Seal Driveway Sealing, "The Fast Professionals" and the Northeast Racing Products. Auction. Trade Show and Swap Meet.
or call (315) 622-5221. As always, support those who support racing.
The Speedway also welcomes, Northeast Racing Products. Auction. Trade Show and Swap Meet. Their name "Northeast," says it all as they are the largest show of its kind in the region.
With vendors from all over the country, you will find the latest and best products for dirt, asphalt, circle track, drag racing and other types of racing too numerous to mention. Looking to upgrade your racing program? You will find top cars and parts in the auction portion of the weekend.
The show will take place the weekend of November 17-18 at the New York State Fairgrounds.
For more information you need to know if you are vendor, seller, or buyer go to www.northeastracingproducts.com (315) 374-2839 or by email NortheastRacingProducts@yahoo.com. And don't forget to like their Facebook page.
We all know if there is one thing that goes together they are racing people and their pets. Not all of our furry friends are as fortunate as the ones we have at home. When there is a need the racing family always steps up in a big way. This Saturday, August 18 there will be a silent auction in the midway to benefit Bernard's Beagle Rescue & Misfits Animal Rescue & Sanctuary. To learn more, go to the www.fultonspeedway.com and the track Facebook page to learn more and to see all the awesome items that will be up for auction.
A big welcome to Parratt Wolff and their employees. To see all the services, they offer in the drilling industry go to www.pwinc.com.


text:
The Many Forms of Entrepreneurialism
Trace Mitchell
What is an entrepreneur?
While it may seem straightforward, this question is deceptively complex. The term can be used in many different ways to describe a variety of individuals who engage in economic, political, or even social activities. Entrepreneurs affect almost every aspect of modern society. While most people probably have a general sense of what is meant when they hear the term entrepreneur, it can be difficult to provide a precise definition. This is due in no small part to the fact that some of the primary thinkers who have given substance to the term have placed their focus on different aspects of entrepreneurialism.
How Economists Talk About Entrepreneurs
Austrian economist Joseph Schumpeter thought that the purpose of an entrepreneur was "to reform or revolutionize the pattern of production by exploiting an invention." Schumpeterian entrepreneurs [1] are highly creative, disruptive innovators who challenge the status quo in order to bring about new economic opportunities. American economist Israel Kirzner viewed the defining characteristic of entrepreneurs as "alertness." Kirznerian entrepreneurs [2] are individuals who are able to identify the ways in which a market could be moved closer to its equilibrium, such as recognizing a gap in knowledge between different economic actors.
In the time since Schumpeter and Kirzner helped lay the groundwork, a number of George Mason University-affiliated scholars have made major contributions to our understanding of entrepreneurialism. Don Boudreaux [3], Jerry Ellig and Daniel Lin [4], and Virgil Storr, Stefanie Haeffele and Laura Grube [5], have offered a merged view of Schumpeterian and Kirznerian entrepreneurialism, showing the significant overlap between the two approaches.
In this new way of looking at the issue, entrepreneurs are crucial to innovation, economic growth, and societal change. They are dynamic actors who respond to incentives and market signals. "Greater discovery and innovation are the benchmarks of dynamic competition," note Ellig and Lin [4], "not the driving down of price to marginal cost."
Productive and Unproductive Entrepreneurs
But are all of these dynamic entrepreneurs good for society? Among modern economists and political scientists, there is a general consensus that Schumpeterian-Kirznerian entrepreneurs are individuals who either find or create value within society. In recent decades, therefore, scholars have focused on applying those insights more broadly and developing a more robust way to categorize different types of entrepreneurial activity.
Another American economist, William Baumol, drew an important distinction between productive and unproductive entrepreneurs [6]. He described productive entrepreneurs as people engaged in enterprising activity that generates value within society, such as the creation of new and innovative technologies. However, he also found that entrepreneurs could be unproductive if they did not create value or actively harmful if they destroyed value. "Indeed, at times the entrepreneur may even lead a parasitical existence that is actually damaging to the economy." For Baumol, entrepreneurs are not defined as individuals who develop new methods of creating value but rather "persons who are ingenious and creative in finding ways that add to their own wealth, power, and prestige."
Entrepreneurs in the Political Arena
An individual who is highly skilled at lobbying a particular governmental agency might be considered an entrepreneur, but that does not mean they are necessarily contributing value to society overall. Some scholars refer to this as political entrepreneurialism. Economists Peter Boettke and Christopher Coyne define [7] political entrepreneurs as, "individuals who operate in political institutions and who are alert to profit opportunities created by those institutions." Utah State University professors Randy Simmons, Ryan Yonk and Diana Thomas observe [8] how such entrepreneurs seek specific rewards or privileges from political institutions and interactions through "alertness to previously unnoticed rent-seeking opportunities." 'Rent-seeking' is an economic concept where one person or group is able to derive certain benefits from a particular institutional arrangement without actually creating value for others.
Our Mercatus Center colleague Matthew Mitchell has documented [9] the "long list of privileges that governments occasionally bestow upon particular firms or particular industries." Mitchell offers a taxonomy of the sort of privileges that political entrepreneurs seek. They include: "monopoly status, favorable regulations, subsidies, bailouts, loan guarantees, targeted tax breaks [10], protection from foreign competition [11], and noncompetitive contracts [12]."
All of these privileges could qualify as a form of Baumol's "unproductive entrepreneurship" or, in the extreme, what he called destructive entrepreneurialism. Professors Sameeksha Desai, Zoltan Acs and Utz Weitzel define [13] destructive entrepreneurship as "wealth-destroying (such as the destruction of inputs for production activities)." Whereas unproductive entrepreneurship "seeks to redistribute from one individual to another individual," Boettke and Coyne note [7], "destructive entrepreneurship reduces the total surplus in an attempt by the entrepreneur to increase his own wealth." Outright theft and violent conflict over resources are examples of destructive entrepreneurship.
When policymakers reward political destructive or unproductive entrepreneurs, it has profound effects [14] on the well-being of ordinary people and entire nations.
Evasive and Regulatory Entrepreneurs
Not all political entrepreneurs are necessarily out to gain privileges from government at the expense of others, however. Some entrepreneurs are more interested in simply gaining greater freedom to innovate. Scholars have used the terms evasive entrepreneurs or regulatory entrepreneurs to describe such actors. Researchers Niklas Elert and Magnus Henrekson define [15] evasive entrepreneurialism as "profit-driven business activity in the market aimed at circumventing the existing institutional framework by using innovations to exploit contradictions in that framework." GMU economists Christopher Coyne and Peter Leeson argue [16] that "[e]vasive activities include the expenditure of resources and efforts in evading the legal system or in avoiding the unproductive activities of other agents." Regulatory entrepreneurs, according [17] to legal scholars Elizabeth Pollman and Jordan Barry, are innovators who "are in the business of trying to change or shape the law" and are "strategically operating in a zone of questionable legality or breaking the law until they can (hopefully) change it." Evasive or regulatory entrepreneurs generally adopt a "permissionless innovation [18]" approach to both business and political activities.
Generally speaking, evasive and regulatory entrepreneurs are synonymous, although regulatory entrepreneurialism implies a more active intent to change policy through entrepreneurial acts. Evasive entrepreneurs might also be ignorant of what the law says, whereas regulatory entrepreneurs, by definition, understand how the law negatively affects their efforts and seek to change policy through their actions.
However, both evasive and regulatory entrepreneurs are distinct from what economists Alexandre Padilla and Nicolas Cachanosky call [19] indirectly productive entrepreneurs. They argue that regulation often creates unintended consequences which lead to new entrepreneurial opportunities. Indirectly productive entrepreneurs seize upon these opportunities by finding ways to mitigate the costs associated with specific regulations. Unlike regulatory entrepreneurs, who desire to change policy, or evasive entrepreneurs, who seek to avoid it, indirectly productive entrepreneurs create value by reducing the harm caused by policies. For example, the Transportation Safety Administration (TSA) has a policy [20] prohibiting passengers from bringing liquids on an airplane unless they are kept in a container that is smaller than 3.4 ounces. As a response, several indirectly productive entrepreneurs have created "TSA Approved" containers [21] for shampoo, mouthwash, and other toiletries that make it easier for passengers to comply with the regulation.
There is also a growing acknowledgment that entrepreneurial behavior can transcend economic or political activities. Mercatus scholars have defined [5] social entrepreneurs as individuals who engage in "innovative, social value-creating activity that can occur within or across the nonprofit, business, or government sectors." Social entrepreneurial activities are not typically in pursuit of compensation or profit, but that need not always be the case and "the distinction between social and commercial entrepreneurship is not dichotomous, but… a continuum ranging from purely social to purely economic," they note.
Some sort of social mission drives this type of entrepreneurship, and social entrepreneurialism will often incorporate what MIT economist Eric von Hippel refers to as "free innovation [22]." He defines a free innovation as "a functionally novel product, service, or process that (1) was developed by consumers at private cost during their unpaid discretionary time (that is, no one paid them to do it) and (2) is not protected by its developers, and so is potentially acquirable by anyone without payment—for free." A good example of free innovation would be social entrepreneurs using 3D printers and open source designs [23] to voluntarily create prosthetics for children with limb deficiencies.
As this brief survey reveals, there are many different forms of entrepreneurialism. Individuals can act in an entrepreneurial fashion in pursuit of many different objectives: profits, fame, social or legal change, or even personal or organizational privileges that come at the expense of others. Clearly, not all forms of entrepreneurialism produce socially beneficial outcomes. Policymakers should seek to foster and reward Schumpeterian-Kirznerian entrepreneurs given the positive implications for innovation and economic growth and avoid falling into the trap of rewarding political entrepreneurs, who instead seek to game laws and regulations to their own advantage.
Given the extensive research and academic literature inherent to this subject, we've curated a list of selected readings below.
Photo credit: Morgan Lee/AP/Shutterstock
Austin, J., Stevenson, H., & Wei-Skillern, J. (2006). Social and Commercial Entrepreneurship: Same, Different, or Both? Entrepreneurship Theory and Practice, 30(1), 370-384. Retrieved from https://onlinelibrary.wiley.com/doi/full/10.1111/j.1540-6520.2006.00107.x [24]
Baumol, W. (1968). Entrepreneurship in Economic Theory. The American Economic Review,58(2), 64-71. Retrieved from https://www.jstor.org/stable/1831798?seq=1#page_scan_tab_contents [25]
Baumol, W. (1990). Entrepreneurship: Productive, Unproductive and Destructive. Journal of Political Economy, 98(5), 893-921. Retrieved from https://www.jstor.org/stable/2937617?seq=1#page_scan_tab_contents [6].
Boettke, P. J., & Coyne, C. J. (2009). Context Matters: Institutions and Entrepreneurship. Foundations and Trends in Entrepreneurship, 5(3), 135-209. Retrieved from https://www.nowpublishers.com/article/Details/ENT-018 [7].
Boudreaux, D. (1994), Schumpeter and Kirzner on Competition and Equilibrium. In P. Boetkke & D. Prychitko (Eds.), The Market Process: Essays in the Contemporary Austrian Economics (pp. 52-61). Cheltenham, UK: Edward Elgar. Retrieved from http://cafehayek.com/wp-content/uploads/2011/02/Heres-a-paper-that-I-wrote-back-in-1986-or-1987.-In-it-I-attempt-to-explain-how-non-price-competition-can-be-equilibrating..pdf [3]
Coyne, C. J., & Leeson, P. T. (2004). The Plight of Underdeveloped Countries. Cato Journal, 24(3), 235-249. Retrieved from https://papers.ssrn.com/sol3/papers.cfm?abstract_id=869123 [16]
Desai, S., & Acs, Z. J. (2007). A theory of destructive entrepreneurship. Jena Economic Research Papers no. 85, Friedrich-Schiller University and Max Planck Institute of Economics, Jena, Germany, October, Retrieved from https://www.econstor.eu/bitstream/10419/25657/1/553834517.PDF [26]
Dees, J. G. (2001), 'The meaning of Social Entrepreneurship'. The Fuqua School of Business, Center for the Advancement of Social Entrepreneurship.
Desai, S., Acs, Z.J., and Weitzel, U. (2013), "A model of destructive entrepreneurship: insight for conflict and post-conflict recovery," Journal of Conflict Resolution, Vol. 57, No. 1, pp. 20–40, Retrieved from https://repository.ubn.ru.nl/bitstream/handle/2066/170796/170796.pdf [13]
Elert, N. & Henrekson, M. (2016). Evasive Entrepreneurialism. Small Business Economics, 47(1), 95-113. Retrieved from http://www.ifn.se/wfiles/wp/wp1044.pdf [15].
Ellig, J. & Lin, D. (2001). A Taxonomy of Dynamic Competition Theories. In J. Ellig (Ed.), Dynamic Competition and Public Policy: Technology, Innovation, and Antitrust Issues (pp. 16-44). Cambridge: Cambridge University Press. Retrieved from https://www.cambridge.org/core/books/dynamic-competition-and-public-policy/taxonomy-of-dynamic-competition-theories/C536918DD453ADB34A47F48EDA6D21B7 [27].
Hippel, E. V. (2017). Free Innovation. Cambridge, MA: The MIT Press. Retrieved from https://mitpress.mit.edu/books/free-innovation [22].
Kirzner, I. M. (2009). The Alert and Creative Entrepreneur: A Clarification. Small Business Economics, 32(2), 145-152. Retrieved from https://link.springer.com/article/10.1007/s11187-008-9153-7 [2]
Lucas, D. S. & Fuller, C. S. (2015). Entrepreneurship: Productive, Unproductive, and Destructive—Relative to What? Journal of Business Venturing Insights, 7, 45-49. Retrieved from https://www.sciencedirect.com/science/article/pii/S2352673417300033 [28].
Mitchell, M. D. (2012). The Pathology of Privilege: The Economic Consequences of Government Favoritism. Mercatus Center. Retrieved from https://www.mercatus.org/publication/pathology-privilege-economic-consequences-government-favoritism [9].
Murphy, K.M., Shleifer, A. and Vishny, R.W. (1991) "The Allocation of Talent: Implications for Growth," The Quarterly Journal of Economics, 106(2): 503-530. Retrieved from http://www.nber.org/papers/w3530
Murphy, K.M., Shleifer, A. and Vishny, R.W. (1993) "Why is rent-seeking so costly to growth?" American Economic Review Papers and Proceedings, 83 (2): 409-414. Retrieved from https://scholar.harvard.edu/shleifer/publications/why-rent-seeking-so-costly-growth [29]
Padilla, A. & Cachanosky, N. (2016). Indirectly Productive Entrepreneurship. Journal of Enterprise and Public Policy, 5(2), 161–175. Retrieved from https://papers.ssrn.com/sol3/papers.cfm?abstract_id=2584741 [19].
Pollman, E. & Barry, J. M. (2017). Regulatory Entrepreneurship. Southern California Law Review, 90, 383-448. Retrieved from https://papers.ssrn.com/sol3/papers.cfm?abstract_id=2741987 [17].
Schumpeter, J. (1942, 2008). Capitalism, Socialism and Democracy (3rd ed.). New York, NY: HarperCollins Publishers. Retrieved from https://www.amazon.com/Capitalism-Socialism-Democracy-Joseph-Schumpeter/dp/0061561614 [1].
Simmons, R. T., Yonk, R. M., & Thomas, D. W. (2011). Bootleggers, Baptists, and Political Entrepreneurs: Key Players in the Rational Game and Morality Play of Regulatory Politics. The Independent Review, 15(3), 367-381. Retrieved from http://www.independent.org/pdf/tir/tir_15_03_3_simmons.pdf [8].
Storr, V., Haeffele, S., & Grube, L. (2015). The Entrepreneur as a Driver of Social Change. In Community Revival in the Wake of Disaster (pp. 11-31) New York, NY: Palgrave Macmillan. Retrieved from
https://www.palgrave.com/us/book/9781137286086 [5]
Thierer, A. (2018). Evasive Entrepreneurialism and Technological Civil Disobedience: Basic Definitions, The Bridge. Retrieved from https://www.mercatus.org/bridge/commentary/evasive-entrepreneurialism-and-technological-civil-disobedience-basic-definitions [30]
Thierer, A. (2016). Permissionless Innovation: The Continuing Case for Comprehensive Technological Freedom. Retrieved from https://www.mercatus.org/publication/permissionless-innovation-continuing-case-comprehensive-technological-freedom [18]
Thierer, A. (2017). You're in Joseph Schumpeter's economy now. Learn Liberty, Retrieved from http://www.learnliberty.org/blog/youre-in-joseph-schumpeters-economy-now [31]
The Word 'Entrepreneur' Gets Used a Lot, but It Can Have Many Different Meanings
Source URL: https://www.mercatus.org/bridge/commentary/many-forms-entrepreneurialism
[1] https://www.amazon.com/Capitalism-Socialism-Democracy-Joseph-Schumpeter/dp/0061561614
[2] https://link.springer.com/article/10.1007/s11187-008-9153-7
[3] http://cafehayek.com/wp-content/uploads/2011/02/Heres-a-paper-that-I-wrote-back-in-1986-or-1987.-In-it-I-attempt-to-explain-how-non-price-competition-can-be-equilibrating..pdf
[4] http://assets.cambridge.org/052178/2503/sample/0521782503ws.pdf
[5] https://www.palgrave.com/us/book/9781137286086
[6] https://www.jstor.org/stable/2937617?seq=1#page_scan_tab_contents
[7] https://www.nowpublishers.com/article/Details/ENT-018
[8] http://www.independent.org/pdf/tir/tir_15_03_3_simmons.pdf
[9] https://www.mercatus.org/publication/pathology-privilege-economic-consequences-government-favoritism
[10] https://www.mercatus.org/bridge/commentary/government-privilege-using-and-abusing-tax-code
[11] https://www.mercatus.org/bridge/commentary/government-privilege-trade-barriers
[12] https://www.mercatus.org/bridge/commentary/government-privilege-contracting-abuses
[13] https://repository.ubn.ru.nl/bitstream/handle/2066/170796/170796.pdf
[14] https://scholar.harvard.edu/files/shleifer/files/rent_seeking.pdf
[15] http://www.ifn.se/wfiles/wp/wp1044.pdf
[16] https://papers.ssrn.com/sol3/papers.cfm?abstract_id=869123
[17] https://papers.ssrn.com/sol3/papers.cfm?abstract_id=2741987
[18] https://www.mercatus.org/publication/permissionless-innovation-continuing-case-comprehensive-technological-freedom
[20] https://www.tsa.gov/travel/security-screening/liquids-rule
[21] https://www.amazon.com/Approved-Toiletry-Cosmetic-Tovla-Accessory/dp/B01G2UPH8Q/ref=asc_df_B01G2UPH8Q/?tag=hyprod-20&linkCode=df0&hvadid=192287662223&hvpos=1o3&hvnetw=g&hvrand=6308093255935340825&hvpone=&hvptwo=&hvqmt=&hvdev=c&hvdvcmdl=&hvlocint=&hvlocphy=9008162&hvtargid=pla-309752597903&psc=1
[22] https://mitpress.mit.edu/books/free-innovation
[23] https://www.mercatus.org/bridge/commentary/3d-printers-evasive-entrepreneurs-and-future-tech-regulation
[24] https://onlinelibrary.wiley.com/doi/full/10.1111/j.1540-6520.2006.00107.x
[25] https://www.jstor.org/stable/1831798?seq=1#page_scan_tab_contentsc
[26] https://www.econstor.eu/bitstream/10419/25657/1/553834517.PDF
[27] https://www.cambridge.org/core/books/dynamic-competition-and-public-policy/taxonomy-of-dynamic-competition-theories/C536918DD453ADB34A47F48EDA6D21B7
[28] https://www.sciencedirect.com/science/article/pii/S2352673417300033
[29] https://scholar.harvard.edu/shleifer/publications/why-rent-seeking-so-costly-growth
[30] https://www.mercatus.org/bridge/commentary/evasive-entrepreneurialism-and-technological-civil-disobedience-basic-definitions
[31] http://www.learnliberty.org/blog/youre-in-joseph-schumpeters-economy-now
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