Being An Entrepreneur….

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Being an entrepreneur is about more than just starting a business or two, it is about having attitude and the drive to succeed in business. All successful Entrepreneurs have a similar way of thinking and posses several key personal qualities that make them so successful in business. Successful entrepreneurs like the ambitious Richard Branson have an inner drive to succeed and grow their business, rather than having a Harvard Business degree or technical knowledge in a particular field.

All successful entrepreneurs have the following qualities:

Inner Drive to Succeed
Entrepreneurs are driven to succeed and expand their business. They see the bigger picture and are often very ambitious. Entrepreneurs set massive goals for themselves and stay committed to achieving them regardless of the obstacles that get in the way.

Strong Belief in themselves
Successful entrepreneurs have a healthy opinion of themselves and often have a strong and assertive personality. They are focused and determined to achieve their goals and believe completely in their ability to achieve them. Their self optimism can often been seen by others as flamboyance or arrogance but entrepreneurs are just too focused to spend too much time thinking about un-constructive criticism.

Search for New Ideas and Innovation
All entrepreneurs have a passionate desire to do things better and to improve their products or service. They are constantly looking for ways to improve. They’re creative, innovative and resourceful.

Openness to Change
If something is not working for them they simply change. Entrepreneurs know the importance of keeping on top of their industry and the only way to being number one is to evolve and change with the times. They’re up to date with the latest technology or service techniques and are always ready to change if they see a new opportunity arise.

Competitive by Nature
Successful entrepreneurs thrive on competition. The only way to reach their goals and live up to their self imposed high standards is to compete with other successful businesses.

Highly Motivated and Energetic
Entrepreneurs are always on the move, full of energy and highly motivated. They are driven to succeed and have an abundance of self motivation. The high standards and ambition of many entrepreneurs demand that they have to be motivated!

Accepting of Constructive Criticism and Rejection
Innovative entrepreneurs are often at the forefront of their industry so they hear the words “it can’t be done” quite a bit. They readjust their path if the criticism is constructive and useful to their overall plan, otherwise they will simply disregard the comments as pessimism. Also, the best entrepreneurs know that rejection and obstacles are a part of any leading business and they deal with them appropriately.

True entrepreneurs are resourceful, passionate and driven to succeed and improve. They’re pioneers and are comfortable fighting on the frontline The great ones are ready to be laughed at and criticized in the beginning because they can see their path ahead and are too busy working towards their dream.

Article By: Tele Innova and iResearchers

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University of Glasgow – Scottish University of the Year

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University of Glasgow – Scottish University of the Year

The University of Glasgow has been named Scottish University of the Year by the Sunday Times newspaper. The title was awarded for the University’s “outstanding academic reputation, growing international standing and popularity with students”.

Teaching quality has been independently rated as among the top ten in the UK and our medical and veterinary schools are consistently rated amongst the very best in the UK.



K201

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K201 Still Active With AIP

The drug K201 (JTV-519) is a 1, 4 benzothiazepine derivative which is known to be a Ca2+ channel antagonist. Previous studies have shown that K201 inhibits the activity of Sarcoplasmic Reticulam (SR) Ca2+-ATPase (SERCA) thereby showing a declined Ca2+ uptake by SR. The aim of this study was to find the effect of K201 on Ca2+ uptake by normal rabbit cardiac Myocytes and also to reveal the effect of Autocamtide-2 related Inhibitory Peptide myristoylated (AIP), which is a CaM Kinase II inhibitor.

The protocol involved challenging oxalate-equilibrated SR with repeated doses of Ca2+ with different concentration of drug K201. The cells were subjected to test the role of CaMKII by incubating in two different concentrations of AIP (5μM and 15 μM). All the experiments had a standard Ca2+ run to compare the differences in the Ca2+ up taking. The results showed that K201 did not inhibit SERCA significantly at 3μM. But when cells were incubated with 5μM AIP the drug K201 inhibited SERCA. However at higher concentration of AIP (15μM), the drug K201 did not showed any significant effect. This study suggests that inhibition of CaMKinase facilitates the inhibition of SERCA by K201.

Jayanth, 2007

Jayanth, 2007

Original Post: researchers.blogspot.com

All About NO In CAD….!!!!

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Coronary artery disease (CAD) is a kind of atherosclerosis where the arteries that supply blood to heart muscle will become hardened and narrowed. This condition occurs due to the formation plaque inside the arteries, plaques usually contain cholesterol and other materials. This leads to the insufficient supply of blood and oxygen to the heart which will in turn leads to the angina, heart attack, heart failure, and arrhythmias. CAD will cause changes in the structure and function of the blood vessel. The endothelial cells of coronary artery produces important substances such as nitric oxide and prostacyclin which are necessary for the normal function of coronary arteries, if the endothelial cells become damaged it leads to the impaired relaxation and blood clot formation. These clots can partially or completely blocks the vessels.

Atherosclerosis:

Atherosclerosis literally means narrowing of vessels (‘Athero’ means fatty and ‘sclerosis’ means hardening). Blood is a fluid connective tissue which consists of several types of cells like red blood cells, white blood cells and platelets. Blood plasma carries variety of substances from one part to another part of the body including cholesterol on special particles called lipoproteins. The low-density lipoprotein (LDL) carries cholesterol to the walls of arteries, when LDL supplies excess of cholesterol to the artery than the required amount, another type of lipoprotein called high-density lipoprotein (HDL) will carry the cholesterol away from the tissues to liver. Hence there is a direct link between LDL and HDL in controlling the cholesterol deposition, if there is an impair in the LDL or HDL function or availability it will lead to the atherosclerosis.

Atherosclerosis Is An Inflammatory Disease:

Previously scientists thought that the atherosclerosis was result of cholesterol storage, but recent studies show that atherosclerosis is an inflammatory disease (Russell Ross, N Engl J Med 1999). Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1. If the blood contains high concentration of LDL, a small amount of LDL which is in artery will be oxidised. The oxidisation process will take place with the help of chemical reactions in the endothelium, this oxidation triggers set of chain reactions. LDL which can be modified by oxidation and triggers immune response is the main cause for injury of endothelium underlying smooth muscle (Khoo JC et al., 1988, 1992; Navab M et al., 1996; Morel DW et al., 1983; Griendling KK et al., 1997). The oxidised LDL leads to the expression of a molecular glue called endothelial-leukocyte adhesion molecules. Production of this molecule attracts monocyte derived macrophages and T lymphocytes to endothelium. The lesions of atherosclerosis represent a series of highly specific cellular and molecular responses that can best be described, in aggregate, as an inflammatory disease (Ross R, Glomset JA, N Engl J Med 1973, 1976, 1986, 1993).

Endothelial Dysfunction:

The first stage of formation of atherosclerosis lesion takes place in endothelium with increased permeability to lipoproteins, which is mediated by nitric acid and other growth factors. The oxidised LDL leads to the migration of leucocytes into artery walls. This process is mediated by monocytes, Interlukin-8, Platelet derived growth factors, macrophage stimulating factors.

Endothelial Dysfunction in Atherosclerosis (Ross; NEJM 1999)

Formation of Fatty Streaks:

Fatty streaks basically consist of foam cells (Cells that are derived from both macrophages and smooth muscle cells which have accumulated LDL’s). In the later stages foam cells will join various smooth muscle cells. The foam-cell formation is mediated by oxidized low-density lipoprotein, macrophage colony-stimulating factor, tumour necrosis factor {alpha}, and interleukin-1 and platelet adherence and aggregation, which are stimulated by integrins, P-selectin, fibrin, thromboxane A2, tissue factor, and the factors are responsible for the adherence and migration of leukocytes (Russell Ross, N Engl J Med 1999).

Fatty-Streak and Lesion Formation in Atherosclerosis (Ross; NEJM 1999)

The fatty streaks lead to the intermediate and advanced lesions which in turn form a fibrous cap. This triggers a type of healing process. Number of lipids leucocytes and debris will form a necrotic core under the fibrous cap. The lesions will expand due to the continuous leukocyte adhesion and entry of other factors. The necrotic core leads to the apoptosis and necrosis and lipid accumulation.
Rupture of Fibrous Cap:

The thin sites of fibrous cap that covers the advanced lesion can lead to the rupture of fibrous cap. This rupture will rapidly cause thrombosis. The thrombosis will block the artery.
Rupture of the fibrous cap (Ross; NEJM 1999)

Role of NO:

Nitric oxide (NO) released by the coronary arterial endothelium will play an important role in basal myocardial flow regulation and contractility (Amrani et al. 1992; Ueeda, Silvia & Olsson, 1992; Brown, Thompson & Belloni, 1993).
The abnormal function of NO due to the various diseases like atherosclerosis and hypertension can affect the normal blood flow and other abnormalities of vascular functions.

Basic Properties Of Nitric Oxide:

Nitric Oxide is a highly reactive free radical in nature.
It is a highly diffusible water soluble gas.
Freely crosses cell membranes.
It can be synthesised easily when required from an precursor.

Biosynthesis of Nitric Oxide:

The amino acid L-arginine produces Nitric Oxide using an enzyme called nitric oxide synthase (NOS). The enzyme endothelial synthase exists in three endothelial forms namely constitutive soluble NOS (cNOS; type III), inducible soluble NOS (iNOS; type II) and constitutive particulate. NO can easily diffuse through membranes and provides communication endothelial and smooth muscle cells as well as between nerve endings and smooth muscle cells (Int Angiol. Et al., 1992). Decreased production of nitric oxide may lead to vasospasm, whereas its overproduction may cause pathological vasodilatation. Understanding of the role of nitric oxide signal transduction pathway in regulation of vascular tone will facilitate design of better strategies for the prevention and treatment of vascular diseases (Int Angiol. Et al., 1992). cNOS which is calcium and calmodulin dependent enzyme produces NO under normal conditions of blood vessels. cNOS are stimulated by two basic pathways, both the pathways requires release of calcium ions from subsarcolemmal storage sites.

Pathway 1 – Flow-Dependent NO Formation:
The blood flow on vascular endothelium triggers a shearing force on the cells which leads to the release of calcium and thereby activating the cNOS. Hence if the blood flow is increased it will stimulate the NO formation

Pathway 2 – Receptor-Stimulated NO Formation:
The endothelial cells contains receptors for acetylcholine, adenosine, bradykinin and others. A variety class of ligands will stimulate these receptors and leading the release of calcium and subsequent production of NO.

In year 1914 Dale found that acetylcholine is responsible for powerful vasodilatation.
In 1980, Furchgott and Zawadski discovered that intact endothelial cells produced a substance in response to acetylcholine stimulation known as termed endothelium-derived relaxing factor (EDRF) (Furchgott RF et al., 1980) The EDRF was produced only when endothelial cells acted on vascular smooth muscle cells to produce relaxation. Later studies showed that EDRF is NO. Palmer et al., in 1987 demonstrated NO release from endothelial cells using a chemilumin assay (Palmer, R.M.J et al., 1987).

The discovery of relationship between NO and cardiovascular system is an major milestone in the field of cardiovascular research. Endothelial dysfunction has now become synonymous with the reduced biologic activity of NO (Yetik-Anacak G et al., 2006).

Conversion Of NG-L arginine to NO:

Conversion of NG-L arginine to NO is carried out by family of nitric oxide synthase. During the process NADPH donates 5 electrons for the process which will be carried out by co-factors FAD, FMN and BH4. L-arginine and oxygen acts as co substrates to form NO.

Generation Of Nitric Oxide

Intracellular Mechanisms Of NO:
Superoxide anion have high affinity towards NO, these molecules have unpaired electron making them highly reactive. The presence of superoxide anion reduces NO bioavailability.

NO readily binds to the hemoglobin, the NO binds to a specific moiety of hemoglobin called heme moiety, which is present in vascular smooth muscle along with an enzyme called guanylyl.

The NO formed from vascular endothelium will diffuse into blood ultimately binds to the haemoglobin and breaks down. NO will also activates guanylyl cyclase.

This enzyme guanylyl catalyzes the dephosphorylation of GTP to cGMP, which is a second messenger and important cellular functions. cGMP plays an important role in the signalling smooth muscle relaxation.

Conclusion:

NO Has Many Beneficial Effects On The Vasculature:

NO helps in relaxation which leads to the vessel vasodilation (Moncada S, et al., 2002), it stimulates endothelial cell proliferation (Ziche M et al., 1994) and prevents endothelial cell apoptosis, (Tzeng E, Kim YM, Pitt BR, et al 1997) it inhibits Vascular Smooth Muscle Cell (VSMC) growth and migration (Garg UC et al., 1989; Mooradian DL et al., 1995) and stimulates VSMC apoptosis (Kibbe MR, Li JR, Nie SH, et al 2002).

NO leads to the inhibition of platelet aggregation and activation14, and also leukocyte adhesion to the cells and migration15. The NO shows thromboresistant properties, such as inhibition of platelet aggregation, adhesion, and activation; (Radomski MW et al., 1987). The damage or dysfunction of the endothelium leads to the abnormal production of NO by endothelial cells and this leads to the aggregation of platelets sequentially leading to inflammatory response. Impaired activity of NO can lead to the hyper – tension, atherosclerosis and excess of NO activity can lead to the inflammatory diseases.

References:
1. AMRANI, M., O’SHEA, J., ALLEN, N. J., HARDING, S. E., JAYAKUMAR,
J., PEPPER, J. R., MONCADA, S. & YACOUB, M. H. (1992). Role of
basal releiase of nitric oxide on coronary flow and mechanical
performance of the isolated rat heart. Journal of Physiology 456,
681-687.

2.Furchgott RF, Zawadski J. The obligatory role of the endothelium in the relaxation of arterial smooth-muscle by acetylcholine Blood Vessels 1980;17:151.).

3. Griendling KK, Alexander RW. Oxidative stress and cardiovascular disease. Circulation 1997;96:3264-3265.

4. Garg UC, Hassid A. nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine-monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth-muscle cells J Clin Invest 1989;83:1774-7.

5.Int Angiol. Role of nitric oxide signal transduction pathway in regulation of vascular tone.1992 Jan-Mar;11(1):14-9.)

6. Kibbe MR, Li JR, Nie SH, et al. Potentiation of nitric oxide-induced apoptosis in p53(-/-) vascular smooth muscle cells Am J Physiol Cell Physiol 2002;282:C625-34.

7. Khoo JC, Miller E, McLoughlin P, Steinberg D. Enhanced macrophage uptake of low density lipoprotein after self-aggregation. Arteriosclerosis 1988;8:348-358.

8. Khoo JC, Miller E, Pio F, Steinberg D, Witztum JL. Monoclonal antibodies against LDL further enhance macrophage uptake of LDL aggregates. Arterioscler Thromb 1992;12:1258-1266.

9. Mooradian DL, Hutsell TC, Keefer LK. Nitric-oxide (NO) donor molecules-effect of NO release rate on vascular smooth-muscle cell-proliferation in-vitro J Cardiovasc Pharmacol 1995;25:674-8.

10. Moncada S, Higgs A. The l-arginine nitric-oxide pathway N Engl J Med 1993;329:2002-12.

11. Morel DW, Hessler JR, Chisholm GM. Low density lipoprotein cytotoxicity induced by free radical peroxidation of lipid. J Lipid Res 1983;24:1070-1076.

12. Navab M, Berliner JA, Watson AD, et al. The Yin and Yang of oxidation in the development of the fatty streak: a review based on the 1994 George Lyman Duff Memorial Lecture. Arterioscler Thromb Vasc Biol 1996;16:831-842.

13. Palmer, R.M.J., Ferrige, A.G. & Moncada, S. (1987). Nitric oxide release accounts for the biological actions of endothelium-derived relaxing factor. Nature,327, 524-526.

14. Russell Ross, Atherosclerosis — An Inflammatory Disease. N Engl J Med 1999; 340:115-126.

15. Radomski MW, Palmer RMJ, Moncada S. The role of nitric-oxide and CGMP in platelet-adhesion to vascular endothelium Biochem Biophys Res Commun 1987;148:1482-9.

16. Ross R, Glomset JA. Atherosclerosis and the arterial smooth muscle cell: proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science 1973;180:1332-1339.

17. Ross R, Glomset JA. The pathogenesis of atherosclerosis. N Engl J Med 1976;295:369-77, 420.

18. Ross R. The pathogenesis of atherosclerosis — an update. N Engl J Med 1986;314:488-500.

19. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993;362:801-809.

20. Ross R. Atherosclerosis: a defense mechanism gone awry. Am J Pathol 1993;143:987-1002.

21. Tzeng E, Kim YM, Pitt BR, et al. Adenoviral transfer of the inducible nitric oxide synthase gene blocks endothelial cell apoptosis Surgery 1997;122:255-63.

22. UEEDA, M., SILVIA, S. K. & OLSsoN, R. A. (1992). Nitric oxide
modulates coronary autoregulation in the guinea pig. Circulation
Research 70, 1296-1303.

23. Yetik-Anacak G, Catravas JD. Nitric oxide and the endothelium: history and impact on cardiovascular disease Vasc Pharmacol 2006;45:268-76.

24. Ziche M, Morbidelli L, Masini E, et al. Nitric-oxide mediates angiogenesis in-vivo and endothelial-cell growth and migration in-vitro promoted by substance-P J Clin Invest 1994;94:2036-44.