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Hai cercato: counterintuitive    [ Disattiva i colori ]

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I've done several types of work over the years but I don't know another as counterintuitive as startup investing.

Ho fatto diversi tipi di lavoro nel corso degli anni, ma non so gli altri, come un controsenso, come investimento di avvio.

Ultimo aggiornamento 2012-12-10
Frequenza di utilizzo: 1

playing a prominent role in the regulation of energy balance. One population synthesizes proopiomelanocortin (POMC) and cocaine–amphetamine-regulated transcript (CART), whereas the other produces neuropeptide Y (NPY) and agouti-related protein (AgRP). POMC and CART are catabolic (leading to a reduction in energy stores)44–46, whereas NPYand AgRP are anabolic (leading to an increase in energy stores).47–50 POMC/CART neurons exert their catabolic effect mainly via a-MSH, a peptidergic fragment ensuing from POMC cleavage. Within the PVH, a-MSH binds to melanocortin 3 (MC3R) and 4 (MC4R) receptors with which it constitutes, together with AgRP, the metabolic melanocortin system.44,46,51,52 AgRP acts as a natural antagonist of MC3R and MC4R, thereby reducing the effects of a-MSH. The functional significance of the melanocortin receptors in energy homeostasis has been validated in Mc3r and Mc4r knockout (KO) mice, which exhibit enhanced visceral or widespread fat depositions.52,53 In humans, Mc4r deficiency seems to represent one of the most (if not the most) commonly known monogenic forms of obesity.54 The MC4R is found in abundance in the PVH descending division, a part of the PVH likely involved in the control of energy intake55 and energy expenditure.56,57 The PVH also expresses Y158 and Y5 receptors59, the main receptors mediating the anabolic action of NPY.60 NPY expression appears constitutively stimulated in obese61 and food-deprived animals.61,62 The functional importance of NPY as well as that of AgRP in the regulation of energy balance have recently found a genetic endorsement when mice genetically engineered for a selective deletion of AgRP–NPYexpressing neuronswere shown to exhibit, at the adult stage, an acute reduction in feeding.47,50 Both the NPYand/or POMC neurons harbor receptors for the peripheral hormones leptin, insulin, glucocorticoids, ghrelin, peptide tyrosine–tyrosine and glucagon-like peptide 1, which are all known to be capable of signaling the brain about changes in energy stores and the nutritional status.14,45 There is evidence to suggest an involvement of the ARC–PVH axis in the metabolic action of the endocannabinoid system on energy balance. Both the PVH and the ARC neurons express the CB1 receptor protein and exhibit c-fos expression (a widely used marker of neuronal activation) in response to CB1 agonism and antagonism.63–65 In addition, both structures represent sensible targets for the apparently inhibitory effect of leptin on the hypothalamic production of endocannabinoids.16 Despite the fact that some published data tend to predict a role for the ARC–PVH axis in the metabolic influence of the endocannabinoid19,64, there is still work to be accomplished before being able to delineate the exact role of the ARC–PVH duet in the endocannabinoid effects on energy balance regulation. Incidentally, neither the melanocortin66 nor the NPY16 system appears to be essential to the effect of the endocannabinoids in energy balance regulation. In fact, the CB1 receptor agonist WIN 55,212-2 and the CB1 receptor antagonist AM251 have recently been shown to exert their respective stimulating and inhibiting effect in the agouti yellow (Ay) mouse, which lacks a functional melanocortin system due to the aberrant constitutive over-expression of the Agouti protein (an endogenous inverse agonist of the MC3R and MC4R).66 Similarly, it has been demonstrated that the pharmacological CB1 blockade is as efficacious to reduce food intake in NPY knockout mice as in wild type animals.16 Furthermore, there is as yet no clear evidence that endocannabinoids create a positive energy balance by stimulating the ARC orexigenic NPY/AgRP neurons or by inhibiting the ARC POMC/ CART neurons. Indeed, none of these neurons expresses the CB1 receptor mRNA19, which implies that the CB1 receptor probably cannot modulate the secretion of the main ARC orexigenic and anorexigenic neurons at the level of their terminals. There is also no evidence that the CB1 receptor agonism or CB1 receptor modulates ARC expression of either POMC, CART, NPY or AgRP in a way to explain the orexigenic/non-thermogenic action of endocannabinoids. Subchronic treatment with rimonabant (a CB1 receptor antagonist) has been reported to increase the expression of NPY, which is counterintuitive when one considers the catabolic action of rimonabant.24 The only reported indication that endocannabinoids can affect the activity of the NPY neurons is that demonstrating an increased release of NPY in hypothalamic explants stimulated by endocannabinoid agonists.67 That NPY neurons can be modulated by endocannabinoids is certainly not inconsistent with the presence of the CB1 receptor in neuron terminals forming both symmetric (inhibitory) and asymmetric (excitatory) synapses in the ARC.30 However, studies need to be conducted to better delineate the function of the hypothalamic CB1 receptor protein, whose amount in the ARC is apparently low compared to the quantity of the receptor seen in the cortex and hippocampus.30 While the role of the ARC in the endocannabinoid effects on energy balance appears indeterminate, that of the PVH seems more certain. Intra-PVH injection of D9-THC produced a significant increase in

scientific articles

Ultimo aggiornamento 2013-08-21
Argomento: Medicina
Frequenza di utilizzo: 1
Riferimento: Anonimo
Attenzione: Questo allineamento potrebbe essere errato.
Eliminalo se ritieni che sia così.

[1] I haven't really assimilated that fact, partly because it's so counterintuitive, and partly because we're not doing this just for financial reasons; YC would be a pretty lonely place if we only had one company per batch.

[1]io non ho davvero assimilato questo fatto, in parte perché è così controintuitivo, e in parte perché non stiamo facendo questo solo per motivi finanziari; YC sarebbe un luogo abbastanza isolato, se abbiamo avuto solo una società per ogni batch.

Ultimo aggiornamento 2012-12-10
Frequenza di utilizzo: 3
Attenzione: contiene formattazione HTML nascosta

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