mTOR signaling in neural stem cells: from basic biology to disease

The mammalian target of rapamycin (mTOR) pathway is a central controller of growth and homeostasis, and, as such, is implicated in disease states where growth is deregulated, namely cancer, metabolic diseases, and hamartoma syndromes like tuberous sclerosis complex (TSC). Accordingly, mTOR is also a pivotal regulator of the homeostasis of several distinct stem cell pools in which it finely tunes the balance between stem cell self-renewal and differentiation. mTOR hyperactivation in neural stem cells (NSCs) has been etiologically linked to the development of TSC-associated neurological lesions, such as brain hamartomas and benign tumors. Animal models generated by deletion of mTOR upstream regulators in different types of NSCs reproduce faithfully some of the TSC neurological alterations. Thus, mTOR dysregulation in NSCs seems to be responsible for the derangement of their homeostasis, thus leading to TSC development. Here we review recent advances in the molecular dissection of the mTOR cascade, its involvement in the maintenance of stem cell compartments, and in particular the implications of mTOR hyperactivation in NSCs in vivo and in vitro.     

Factor(s) from nonmacrophage bone marrow stromal cells inhibit Lewis lung carcinoma and B16 melanoma growth in mice

Bone marrow stroma produces positive and negative growth regulators which constitute the hematopoietic microenvironment. As many tumors metastasize to the bones, these regulators may also influence tumor growth. Hematopoietic cytokines may indeed exert both positive and negative effect on tumor growth. We report that, when mixed with tumor cells. adherent bone marrow cells inhibit primary tumor growth and metastases formation in mice transplanted with Lewis lung carcinoma or B16 melanoma. Peritoneal macrophages or lymph node cells did not exert any influence. The tumor inhibition was apparently due to soluble factor(s) released by marrow stromal cells. In cocultures with B16 melanoma cells, adherent bone marrow cells exerted a significant antiproliferative effect which was increased by previous culture of the bone marrow cells with granulocyte-macrophage colony-stimulating factor but not with macrophage colony-stimulating factor. Neither neutralizing antibodies against tumor necrosis factor-alpha, transforming growth factor-beta or interferon alpha/beta nor addition of Escherichia coli lipopolysaccharide to generate inflammatory cytokines could affect the antiproliferative effect of bone marrow stromal cells. The bone marrow stroma factor(s) which inhibit tumor growth might, therefore, be a novel growth regulator.     

A quantum fluid of metallic hydrogen suggested by first-principles calculations

It is generally assumed that solid hydrogen will transform into a metallic alkali-like crystal at sufficiently high pressure. However, some theoretical models have also suggested that compressed hydrogen may form an unusual two-component (protons and electrons) metallic fluid at low temperature, or possibly even a zero-temperature liquid ground state. The existence of these new states of matter is conditional on the presence of a maximum in the melting temperature versus pressure curve (the 'melt line'). Previous measurements of the hydrogen melt line up to pressures of 44 GPa have led to controversial conclusions regarding the existence of this maximum. Here we report ab initio calculations that establish the melt line up to 200 GPa. We predict that subtle changes in the intermolecular interactions lead to a decline of the melt line above 90 GPa. The implication is that as solid molecular hydrogen is compressed, it transforms into a low-temperature quantum fluid before becoming a monatomic crystal. The emerging low-temperature phase diagram of hydrogen and its isotopes bears analogies with the familiar phases of 3He and 4He (the only known zero-temperature liquids), but the long-range Coulomb interactions and the large component mass ratio present in hydrogen would result in dramatically different properties.     

Mast cells promote homeostasis by limiting endothelin-1-induced toxicity

Endothelin-1 (ET-1) is a 21-amino-acid peptide, derived from vascular endothelial cells, with potent vasoconstrictor activity. ET-1 has been implicated in diverse physiological or pathological processes, including the vascular changes associated with sepsis. However, the factors that regulate ET-1-associated toxicity during bacterial infections, or in other settings, are not fully understood. Both the pathology associated with certain allergic and autoimmune disorders, and optimal host defence against bacterial and parasitic infections are mediated by mast cells. In vitro, mast cells can produce ET-1 (ref. 11), undergo ET-1-dependent and endothelin-A receptor (ET(A))-dependent activation, and release proteases that degrade ET-1 (ref. 14). Although the potential relationships between mast cells and the ET-1 system thus may be complex, the importance of interactions between ET-1 and mast cells in vivo is obscure. Here we show that ET(A)-dependent mast-cell activation can diminish both ET-1 levels and ET-1-induced pathology in vivo, and also can contribute to optimal survival during acute bacterial peritonitis. These findings identify a new biological function for mast cells: promotion of homeostasis by limiting the toxicity associated with an endogenous mediator.     

Formation of 2-hydroxy-6-oxo-2,trans-4,trans-heptadienoic acid from 3-methylcatechol by aPseudomonas

Riassunto Ps. desmolyticum ossida la 3-metilpirocatechina ad acido 2-ossi-6-oxo-2,trans-4,trans-eptadienoico. Vengono descritte le proprietà chimicofisiche che hanno condotto all'identificazione di questo intermedio metabolico.

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This work was supported by C.N.R. (Consiglio nazionale delle Ricerche).     

Adrenergic supersensitivity of the pupil in idiopathic headache.

In idiopathic headache (IH) sufferers, phenylephrine and fenfluramine induce a pupillary dilatation respectively greater and lesser than in controls. The difference may be due to a supersensitivity of the iris alpha adrenoceptors caused by a deficiency of noradrenaline in the iris adrenergic nerve terminal of the IH sufferer. These findings seem to support the hypothesis of a brain receptorial, monoamine supersensitivity in IH.