Hyperpolarization and relaxation of arterial smooth muscle caused by nitric oxide derived from the endothelium

Stimulation of the endothelial lining of arteries with acetylcholine results in the release of a diffusible substance that relaxes and hyperpolarizes the underlying smooth muscle. Nitric oxide (NO) has been a candidate for this substance, termed endothelium-derived relaxing factor. But there are several observations that argue against the involvement of NO in acetylcholine-induced hyperpolarization. First, exogenous NO has no effect on the membrane potential of canine mesenteric arteries. Second, although haemoglobin (believed to bind and inactivate NO (refs 11-15)) and methylene blue (which prevents the stimulation of guanylate cyclase) inhibit relaxation, neither has an effect on hyperpolarization. Finally, nitroprusside, thought to generate NO in vascular smooth muscle, relaxes rat aorta without increasing rubidium efflux. Nevertheless, nitrovasodilators, nitroprusside and nitroglycerin cause hyperpolarization in some arteries. NO might therefore be responsible for at least part of the hyperpolarization induced by acetylcholine. We now report that hyperpolarization and relaxation evoked by acetylcholine are reduced by NG-monomethyl-L-arginine, an inhibitor of NO biosynthesis from L-arginine. Thus NO derived from the endothelium can cause hyperpolarization of vascular smooth muscle, which might also contribute to relaxation by closing voltage-dependent calcium channels. Our findings raise the possibility that hyperpolarization might be a component of NO signal transduction in neurons or inflammatory cells.     

Vascular respiratory uncoupling increases blood pressure and atherosclerosis

The observations that atherosclerosis often occurs in non-smokers without elevated levels of low-density lipoprotein cholesterol, and that most atherosclerosis loci so far identified in mice do not affect systemic risk factors associated with atherosclerosis, suggest that as-yet-unidentified mechanisms must contribute to vascular disease. Arterial walls undergo regional disturbances of metabolism that include the uncoupling of respiration and oxidative phosphorylation, a process that occurs to some extent in all cells and may be characteristic of blood vessels being predisposed to the development of atherosclerosis. To test the hypothesis that inefficient metabolism in blood vessels promotes vascular disease, we generated mice with doxycycline-inducible expression of uncoupling protein-1 (UCP1) in the artery wall. Here we show that UCP1 expression in aortic smooth muscle cells causes hypertension and increases dietary atherosclerosis without affecting cholesterol levels. UCP1 expression also increases superoxide production and decreases the availability of nitric oxide, evidence of oxidative stress. These results provide proof of principle that inefficient metabolism in blood vessels can cause vascular disease.     

The break-up of heavy electrons at a quantum critical point

The point at absolute zero where matter becomes unstable to new forms of order is called a quantum critical point (QCP). The quantum fluctuations between order and disorder that develop at this point induce profound transformations in the finite temperature electronic properties of the material. Magnetic fields are ideal for tuning a material as close as possible to a QCP, where the most intense effects of criticality can be studied. A previous study on the heavy-electron material YbRh2Si2 found that near a field-induced QCP electrons move ever more slowly and scatter off one another with ever increasing probability, as indicated by a divergence to infinity of the electron effective mass and scattering cross-section. But these studies could not shed light on whether these properties were an artefact of the applied field, or a more general feature of field-free QCPs. Here we report that, when germanium-doped YbRh2Si2 is tuned away from a chemically induced QCP by magnetic fields, there is a universal behaviour in the temperature dependence of the specific heat and resistivity: the characteristic kinetic energy of electrons is directly proportional to the strength of the applied field. We infer that all ballistic motion of electrons vanishes at a QCP, forming a new class of conductor in which individual electrons decay into collective current-carrying motions of the electron fluid.     

Hidden orbital order in the heavy fermion metal URu(2)Si(2)

When matter is cooled from high temperatures, collective instabilities develop among its constituent particles that lead to new kinds of order. An anomaly in the specific heat is a classic signature of this phenomenon. Usually the associated order is easily identified, but sometimes its nature remains elusive. The heavy fermion metal URu(2)Si(2) is one such example, where the order responsible for the sharp specific heat anomaly at T(0) = 17 K has remained unidentified despite more than seventeen years of effort. In URu(2)Si(2), the coexistence of large electron electron repulsion and antiferromagnetic fluctuations leads to an almost incompressible heavy electron fluid, where anisotropically paired quasiparticle states are energetically favoured. Here we develop a proposal for the nature of the hidden order in URu(2)Si(2). We show that incommensurate orbital antiferromagnetism, associated with circulating currents between the uranium ions, can account for the local fields and entropy loss observed at the 17 K transition. We make detailed predictions for the outcome of neutron scattering measurements based on this proposal, so that it can be tested experimentally.     

Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes

The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 x 10(-7) between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (P(follow-up) 相似文献   

Mutations in RNF135, a gene within the NF1 microdeletion region, cause phenotypic abnormalities including overgrowth

17q11 microdeletions that encompass NF1 cause 5%-10% of cases of neurofibromatosis type 1, and individuals with microdeletions are typically taller than individuals with intragenic NF1 mutations, suggesting that deletion of a neighboring gene might promote human growth. We identified mutations in RNF135, which is within the NF1 microdeletion region, in six families characterized by overgrowth, learning disability, dysmorphic features and variable additional features. These data identify RNF135 as causative of a new overgrowth syndrome and demonstrate that RNF135 haploinsufficiency contributes to the phenotype of NF1 microdeletion cases.