A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome

Opitz-Kaveggia syndrome (also known as FG syndrome) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation. We report here that the original family for whom the condition is named and five other families have a recurrent mutation (2881C>T, leading to R961W) in MED12 (also called TRAP230 or HOPA), a gene located at Xq13 that functions as a thyroid receptor-associated protein in the Mediator complex.     

Optimization of the cellular import of functionally active SH2-domain-interacting phosphopeptides

Phosphopeptides interacting with src homology 2 (SH2) domains can activate essential signaling enzymes in vitro. When delivered to cells, they may disrupt protein-protein interactions, thereby influencing intracellular signaling. We showed earlier that phosphopeptides corresponding to the inhibitory motif of Fcγ receptor IIb and a motif of the Grb2-associated binder 1 adaptor protein activate SH2-containing tyrosine phosphatase 2 in vitro. To study the ex vivo effects of these peptides, we have now compared different methods for peptide delivery: (i) permeabilization of the target cells and (ii) the use of cell-permeable vectors, which are potentially able to transport biologically active compounds into B cells. We found octanoyl-Arg₈ to be an optimal carrier for the delivery of phosphopeptides to the cells. With this strategy, the function of cell-permeable SHP-2-binding phosphopeptides was analyzed. These peptides modulated the protein phosphorylation in B cells in a dose- and time-dependent manner. Received 27 July 2006; received after revision 4 September 2006; accepted 18 September 2006     

Functional interactions of protein kinase A and C in signalling networks: a recapitulation

On the basis of evidence collected from the literature, we propose a general model by which protein kinase (PK) A and the different PKC isoforms can inversely affect cell growth. Molecular switches, which are able to direct the signal towards antiproliferative or mitogenic pathways, are the different isoforms of Raf and PKC. Conflicting data are also reported and discussed in an attempt to reconcile them. Received 10 November 2005; received after revision 28 December 2005; accepted 3 January 2006     

The molecular sociology of the cell

Proteomic studies have yielded detailed lists of the proteins present in a cell. Comparatively little is known, however, about how these proteins interact and are spatially arranged within the 'functional modules' of the cell: that is, the 'molecular sociology' of the cell. This gap is now being bridged by using emerging experimental techniques, such as mass spectrometry of complexes and single-particle cryo-electron microscopy, to complement traditional biochemical and biophysical methods. With the development of integrative computational methods to exploit the data obtained, such hybrid approaches will uncover the molecular architectures, and perhaps even atomic models, of many protein complexes. With these structures in hand, researchers will be poised to use cryo-electron tomography to view protein complexes in action within cells, providing unprecedented insights into protein-interaction networks.     

South-polar features on Venus similar to those near the north pole

Venus has no seasons, slow rotation and a very massive atmosphere, which is mainly carbon dioxide with clouds primarily of sulphuric acid droplets. Infrared observations by previous missions to Venus revealed a bright 'dipole' feature surrounded by a cold 'collar' at its north pole. The polar dipole is a 'double-eye' feature at the centre of a vast vortex that rotates around the pole, and is possibly associated with rapid downwelling. The polar cold collar is a wide, shallow river of cold air that circulates around the polar vortex. One outstanding question has been whether the global circulation was symmetric, such that a dipole feature existed at the south pole. Here we report observations of Venus' south-polar region, where we have seen clouds with morphology much like those around the north pole, but rotating somewhat faster than the northern dipole. The vortex may extend down to the lower cloud layers that lie at about 50 km height and perhaps deeper. The spectroscopic properties of the clouds around the south pole are compatible with a sulphuric acid composition.     

Low-energy acoustic plasmons at metal surfaces

Nearly two-dimensional (2D) metallic systems formed in charge inversion layers and artificial layered materials permit the existence of low-energy collective excitations, called 2D plasmons, which are not found in a three-dimensional (3D) metal. These excitations have caused considerable interest because their low energy allows them to participate in many dynamical processes involving electrons and phonons, and because they might mediate the formation of Cooper pairs in high-transition-temperature superconductors. Metals often support electronic states that are confined to the surface, forming a nearly 2D electron-density layer. However, it was argued that these systems could not support low-energy collective excitations because they would be screened out by the underlying bulk electrons. Rather, metallic surfaces should support only conventional surface plasmons-higher-energy modes that depend only on the electron density. Surface plasmons have important applications in microscopy and sub-wavelength optics, but have no relevance to the low-energy dynamics. Here we show that, in contrast to expectations, a low-energy collective excitation mode can be found on bare metal surfaces. The mode has an acoustic (linear) dispersion, different to the dependence of a 2D plasmon, and was observed on Be(0001) using angle-resolved electron energy loss spectroscopy. First-principles calculations show that it is caused by the coexistence of a partially occupied quasi-2D surface-state band with the underlying 3D bulk electron continuum and also that the non-local character of the dielectric function prevents it from being screened out by the 3D states. The acoustic plasmon reported here has a very general character and should be present on many metal surfaces. Furthermore, its acoustic dispersion allows the confinement of light on small surface areas and in a broad frequency range, which is relevant for nano-optics and photonics applications.     

Eruptions arising from tidally controlled periodic openings of rifts on Enceladus

In 2005, plumes were detected near the south polar region of Enceladus, a small icy satellite of Saturn. Observations of the south pole revealed large rifts in the crust, informally called 'tiger stripes', which exhibit higher temperatures than the surrounding terrain and are probably sources of the observed eruptions. Models of the ultimate interior source for the eruptions are under consideration. Other models of an expanding plume require eruptions from discrete sources, as well as less voluminous eruptions from a more extended source, to match the observations. No physical mechanism that matches the observations has been identified to control these eruptions. Here we report a mechanism in which temporal variations in tidal stress open and close the tiger-stripe rifts, governing the timing of eruptions. During each orbit, every portion of each tiger stripe rift spends about half the time in tension, which allows the rift to open, exposing volatiles, and allowing eruptions. In a complementary process, periodic shear stress along the rifts also generates heat along their lengths, which has the capacity to enhance eruptions. Plume activity is expected to vary periodically, affecting the injection of material into Saturn's E ring and its formation, evolution and structure. Moreover, the stresses controlling eruptions imply that Enceladus' icy shell behaves as a thin elastic layer, perhaps only a few tens of kilometres thick.     

Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.