Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma

We performed exome sequencing to detect somatic mutations in protein-coding regions in seven melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in two metastases derived from the same individual. Two melanomas with non-canonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK1 and MEK2, respectively) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Furthermore, missense and nonsense somatic mutations were frequently found in three candidate melanoma genes, FAT4, LRP1B and DSC1.     

Mass spectrometric determination of the amino acid sequence in arginine-containing peptides

aa, a-a a- a aa - aa a -a .     

Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features.

The epilepsies are a common, clinically heterogeneous group of disorders defined by recurrent unprovoked seizures. Here we describe identification of the causative gene in autosomal-dominant partial epilepsy with auditory features (ADPEAF, MIM 600512), a rare form of idiopathic lateral temporal lobe epilepsy characterized by partial seizures with auditory disturbances. We constructed a complete, 4.2-Mb physical map across the genetically implicated disease-gene region, identified 28 putative genes (Fig. 1) and resequenced all or part of 21 genes before identifying presumptive mutations in one copy of the leucine-rich, glioma-inactivated 1 gene (LGI1) in each of five families with ADPEAF. Previous studies have indicated that loss of both copies of LGI1 promotes glial tumor progression. We show that the expression pattern of mouse Lgi1 is predominantly neuronal and is consistent with the anatomic regions involved in temporal lobe epilepsy. Discovery of LGI1 as a cause of ADPEAF suggests new avenues for research on pathogenic mechanisms of idiopathic epilepsies.     

Geometric frustration in compositionally modulated ferroelectrics

Geometric frustration is a broad phenomenon that results from an intrinsic incompatibility between some fundamental interactions and the underlying lattice geometry. Geometric frustration gives rise to new fundamental phenomena and is known to yield intriguing effects such as the formation of exotic states like spin ice, spin liquids and spin glasses. It has also led to interesting findings of fractional charge quantization and magnetic monopoles. Mechanisms related to geometric frustration have been proposed to understand the origins of relaxor and multiferroic behaviour, colossal magnetocapacitive coupling, and unusual and novel mechanisms of high-transition-temperature superconductivity. Although geometric frustration has been particularly well studied in magnetic systems in the past 20 years or so, its manifestation in the important class formed by ferroelectric materials (which are compounds with electric rather than magnetic dipoles) is basically unknown. Here we show, using a technique based on first principles, that compositionally graded ferroelectrics possess the characteristic 'fingerprints' associated with geometric frustration. These systems have a highly degenerate energy surface and display critical phenomena. They further reveal exotic orderings with novel stripe phases involving complex spatial organization. These stripes display spiral states, topological defects and curvature. Compositionally graded ferroelectrics can thus be considered the 'missing link' that brings ferroelectrics into the broad category of materials able to exhibit geometric frustration. Our ab initio calculations allow deep microscopic insight into this novel geometrically frustrated system.     

Physiology: Dynamic instabilities in the inflating lung

In lung diseases such as asthma, expiratory flow becomes limited, airways can collapse and the vital exchange of gases is compromised. Here we model the inflation of collapsed regions of the lung during inspiration in terms of avalanches propagating through a bifurcating network of airways, and find that the accompanying cascade of dynamic pressure instabilities -- avalanche 'shocks' -- manifests as negative elastic resistance of the lung. Our analysis of this apparent thermodynamic paradox provides a better understanding of aeration in the deep regions of the lung, which may find application in medical conditions in which gas exchange is impaired.     

Single-electron transistor of a single organic molecule with access to several redox states

A combination of classical Coulomb charging, electronic level spacings, spin, and vibrational modes determines the single-electron transfer reactions through nanoscale systems connected to external electrodes by tunnelling barriers. Coulomb charging effects have been shown to dominate such transport in semiconductor quantum dots, metallic and semiconducting nanoparticles, carbon nanotubes, and single molecules. Recently, transport has been shown to be also influenced by spin--through the Kondo effect--for both nanotubes and single molecules, as well as by vibrational fine structure. Here we describe a single-electron transistor where the electronic levels of a single pi-conjugated molecule in several distinct charged states control the transport properties. The molecular electronic levels extracted from the single-electron-transistor measurements are strongly perturbed compared to those of the molecule in solution, leading to a very significant reduction of the gap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital. We suggest, and verify by simple model calculations, that this surprising effect could be caused by image charges generated in the source and drain electrodes resulting in a strong localization of the charges on the molecule.     

Revisiting Lévy flight search patterns of wandering albatrosses, bumblebees and deer

The study of animal foraging behaviour is of practical ecological importance, and exemplifies the wider scientific problem of optimizing search strategies. Lévy flights are random walks, the step lengths of which come from probability distributions with heavy power-law tails, such that clusters of short steps are connected by rare long steps. Lévy flights display fractal properties, have no typical scale, and occur in physical and chemical systems. An attempt to demonstrate their existence in a natural biological system presented evidence that wandering albatrosses perform Lévy flights when searching for prey on the ocean surface. This well known finding was followed by similar inferences about the search strategies of deer and bumblebees. These pioneering studies have triggered much theoretical work in physics (for example, refs 11, 12), as well as empirical ecological analyses regarding reindeer, microzooplankton, grey seals, spider monkeys and fishing boats. Here we analyse a new, high-resolution data set of wandering albatross flights, and find no evidence for Lévy flight behaviour. Instead we find that flight times are gamma distributed, with an exponential decay for the longest flights. We re-analyse the original albatross data using additional information, and conclude that the extremely long flights, essential for demonstrating Lévy flight behaviour, were spurious. Furthermore, we propose a widely applicable method to test for power-law distributions using likelihood and Akaike weights. We apply this to the four original deer and bumblebee data sets, finding that none exhibits evidence of Lévy flights, and that the original graphical approach is insufficient. Such a graphical approach has been adopted to conclude Lévy flight movement for other organisms, and to propose Lévy flight analysis as a potential real-time ecosystem monitoring tool. Our results question the strength of the empirical evidence for biological Lévy flights.     

Activating mutations in ALK provide a therapeutic target in neuroblastoma

Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer. High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal. Here we report the detection of previously unknown mutations in the ALK gene, which encodes a receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous sequence variations were identified in the kinase domain of ALK, of which three were somatic and two were germ line. The most frequent mutation, F1174L, was also identified in three different neuroblastoma cell lines. ALK complementary DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4). Furthermore, two human neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibition with small molecules, providing a molecular rationale for targeted therapy of this disease.