Structure of the human histamine H1 receptor complex with doxepin

The biogenic amine histamine is an important pharmacological mediator involved in pathophysiological processes such as allergies and inflammations. Histamine H(1) receptor (H(1)R) antagonists are very effective drugs alleviating the symptoms of allergic reactions. Here we show the crystal structure of the H(1)R complex with doxepin, a first-generation H(1)R antagonist. Doxepin sits deep in the ligand-binding pocket and directly interacts with Trp?428(6.48), a highly conserved key residue in G-protein-coupled-receptor activation. This well-conserved pocket with mostly hydrophobic nature contributes to the low selectivity of the first-generation compounds. The pocket is associated with an anion-binding region occupied by a phosphate ion. Docking of various second-generation H(1)R antagonists reveals that the unique carboxyl group present in this class of compounds interacts with Lys?191(5.39) and/or Lys?179(ECL2), both of which form part of the anion-binding region. This region is not conserved in other aminergic receptors, demonstrating how minor differences in receptors lead to pronounced selectivity differences with small molecules. Our study sheds light on the molecular basis of H(1)R antagonist specificity against H(1)R.     

Cursoriality in bipedal archosaurs

Modern birds have markedly foreshortened tails and their body mass is centred anteriorly, near the wings. To provide stability during powered flight, the avian centre of mass is far from the pelvis, which poses potential balance problems for cursorial birds. To compensate, avians adapted to running maintain the femur subhorizontally, with its distal end situated anteriorly, close to the animal's centre of mass; stride generation stems largely from parasagittal rotation of the lower leg about the knee joint. In contrast, bipedal dinosaurs had a centre of mass near the hip joint and rotated the entire hindlimb during stride generation. Here we show that these contrasting styles of cursoriality are tightly linked to longer relative total hindlimb length in cursorial birds than in bipedal dinosaurs. Surprisingly, Caudipteryx, described as a theropod dinosaur, possessed an anterior centre of mass and hindlimb proportions resembling those of cursorial birds. Accordingly, Caudipteryx probably used a running mechanism more similar to that of modern cursorial birds than to that of all other bipedal dinosaurs. These observations provide valuable clues about cursoriality in Caudipteryx, but may also have implications for interpreting the locomotory status of its ancestors.     

Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis

We identified a SNP in the DPP6 gene that is consistently strongly associated with susceptibility to amyotrophic lateral sclerosis (ALS) in different populations of European ancestry, with an overall P value of 5.04 x 10(-8) in 1,767 cases and 1,916 healthy controls and with an odds ratio of 1.30 (95% confidence interval (CI) of 1.18-1.43). Our finding is the first report of a genome-wide significant association with sporadic ALS and may be a target for future functional studies.     

Covalently closed circles of adenovirus 5 DNA

The genome of adenoviruses is a double-stranded linear DNA molecule with inverted terminal repeats about 100 base pairs (bp) in length and a terminal protein covalently linked to the 5' nucleotide of each strand. Both of these features permit the formation of DNA circles, the inverted repeats allowing the circularization of single-stranded DNA and the terminal protein the joining of one or more molecules to yield double-stranded circles or concatemers. However, although the existence of covalently closed circles has been postulated, double-stranded viral DNA purified from virions or infected cells by conventional methods (that is, using proteases and phenol or chloroform) has always been obtained in a linear form. Here, we present evidence for the existence in adenovirus 5 (Ad5) infected cells of novel structures resulting from covalent head-to-tail joining of viral DNA molecules and show that these structures are due at least in part to the formation of covalently closed circles.     

Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect

Celiac disease is probably the best-understood immune-related disorder. The disease presents in the small intestine and results from the interplay between multiple genes and gluten, the triggering environmental factor. Although HLA class II genes explain 40% of the heritable risk, non-HLA genes accounting for most of the familial clustering have not yet been identified. Here we report significant and replicable association (P = 2.1 x 10(-6)) to a common variant located in intron 28 of the gene myosin IXB (MYO9B), which encodes an unconventional myosin molecule that has a role in actin remodeling of epithelial enterocytes. Individuals homozygous with respect to the at-risk allele have a 2.3-times higher risk of celiac disease (P = 1.55 x 10(-5)). This result is suggestive of a primary impairment of the intestinal barrier in the etiology of celiac disease, which may explain why immunogenic gluten peptides are able to pass through the epithelial barrier.     

A review of the chemical induction of neoplasms in amphibia

Résumé Ce rapport analyse et résume les résultats des travaux de différents auteurs sur la possibilité d'induire des tumeurs par des substances chimiques chez les Amphibiens.Les substances cancérigènes peuvent, dans les cas positifs: (1) induire des tumeurs caractérisées, (2) augmenter l'incidence des tumeurs spontanées, (3) produire des hyperplasies de l'épithélium cutané.On peut se demander si les hyperplasies observés sont une réaction spécifique aux substances cancérigènes et sont réellement de nature néoplasique.On peut s'étonner, aussi, que les Amphibiens dont le pouvoir de régénération est élevé et dont le développement embryonnaire, la vie larvaire et la métamorphose sont bien connus, n'aient pas davantage été utilisés dans létude du cancer.     

Electronic read-out of a single nuclear spin using a molecular spin transistor

Quantum control of individual spins in condensed-matter devices is an emerging field with a wide range of applications, from nanospintronics to quantum computing. The electron, possessing spin and orbital degrees of freedom, is conventionally used as the carrier of quantum information in proposed devices. However, electrons couple strongly to the environment, and so have very short relaxation and coherence times. It is therefore extremely difficult to achieve quantum coherence and stable entanglement of electron spins. Alternative concepts propose nuclear spins as the building blocks for quantum computing, because such spins are extremely well isolated from the environment and less prone to decoherence. However, weak coupling comes at a price: it remains challenging to address and manipulate individual nuclear spins. Here we show that the nuclear spin of an individual metal atom embedded in a single-molecule magnet can be read out electronically. The observed long lifetimes (tens of seconds) and relaxation characteristics of nuclear spin at the single-atom scale open the way to a completely new world of devices in which quantum logic may be implemented.     

Cancer and super-regeneration inTriturus viridescens limbs

Résumé Du rein deRana pipiens adultes a été transplanté dans les membres antérieurs de vingtTriturus viridescens qui étaient en train de développer des lymphosarcomes. Parmi les 12 pattes analysées, six étaient infiltrées par le cancer et avaient répondu à la présence des greffes xénogéniques en formant des structures accessoires de la patte. Nous en avons conclu que le champ de régénération n'est pas capable de contrôler le développement de ce cancer.     

Brain-wide neuronal dynamics during motor adaptation in zebrafish

A fundamental question in neuroscience is how entire neural circuits generate behaviour and adapt it to changes in sensory feedback. Here we use two-photon calcium imaging to record the activity of large populations of neurons at the cellular level, throughout the brain of larval zebrafish expressing a genetically encoded calcium sensor, while the paralysed animals interact fictively with a virtual environment and rapidly adapt their motor output to changes in visual feedback. We decompose the network dynamics involved in adaptive locomotion into four types of neuronal response properties, and provide anatomical maps of the corresponding sites. A subset of these signals occurred during behavioural adjustments and are candidates for the functional elements that drive motor learning. Lesions to the inferior olive indicate a specific functional role for olivocerebellar circuitry in adaptive locomotion. This study enables the analysis of brain-wide dynamics at single-cell resolution during behaviour.