Complex gas hydrate from the Cascadia margin

Natural gas hydrates are a potential source of energy and may play a role in climate change and geological hazards. Most natural gas hydrate appears to be in the form of 'structure I', with methane as the trapped guest molecule, although 'structure II' hydrate has also been identified, with guest molecules such as isobutane and propane, as well as lighter hydrocarbons. A third hydrate structure, 'structure H', which is capable of trapping larger guest molecules, has been produced in the laboratory, but it has not been confirmed that it occurs in the natural environment. Here we characterize the structure, gas content and composition, and distribution of guest molecules in a complex natural hydrate sample recovered from Barkley canyon, on the northern Cascadia margin. We show that the sample contains structure H hydrate, and thus provides direct evidence for the natural occurrence of this hydrate structure. The structure H hydrate is intimately associated with structure II hydrate, and the two structures contain more than 13 different hydrocarbon guest molecules. We also demonstrate that the stability field of the complex gas hydrate lies between those of structure II and structure H hydrates, indicating that this form of hydrate is more stable than structure I and may thus potentially be found in a wider pressure-temperature regime than can methane hydrate deposits.     

Catastrophic flooding origin of shelf valley systems in the English Channel

Megaflood events involving sudden discharges of exceptionally large volumes of water are rare, but can significantly affect landscape evolution, continental-scale drainage patterns and climate change. It has been proposed that a significant flood event eroded a network of large ancient valleys on the floor of the English Channel-the narrow seaway between England and France. This hypothesis has remained untested through lack of direct evidence, and alternative non-catastrophist ideas have been entertained for valley formation. Here we analyse a new regional bathymetric map of part of the English Channel derived from high-resolution sonar data, which shows the morphology of the valley in unprecedented detail. We observe a large bedrock-floored valley that contains a distinct assemblage of landforms, including streamlined islands and longitudinal erosional grooves, which are indicative of large-scale subaerial erosion by high-magnitude water discharges. Our observations support the megaflood model, in which breaching of a rock dam at the Dover Strait instigated catastrophic drainage of a large pro-glacial lake in the southern North Sea basin. We suggest that megaflooding provides an explanation for the permanent isolation of Britain from mainland Europe during interglacial high-sea-level stands, and consequently for patterns of early human colonisation of Britain together with the large-scale reorganization of palaeodrainage in northwest Europe.     

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.     

Modular and predictable assembly of porous organic molecular crystals

Nanoporous molecular frameworks are important in applications such as separation, storage and catalysis. Empirical rules exist for their assembly but it is still challenging to place and segregate functionality in three-dimensional porous solids in a predictable way. Indeed, recent studies of mixed crystalline frameworks suggest a preference for the statistical distribution of functionalities throughout the pores rather than, for example, the functional group localization found in the reactive sites of enzymes. This is a potential limitation for 'one-pot' chemical syntheses of porous frameworks from simple starting materials. An alternative strategy is to prepare porous solids from synthetically preorganized molecular pores. In principle, functional organic pore modules could be covalently prefabricated and then assembled to produce materials with specific properties. However, this vision of mix-and-match assembly is far from being realized, not least because of the challenge in reliably predicting three-dimensional structures for molecular crystals, which lack the strong directional bonding found in networks. Here we show that highly porous crystalline solids can be produced by mixing different organic cage modules that self-assemble by means of chiral recognition. The structures of the resulting materials can be predicted computationally, allowing in silico materials design strategies. The constituent pore modules are synthesized in high yields on gram scales in a one-step reaction. Assembly of the porous co-crystals is as simple as combining the modules in solution and removing the solvent. In some cases, the chiral recognition between modules can be exploited to produce porous organic nanoparticles. We show that the method is valid for four different cage modules and can in principle be generalized in a computationally predictable manner based on a lock-and-key assembly between modules.     

Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration

Leber congenital amaurosis (LCA) is a blinding retinal disease that presents within the first year after birth. Using exome sequencing, we identified mutations in the nicotinamide adenine dinucleotide (NAD) synthase gene NMNAT1 encoding nicotinamide mononucleotide adenylyltransferase 1 in eight families with LCA, including the family in which LCA was originally linked to the LCA9 locus. Notably, all individuals with NMNAT1 mutations also have macular colobomas, which are severe degenerative entities of the central retina (fovea) devoid of tissue and photoreceptors. Functional assays of the proteins encoded by the mutant alleles identified in our study showed that the mutations reduce the enzymatic activity of NMNAT1 in NAD biosynthesis and affect protein folding. Of note, recent characterization of the slow Wallerian degeneration (Wld(s)) mouse model, in which prolonged axonal survival after injury is observed, identified NMNAT1 as a neuroprotective protein when ectopically expressed. Our findings identify a new disease mechanism underlying LCA and provide the first link between endogenous NMNAT1 dysfunction and a human nervous system disorder.     

Pretender punishment induced by chemical signalling in a queenless ant

Animal societies are stages for both conflict and cooperation. Reproduction is often monopolized by one or a few individuals who behave aggressively to prevent subordinates from reproducing (for example, naked mole-rats, wasps and ants). Here we report an unusual mechanism by which the dominant individual maintains reproductive control. In the queenless ant Dinoponera quadriceps, only the alpha female reproduces. If the alpha is challenged by another female she chemically marks the pretender who is then punished by low-ranking females. This cooperation between alpha and low-rankers allows the alpha to inflict punishment indirectly, thereby maintaining her reproductive primacy without having to fight.     

The physical maps for sequencing human chromosomes 1, 6, 9, 10, 13, 20 and X

We constructed maps for eight chromosomes (1, 6, 9, 10, 13, 20, X and (previously) 22), representing one-third of the genome, by building landmark maps, isolating bacterial clones and assembling contigs. By this approach, we could establish the long-range organization of the maps early in the project, and all contig extension, gap closure and problem-solving was simplified by containment within local regions. The maps currently represent more than 94% of the euchromatic (gene-containing) regions of these chromosomes in 176 contigs, and contain 96% of the chromosome-specific markers in the human gene map. By measuring the remaining gaps, we can assess chromosome length and coverage in sequenced clones.     

Synaptotagmin I is necessary for compensatory synaptic vesicle endocytosis in vivo

Neurotransmission requires a balance of synaptic vesicle exocytosis and endocytosis. Synaptotagmin I (Syt I) is widely regarded as the primary calcium sensor for synaptic vesicle exocytosis. Previous biochemical data suggest that Syt I may also function during synaptic vesicle endocytosis; however, ultrastructural analyses at synapses with impaired Syt I function have provided an indirect and conflicting view of the role of Syt I during synaptic vesicle endocytosis. Until now it has not been possible experimentally to separate the exocytic and endocytic functions of Syt I in vivo. Here, we test directly the role of Syt I during endocytosis in vivo. We use quantitative live imaging of a pH-sensitive green fluorescent protein fused to a synaptic vesicle protein (synapto-pHluorin) to measure the kinetics of endocytosis in sytI-null Drosophila. We then combine live imaging of the synapto-pHluorins with photoinactivation of Syt I, through fluorescein-assisted light inactivation, after normal Syt I-mediated vesicle exocytosis. By inactivating Syt I only during endocytosis, we demonstrate that Syt I is necessary for the endocytosis of synaptic vesicles that have undergone exocytosis using a functional Syt I protein.