X-ray crystallographic structures of two lamotrigine analogues: (I) 3,5-diamino-6-(2-chlorophenyl)-1,2,4-triazine water solvate and (II) 3,5-diamino-6-(3,6-dichlorophenyl)-1,2,4-triazine methanol solvate

The X-ray crystal structures of two lamotrigine derivatives (I) 3,5-diamino-6-(2-chlorophenyl)-1,2,4-triazine, C9H8ClN5, (465BL) as a hydrate, and (II) 3,5-diamino-6-(3,6-dichlorophenyl)-1,2,4-triazine, C9H7Cl2N5, (469BR) as a methanol solvate, have been carried out at liquid nitrogen temperature and room temperature, respectively. A detailed comparison of the two structures is given. Both are centrosymmetric with (I) in the orthorhombic space group Pbca, a = 12.2507(3), b = 15.7160(6), c = 21.71496(9) angstrom, Z = 16, and (II) in the monoclinic space group C2/c, a = 38.553(3), b = 4.9586(2), c = 14.546(2) angstrom, beta = 111.59(1)degrees, Z = 8. Final R indices [I > 2sigma(I)] for (I) are R1 = 0.0670, wR2 = 0.1515 and for (II) R1 = 0.0434, wR2 = 0.1185. Structure (I) has water of crystallization in the lattice and (II) includes a solvated CH3OH. Structure (I) is characterized by having two crystallographically independent molecules, A and B, of 465BL, per asymmetric unit. Molecule B has a very unusual feature in that the 2-chlorophenyl ring is statistically disordered, occupying site (1) in 87.5% of the structure and site (2) in 12.5% of the structure. Sites (1) and (2) are related by an exact 180 degrees pivot of the phenyl ring about the ring linkage bond. The presence of two independent molecules per asymmetric unit provides an ideal opportunity for the conformational flexibility of the molecule 465BL to be studied. Structure (I) also includes a further unusual feature in that the lattice contains one fully occupied water molecule and an additional solvated water which is only 33% occupied.

Low temperature X-ray crystallographic structures of two lamotrigine analogues: (I) 2-methyl,3-amino, 5-imino-6-(2,3-dichlorophenyl)-1,2,4-triazine water solvate and (II) 2-methyl,3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine isethionate, hemi-hydrate

The X-ray crystal structures of two lamotrigine derivatives (I) 2-methyl, 3-amino, 5-imino-6-(2, 3-dichlorophenyl)-1,2,4-triazine, C10H9Cl2N5, as the hemi hydrate and (II) 2-methyl,3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, C10H10Cl2N5, as the isethionate-water solvate, have been carried out at liquid nitrogen temperature. A detailed comparison of the two structures is given. Both are monoclinic and centrosymmetric, with (I) in space group C2/c, and (II) in space group P2(1)/n. For (I) the unit cell dimensions are a = 19.5466(10), b = 7.5483(4), c = 15.7861(8) angstrom, beta = 91.458(3)degrees, volume = 2328.4(2) angstrom(3), Z = 8, density = 1.590 Mg/m(3); for (II). For (II) the unit cell dimensions are a = 6.0566(2), b = 11.0084(4) c = 23.9973(9) angstrom, beta = 92.587(3)degrees, volume = 1598.35(10) angstrom(3), Z = 4, density = 1.597 Mg/m(3). For (I) final R indices [I > 2sigma(I)] are R1 = 0.0356, wR2 = 0.0782 and R indices (all data) are R1 = 0.0424, wR2 = 0.0817. For (II) final R indices [I > 2sigma(I)] are R1 = 0.0380, wR2 = 0.0871 and R indices (all data) R1 = 0.0558, wR2 = 0.0949. Both structures have a molecule of water of crystallization and (II) also includes a solvated CH3SO3. Comparisons are made between the two structures. Structure (I) is very unusual in having a = NH group at position C5' on the triazine ring. No other examples of this particular substitution, which is usually -NH2, have been reported.

X-ray crystallographic structures of neuroprotective pyrimidine derivatives: (I) the mesylate salt of BW1003C87 and (II) sipatrigine base

Drugs based on 5-phenyl-2,4 diamino pyrimidine and 6-phenyl-1,2,4 triazine derivatives are well known for their effects on the central nervous system. The study presented here provides detailed crystal structures of two pyrimidine derivatives which have neuroprotective properties in models of both grey and white matter ischemia. Recently published studies suggest that the compounds lamotrigine (a triazine derivative), and the two pyrimidines BW1003C87 (I) and sipatrigine (II) mediate their primary in vivo mode of action by inhibiting voltage-gated Na+ channels. The X-ray crystal structures will contribute valuable data for applications involving binding and modelling studies of the biological actions of these drugs.

The Architecture of Seduction: An Analysis on Digital Architectures within Consumer Society

Currently new digital tools used in architecture are often at the service of a conception of architecture as a consumer society’s cultural good. Within this neoliberal cultural frame, architects’ social function is no longer seen as the production of urban facts with sense of duty, but as a part within the symbolic logic that rules the social production of cultural values as it was defined by Veblen and developed by Baudrillard. As a result, the potential given by the new digital tools used in representation has shifted from an instrument used to verify a built project to two different main models: At the one hand the development of pure virtual architectures that are exclusively configured within their symbolic value as artistic “images” easily reproducible. On the other hand the development of all those projects which -even maintaining their attention to architecture as a built fact- base their symbolic value on the author’s image and on virtual aesthetics and logics that prevail over architecture’s materiality. Architects’ sense of duty has definitely reached a turning point.

Micro-organic compounds in the Humber rivers

The concentrations of a range of micro-organic compounds in the Humber rivers have been measured at weekly intervals over a period of 1 year. The compounds include the triazine herbicides (simazine, atrazine, propazine, desmetryn and prometryn), selected organophosphorus insecticides (fenitrothion, malathion and parathion), phenylurea (chlorotoluron, diuron, isoproturon and linuron) and phenoxyacid herbicides (2,4-D, MCPA, MCPB and mecoprop), phenol derivatives (phenol, 2-ethylphenol, 2-chlorophenol, 4-nitrophenol, 2-methylphenol, 4-ethylphenol and 2,4-dichlorophenol), organochlorine insecticides (HEOD, DDT, TDE, DDE, HCB, alpha-BHC and lindane), PCB's and some synthetic pyrethroid insecticides (cis/trans-permethrin, fenvalerate and cypermethrin). The results indicate the high frequency of occurrence of many compounds in the southern Humber rivers Aire, Calder, Trent and Don compared with the more occasional concentrations found in the upland rivers with catchments dominated by low intensity agriculture. The more water soluble herbicides, atrazine, simazine, isoproturon and diuron are detected frequently in the southern rivers with the highest concentrations and abundance in the rivers Aire, Calder and Trent. The most abundant phenolic compound is 2,4-dichlorophenol usually occurring at concentrations <1 mu g/l. The organochlorine insecticides and PCB's are generally at concentrations <0.01 mu g/l, cis/trans-permethrin are the only synthetic pyrethroids detected and these are found in the rivers Aire and Calder at about equal concentrations of between 0.01 and 0.11 mu g/l. The results of the occurrence of simazine and atrazine in the rivers Trent, Don and Aire illustrate peaks in concentration in the spring and then later in the year during the early autumn coinciding with the first major storm after the summer. In the rivers Trent and Don, the annual exports (March 1994-95) of atrazine are lower than for simazine whereas in the R. Calder the yield of atrazine is higher than for simazine suggesting differences in use in these catchments. The maximum triazine concentration observed, i.e. 8 mu g/l of atrazine in the R. Calder, could have inhibiting effects on the phytoplankton and algal growth, although because of the transient nature of the peaks, recovery is expected to be rapid. The only other compounds measured at concentrations likely to produce detrimental ecotoxicological effects are cis/trans permethrin in the rivers Aire and Calder. (C) 1997 Elsevier Science B.V.

How much gas can we get from grass?

Grass biomethane has been shown to be a sustainable gaseous transport biofuel, with a good energy balance, and significant potential for economic viability. Of issue for the designer is the variation in characteristics of the grass depending on location of source, time of cut and species. Further confusion arises from the biomethane potential tests (BMP) which have a tendency to give varying results. This paper has dual ambitions. One of these is to highlight the various results for biomethane potential that may be obtained from the same grass silage. The results indicated that methane potential from the same grass silage varied from 350 to 493 L CH4 kg−1 VS added for three different BMP procedures. The second ambition is to attempt to compare two distinct digestion systems again using the same grass: a two stage continuously stirred tank reactor (CSTR); and a sequentially fed leach bed reactor connected to an upflow anaerobic sludge blanket (SLBR–UASB). The two engineered systems were designed, fabricated, commissioned and operated at small pilot scale until stable optimal operating conditions were reached. The CSTR system achieved 451 L CH4 kg−1 VS added over a 50 day retention period. The SLBR–UASB achieved 341 L CH4 kg−1 VS added at a 30 day retention time.

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

Combining global climate and regional landscape models to improve prediction of invasion risk

Aim
It is widely acknowledged that species distributions result from a variety of biotic and abiotic factors operating at different spatial scales. Here, we aimed to (1) determine the extent to which global climate niche models (CNMs) can be improved by the addition of fine-scale regional data; (2) examine climatic and environmental factors influencing the range of 15 invasive aquatic plant species; and (3) provide a case study for the use of such models in invasion management on an island.

Location
Global, with a case study of species invasions in Ireland.

Methods
Climate niche models of global extent (including climate only) and regional environmental niche models (with additional factors such as human influence, land use and soil characteristics) were generated using maxent for 15 invasive aquatic plants. The performance of these models within the invaded range of the study species in Ireland was assessed, and potential hotspots of invasion suitability were determined. Models were projected forward up to 2080 based on two climate scenarios.

Results
While climate variables are important in defining the global range of species, factors related to land use and nutrient level were of greater importance in regional projections. Global climatic models were significantly improved at the island scale by the addition of fine-scale environmental variables (area under the curve values increased by 0.18 and true skill statistic values by 0.36), and projected ranges decreased from an average of 86% to 36% of the island.

Main conclusions
Refining CNMs with regional data on land use, human influence and landscape may have a substantial impact on predictive capacity, providing greater value for prioritization of conservation management at subregional or local scales.

Defining and assessing animal pain

The detection and assessment of pain in animals is crucial to improving their welfare in a variety of contexts in which humans are ethically or legally bound to do so. Thus clear standards to judge whether pain is likely to occur in any animal species is vital to inform whether to alleviate pain or to drive the refinement of procedures to reduce invasiveness, thereby minimizing pain. We define two key concepts that can be used to evaluate the potential for pain in both invertebrate and vertebrate taxa. First, responses to noxious, potentially painful events should affect neurobiology, physiology and behaviour in a different manner to innocuous stimuli and subsequent behaviour should be modified including avoidance learning and protective responses. Second, animals should show a change in motivational state after experiencing a painful event such that future behavioural decision making is altered and can be measured as a change in conditioned place preference, self-administration of analgesia, paying a cost to access analgesia or avoidance of painful stimuli and reduced performance in concurrent events. The extent to which vertebrate and selected invertebrate groups fulfil these criteria is discussed in light of the empirical evidence and where there are gaps in our knowledge we propose future studies are vital to improve our assessment of pain. This review highlights arguments regarding animal pain and defines criteria that demonstrate, beyond a reasonable doubt, whether animals of a given species experience pain.

Defining the role of common variation in the genomic and biological architecture of adult human height

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/I 2-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.