Potential uses of Bayesian networks as tools for synthesis of systematic reviews of complex interventions

Bayesian networks (BNs) are tools for representing expert knowledge or evidence. They are especially useful for synthesising evidence or belief concerning a complex intervention, assessing the sensitivity of outcomes to different situations or contextual frameworks and framing decision problems that involve alternative types of intervention. Bayesian networks are useful extensions to logic maps when initiating a review or to facilitate synthesis and bridge the gap between evidence acquisition and decision-making. Formal elicitation techniques allow development of BNs on the basis of expert opinion. Such applications are useful alternatives to ‘empty’ reviews, which identify knowledge gaps but fail to support decision-making. Where review evidence exists, it can inform the development of a BN. We illustrate the construction of a BN using a motivating example that demonstrates how BNs can ensure coherence, transparently structure the problem addressed by a complex intervention and assess sensitivity to context, all of which are critical components of robust reviews of complex interventions. We suggest that BNs should be utilised to routinely synthesise reviews of complex interventions or empty reviews where decisions must be made despite poor evidence.

Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1

Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.

Genetic insights into common pathways and complex relationships among iImmune-mediated diseases

Shared aetiopathogenic factors among immune-mediated diseases have long been suggested by their co-familiality and co-occurrence, and molecular support has been provided by analysis of human leukocyte antigen (HLA) haplotypes and genome-wide association studies. The interrelationships can now be better appreciated following the genotyping of large immune disease sample sets on a shared SNP array: the 'Immunochip'. Here, we systematically analyse loci shared among major immune-mediated diseases. This reveals that several diseases share multiple susceptibility loci, but there are many nuances. The most associated variant at a given locus frequently differs and, even when shared, the same allele often has opposite associations. Interestingly, risk alleles conferring the largest effect sizes are usually disease-specific. These factors help to explain why early evidence of extensive 'sharing' is not always reflected in epidemiological overlap. © 2013 Macmillan Publishers Limited. All rights reserved.

Using genome-Wwide complex trait analysis to quantify 'missing heritability' in Parkinson's disease

Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17-38, P = 8.08E - 08) phenotypic variance associated with all types of PD, 15% (95% CI -0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17-44, P = 1.34E - 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered. © Published by Oxford University Press 2012.

Spontaneous generation of optical activity in urea inclusion compounds vis-a-vis current theories

A novel test of recent theories of the origin of optical activity has been designed based on the inclusion of certain alkyl 2-methylhexanoates into urea channels.

Structure of the benzene center dot center dot center dot ICI complex: A UVPES and ab initio molecular orbital study

UVPES studies and ab initio and DFT computations have been done on the benzene...ICl complex; electron spectral data and computed orbital energies show that donor orbitals are stabilized and acceptor orbitals are destabilized due to complexation. Calculations predict an oblique structure for the complex in which the interacting site is a C=C bond center in the donor and iodine atom in the acceptor, in full agreement with earlier experimental reports. BSSE-corrected binding energies closely match the enthalpy of complexation reported, and the NBO analysis clearly reveals the involvement of the pi orbital of benzene and the sigma* orbital of ICl in the complex.

An asymmetric homodinuclear complex containing the mu-x-oxobis(mu-x-carboxylato)diruthenium(III) core: X-ray structure of [Ru20(o2ec6H4-p-OMe)3(en) (PPh3)2] (C104)" 3CHC13

Asymmetric tri-bridged diruthenium(III) complexes, [Ru2O(O(2)CR)(3)(en) (PPh(3))(2)](ClO4) (R = C6H4-p-X: X = OMe (1a), Me (1b); en=1,2-diaminoethane), were prepared and structurally characterized. Complex 1a 3CHCl(3), crystallizes in the triclinic space group P (1) over bar with a = 14.029(5), b = 14.205(5), c = 20.610(6) Angstrom, alpha= 107.26(3), beta = 101.84(3), gamma= 97.57(3)degrees, V= 3756(2) Angstrom(3) and Z = 2. The complex has an {Ru-2(mu-O)(mu-O(2)CR)(2)(2+)} core and exhibits [O4PRu(mu-O)RuPO2N2](+) coordination environments for the metal centers. The novel structural feature is the asymmetric arrangement of ligands at the terminal sites of the core which shows an Ru... Ru separation of 3.226(3) Angstrom and an Ru-O-Ru angle of 119.2(5)degrees. An intense visible band observed near 570 nm is assigned to a charge transfer transition involving the d pi-Ru(III) and p pi-mu-O Orbitals. Cyclic voltammetry of the complexes displays a reversible Ru-2(III,III) reversible arrow Ru-2(III,IV) couple near 0.8 V (versus SCE) in MeCN-0.1 M TBAP.

Synthesis based on cyclohexadienes. Part 25. Total synthesis of (+/-)-allo-cedrol (khusiol)

The first stereoselective total synthesis of (+/-)-allo-cedrol 20, an enantiomer of khusiol and a complex sesquiterpene having a novel tricyclo[5.2.2.0(1,5)]undecane framework, is reported from 8-methoxytricyclo[6.2.2.0(1,6)]dodec-6-en-9-one 6c. The methodology involves preparation of 9-methoxytricyclo[7.2.1.0(1,6)]dodec-6-en-8-one 12 from 6c and its conversion through the compounds 8-benzyloxy-7,7-dimethyl-9-methoxytricyclo[7.2.1.0(1,6)]dodec-5-ene 38, 7-benzyloxy-8-methoxy-2,6,6-trimethyltricyclo[6.2.1.0(1,5)]undecane 48 into 8-methoxy-2,6,6-trimethyltricyclo[6.2.1.0(1,5)]undecan-7-one 49. Wittig reaction of 49 affords the olefin 50 which has been smoothly rearranged into khusione 51. Metal-ammonia reduction of khusione under specific conditions affords (+/-)-allo-cedrol. Thus, bridgehead substitution of a methoxy group by a methyl group is the key reaction in this synthesis. In an alternative strategy, attempted conversion of 8-methoxy-2-methyltricyclo[6.2.1.0(1,5)]undec-5-en-7-one 16 into khusione 37 results in an inseparable mixture of the isomers. A notable observation in this synthesis is the unusual formation of a gamma-alkylated product 27 during Woodward methylation of 16.

Synthesis of some copper(II)-chelating (dialkylamino)pyridine amphiphiles and evaluation of their esterolytic capacities in cationic micellar media

Three new (dialkylamino)pyridine (DAAP)-based ligand amphiphiles 3-5 have been synthesized. All of the compounds possess a metal ion binding subunit in the form of a 2,6-disubstituted DAAP moiety. In addition, at least one ortho-CH2OH substituent is present in all the ligands. Complex formation by these ligands with various metal ions were examined under micellar conditions, but only complexes with Cu(II) ions showed kinetically potent esterolytic capacities under micellar conditions. Complexes with Cu(II) were prepared in host comicellar cetyltrimethylammonium bromide (CTABr) media at pH 7.6. Individual complexes were characterized by UV-visible absorption spectroscopy and electron paramagnetic resonance spectroscopy. These metallomicelles speed the cleavage of the substrates p-nitrophenyl hexanoate or p-nitrophenyl diphenyl phosphate. To ascertain the nature of the active esterolytic species, the stoichiometries of the respective Cu(II) complexes were determined from the kinetic version of Job's plot. In all the instances, 2:1 complex ligand/Cu(II) ion are the most kinetically competent species. The apparent pK(a) values of the Cu(II)-coordinated hydroxyl groups of the ligands 3, 4, and 5, in the comicellar aggregate, are 7.8, 8.0, and 8.0, respectively, as estimated from the rate constant vs pH: profiles of the ester cleavage reactions. The nucleophilic metallomicellar reagents and the second-order "catalytic" rate constants toward esterolysis of the substrate p-nitrophenyl hexanoate (at 25 degrees C, pH 7.6) are 37.5 for 3, 11.4 for 4, and 13.8 for 5. All catalytic systems comprising the coaggregates of 3, 4, or 5 and CTABr demonstrate turnover behavior in the presence of excess substrate.

Synthesis, reactivity and structural characterisation of bicyclic tetraphosphapentazanes

The diphenoxy bicyclic tetraphosphapentazane derivatives (EtN)(5)P-4(OPh)(2) 2 and its monoxide (EtN)(5)P-4(O)(OPh)(2) 3 have been prepared. Both 2 and 3 exist as a mixture of two isomers. One isomer of (EtN)(5)P-4(O)(OPh)(2) 3a has been isolated and its reaction with tetrachloro-1,2-benzoquinone yielded (EtN)(5)P-4(O)(OPh)(2)(O2C6Cl4) 5 in which the junction phosphorus atom becomes five-co-ordinated. Treatment of 2 or 3a with [Mo(CO)(4)(nbd)] (nbd = norbornadiene, bicyclo[2.2.1]hepta-2,5-diene), on the other hand, yielded the chelate complex [Mo(CO)(4){(EtN)(5)P-4(O)(n)(OPh)(2)}] (n = 0 or 1; 6 or 7) in which the peripheral phosphorus atoms are bonded to the metal. The structures of 3a and 5-7 have been confirmed by single-crystal X-ray diffraction studies. The two P3N3 rings in 3a and 5 adopt twist/twist and irregular/twist conformations respectively; the phenoxy substituents occupy the 'pseudo axial' positions. However, an ideal chair conformation is observed for the P3N3 rings in 6 and 7 with the phenoxy substituents taking up the 'pseudo equatorial' positions. The NMR spectroscopic data for the compounds are discussed.

The role of lysine-41 in RNase A catalysis - A quantum chemical study on the active site ligand complex

Several mechanisms have been proposed to explain the action of enzymes at the atomic level. Among them, the recent proposals involving short hydrogen bonds as a step in catalysis by Gerlt and Gassman [1] and proton transfer through low barrier hydrogen bonds (LBHBs) [2, 3] have attracted attention. There are several limitations to experimentally testing such hypotheses, Recent developments in computational methods facilitate the study of active site-ligand complexes to high levels of accuracy, Our previous studies, which involved the docking of the dinucleotide substrate UpA to the active site of RNase A [4, 5], enabled us to obtain a realistic model of the ligand-bound active site of RNase A. From these studies, based on empirical potential functions, we were able to obtain the molecular dynamics averaged coordinates of RNase A, bound to the ligand UpA. A quantum mechanical study is required to investigate the catalytic process which involves the cleavage and formation of covalent bonds. In the present study, we have investigated the strengths of some of the hydrogen bonds between the active site residues of RNase A and UpA at the ab initio quantum chemical level using the molecular dynamics averaged coordinates as the starting point. The 49 atom system and other model systems were optimized at the 3-21G level and the energies of the optimized systems were obtained at the 6-31G* level. The results clearly indicate the strengthening of hydrogen bonds between neutral residues due to the presence of charged species at appropriate positions. Such a strengthening manifests itself in the form of short hydrogen bonds and a low barrier for proton transfer. In the present study, the proton transfer between the 2'-OH of ribose (from the substrate) and the imidazole group from the H12 of RNase A is influenced by K41, which plays a crucial role in strengthening the neutral hydrogen bond, reducing the barrier for proton transfer.

Use of a coupled transcriptional system for consistent overexpression and purification of UDG-Ugi complex and Ugi from Escherichia coli

We have designed a novel coupled transcriptional construct wherein Escherichia coil uracil DNA glycosylase (UDC:) and Bacillus subtilis phage PBS-2 encoded uracil DNA glycosylase inhibitor protein (Ugi) genes were cloned in tandem, downstream of an inducible promoter (P-trc). Use of this bicistronic operon has allowed purification of large amounts of UDG-Ugi complex formed in vivo. The system has also been exploited for purification of large amounts of Ugi. While establishing the expression system, one of the constructs showed detectable suppression of UAG termination codon and resulted in accumulation of a minor population of a putative readthrough polypeptide cor responding to UDG. We discuss the likely occurrence of such a phenomenon in overproduction of other recombinant proteins. Finally, the usefulness of the operon construct in convenient mutational analysis to study the mechanism of UDG-Ugi interaction is also discussed.

Void Geometry Driven Spin Crossover in Zeolite-Encapsulated Cobalt Tris(bipyridyl) Complex Ion

The cobalt(II) tris(bipyridyl) complex ion encapsulated in zeolite-Y supercages exhibits a thermally driven interconversion between a low-spin and a high-spin state-a phenomenon not observed for this ion either in solid state or in solution. From a comparative study of the magnetism and optical spectroscopy of the encapsulated and unencapsulated complex ion, supported by molecular modeling, such spin behavior is shown to be intramolecular in origin. In the unencapsulated or free state, the [Co(bipy)(3)](2+) ion exhibits a marked trigonal prismatic distortion, but on encapsulation, the topology of the supercage forces it to adopt a near-octahedral geometry. An analysis using the angular overlap ligand field model with spectroscopically derived parameters shows that the geometry does indeed give rise to a low-spin ground state, and suggests a possible scenario for the spin state interconversion.

Complex crystallization dynamics in amorphous germanium observed with dynamic transmission electron microscopy

Crystallization of amorphous germanium (a-Ge) by laser or electron beam heating is a remarkably complex process that involves several distinct modes of crystal growth and the development of intricate microstructural patterns on the nanosecond to ten microsecond time scales. Here we use dynamic transmission electron microscopy (DTEM) to study the fast, complex crystallization dynamics with 10 nm spatial and 15 ns temporal resolution. We have obtained time-resolved real-space images of nanosecond laser-induced crystallization in a-Ge with unprecedentedly high spatial resolution. Direct visualization of the crystallization front allows for time-resolved snapshots of the initiation and roughening of the dendrites on submicrosecond time scales. This growth is followed by a rapid transition to a ledgelike growth mechanism that produces a layered microstructure on a time scale of several microseconds. This study provides insights into the mechanisms governing this complex crystallization process and is a dramatic demonstration of the power of DTEM for studying time-dependent material processes far from equilibrium.

Synthesis, crystal structure and DNA cleavage activity of (aqua)bis(dipyridophenazine)copper(II) complex

A copper(II) complex of dipyridophenazine, viz., [Cu(dppz)(2)(H2O)](ClO4)(2) (I), has been prepared and structurally characterized by X-ray crystallography. The crystal structure of the complex shows a five-coordinate structure in which two N,N-donor dipyridophenazine (dppz) and one aqua ligand bind to the copper(II) center giving Cu-O and Cu-N bond distances in the range of 1.981(6) to 2.043(6) angstrom. The ESI-MS spectrum of 1 in MeCN shows a peak at m/z value of 313 (100%) indicating the dissociation of the aqua ligand in the solution phase. The complex is one-electron paramagnetic (mu(eff), 1.86 mu(B)). It displays a quasi-reversible Cu(II)/Cu(I) redox process at 0.096 V. The complex is an avid binder to CT DNA giving a binding constant value of 3.5 x 10(5) M-1. It shows significant hydrolytic cleavage of supercoiled pUC19 DNA in dark ill the absence of any external agents. The complex exhibits chemical nuclease activity oil treatment with 3-mercaptopropionic acid as a reducing agent forming hydroxyl radicals. Complex 1 is a model synthetic nuclease and hydrolase showing both modes of DNA cleavage under different reaction conditions. The DNA cleavage activity of 1 is significantly better than its phen analogue but similar to that of the bis-dpq complex.