Williams J

References (15)

Title : Sexually Dimorphic Crosstalk at the Maternal-Fetal Interface - Sun_2020_J.Clin.Endocrinol.Metab_105_e4831
Author(s) : Sun T , Gonzalez TL , Deng N , DiPentino R , Clark EL , Lee B , Tang J , Wang Y , Stripp BR , Yao C , Tseng HR , Karumanchi SA , Koeppel AF , Turner SD , Farber CR , Rich SS , Wang ET , Williams J , Pisarska MD
Ref : J Clinical Endocrinology Metab , 105 :e4831 , 2020
Abstract : CONTEXT: Crosstalk through receptor ligand interactions at the maternal-fetal interface is impacted by fetal sex. This affects placentation in the first trimester and differences in outcomes. Sexually dimorphic signaling at early stages of placentation are not defined. OBJECTIVE: Investigate the impact of fetal sex on maternal-fetal crosstalk. DESIGN: Receptors/ligands at the maternal-fetal surface were identified from sexually dimorphic genes between fetal sexes in the first trimester placenta and defined in each cell type using single-cell RNA-Sequencing (scRNA-Seq). SETTING: Academic institution. SAMPLES: Late first trimester (~10-13 weeks) placenta (fetal) and decidua (maternal) from uncomplicated ongoing pregnancies. MAIN OUTCOME MEASURES: Transcriptomic profiling at tissue and single-cell level; immunohistochemistry of select proteins. RESULTS: We identified 91 sexually dimorphic receptor-ligand pairs across the maternal-fetal interface. We examined fetal sex differences in 5 major cell types (trophoblasts, stromal cells, Hofbauer cells, antigen-presenting cells, and endothelial cells). Ligands from the CC family chemokine ligand (CCL) family were most highly representative in females, with their receptors present on the maternal surface. Sexually dimorphic trophoblast transcripts, Mucin-15 (MUC15) and notum, palmitoleoyl-protein carboxylesterase (NOTUM) were also most highly expressed in syncytiotrophoblasts and extra-villous trophoblasts respectively. Gene Ontology (GO) analysis using sexually dimorphic genes in individual cell types identified cytokine mediated signaling pathways to be most representative in female trophoblasts. Upstream analysis demonstrated TGFB1 and estradiol to affect all cell types, but dihydrotestosterone, produced by the male fetus, was an upstream regulator most significant for the trophoblast population. CONCLUSIONS: Maternal-fetal crosstalk exhibits sexual dimorphism during placentation early in gestation.
ESTHER : Sun_2020_J.Clin.Endocrinol.Metab_105_e4831
PubMedSearch : Sun_2020_J.Clin.Endocrinol.Metab_105_e4831
PubMedID: 32772088

Title : Characterisation of Anopheles strains used for laboratory screening of new vector control products - Williams_2019_Parasit.Vectors_12_522
Author(s) : Williams J , Flood L , Praulins G , Ingham VA , Morgan J , Lees RS , Ranson H
Ref : Parasit Vectors , 12 :522 , 2019
Abstract : BACKGROUND: Insecticides formulated into products that target Anopheles mosquitos have had an immense impact on reducing malaria cases in Africa. However, resistance to currently used insecticides is spreading rapidly and there is an urgent need for alternative public health insecticides. Potential new insecticides must be screened against a range of characterized mosquito strains to identify potential resistance liabilities. The Liverpool School of Tropical Medicine maintains three susceptible and four resistant Anopheles strains that are widely used for screening for new insecticides. The properties of these strains are described in this paper. METHODS: WHO tube susceptibility bioassays were used for colony selection and to screen for resistance to the major classes of public health insecticides. Topical and tarsal contact bioassays were used to produce dose response curves to assess resistance intensity. Bioassays with the synergist piperonyl butoxide were also performed. Taqman assays were used to screen for known target site resistance alleles (kdr and ace-1). RT-qPCR was used to quantify expression of genes associated with pyrethroid resistance. RESULTS: Pyrethroid selection pressure has maintained resistance to this class in all four resistant strains. Some carbamate and organophosphate resistance has been lost through lack of exposure to these insecticide classes. The Anopheles gambiae (sensu lato) strains, VK7 2014, Banfora M and Tiassale 13 have higher levels of pyrethroid resistance than the An. funestus FUMOZ-R strain. Elevated expression of P450s is found in all four strains and the 1014F kdr mutation is present in all three An. gambiae strains at varying frequencies. Tarsal contact data and overexpression of CYP4G16 and SAP2 suggest penetration barriers and/or sequestration also confer resistance in Banfora M. CONCLUSIONS: Continual selection with deltamethrin has maintained a stable pyrethroid-resistant phenotype over many generations. In conjunction with a standardized rearing regime, this ensures quality control of strains over time allowing for robust product comparison and selection of optimal products for further development. The identification of multiple mechanisms underpinning insecticide resistance highlights the importance of screening new compounds against a range of mosquito strains.
ESTHER : Williams_2019_Parasit.Vectors_12_522
PubMedSearch : Williams_2019_Parasit.Vectors_12_522
PubMedID: 31690332

Title : Species composition and insecticide resistance status of Anopheles gambiae (s.l.) (Culicidae) in Kome, southern Chad and the implications for malaria control - Dadzie_2016_Parasit.Vectors_9_465
Author(s) : Dadzie S , Appawu MA , Kerah-Hinzoumbe C , Akogbeto MC , Adimazoya M , Israel DK , Fadel AN , Williams J
Ref : Parasit Vectors , 9 :465 , 2016
Abstract : BACKGROUND: The development and spread of insecticide resistance among malaria vectors, is a threat to the continued effectiveness of interventions to control and eliminate the disease. The status of insecticide resistance among malaria vector populations at two sites in Kome, southern Chad, was evaluated to inform decisions on vector control.
METHODS: Mosquito larvae were collected from temporary rain-filled and semi-permanent breeding places at two sites and reared in a laboratory. Emerging Anopheles gambiae (senso lato) (s.l.) adults were morphologically identified, sorted and evaluated for susceptibility to WHOPES recommended insecticides. Standardized biomolecular and biochemical methods were used to determine sibling species and molecular forms: knockdown resistant alleles (kdr-w) for pyrethroids and DDT; acetylcholinesterase-1 resistant alleles for organophosphate and carbamates; biochemical resistance through measurement of the levels of non-specific esterase (alpha and beta), oxidase and glutathione-s-transferases activities.
RESULTS: Anopheles gambiae (s.l.) was the main vector group in the two study sites and comprised of Anopheles gambiae (senso stricto) (s.s.) and An. arabiensis, respectively, at 71 and 29 % in Site A, and 60 and 40 % at Site B. Anopheles gambiae (s.s.) was composed of M (Anopheles coluzzii) and S [nominotypical An. gambiae (s.s.)] molecular forms. Anopheles coluzzii accounted for over 98 % of the sub-group. There was extensive phenotypic resistance to pyrethroids, DDT and carbamates, but full susceptibility to organophosphates. Population-wide frequency of knockdown resistant allele in An. gambiae (s.l.) was 43 homozygous (RR), 19 heterozygous (RS) and 38 % homozygous susceptible (SS). When segregated by species and molecular forms, An. coluzzii had the highest kdr-w frequency of 37.4 homozygous resistant alleles, and 17.5 % heterozygous, with 8.3 % homozygote susceptible alleles. An. gambiae (s.s.) had 1 % homozygous resistant allele. Levels of esterase, oxidase and glutathione-s-transferases were not significantly different compared to fully susceptible laboratory raised An. gambiae (s.s.) Kisumu reference, although few individuals showed significant elevation of esterases (> 0.04 mug/protein), indicating a likely start of biochemical enzyme resistance.
CONCLUSIONS: There is an urgent need for action to stop and reverse significant insecticide resistance in the area. A comprehensive entomological surveillance and monitoring program is needed to understand the full extent of resistance to enable realistic insecticide resistance management strategy, and also to track future changes in the vector populations.
ESTHER : Dadzie_2016_Parasit.Vectors_9_465
PubMedSearch : Dadzie_2016_Parasit.Vectors_9_465
PubMedID: 27553245

Title : Identification and functional characterization of a novel acetylcholine-binding protein from the marine annelid Capitella teleta - McCormack_2010_Biochemistry_49_2279
Author(s) : McCormack T , Petrovich RM , Mercier KA , DeRose EF , Cuneo MJ , Williams J , Johnson KL , Lamb PW , London RE , Yakel JL
Ref : Biochemistry , 49 :2279 , 2010
Abstract : We identified a homologue of the molluscan acetylcholine-binding protein (AChBP) in the marine polychaete Capitella teleta, from the annelid phylum. The amino acid sequence of C. teleta AChBP (ct-AChBP) is 21-30% identical with those of known molluscan AChBPs. Sequence alignments indicate that ct-AChBP has a shortened Cys loop compared to other Cys loop receptors, and a variation on a conserved Cys loop triad, which is associated with ligand binding in other AChBPs and nicotinic ACh receptor (nAChR) alpha subunits. Within the D loop of ct-AChBP, a conserved aromatic residue (Tyr or Trp) in nAChRs and molluscan AChBPs, which has been implicated directly in ligand binding, is substituted with an isoleucine. Mass spectrometry results indicate that Asn122 and Asn216 of ct-AChBP are glycosylated when expressed using HEK293 cells. Small-angle X-ray scattering data suggest that the overall shape of ct-AChBP in the apo or unliganded state is similar to that of homologues with known pentameric crystal structures. NMR experiments show that acetylcholine, nicotine, and alpha-bungarotoxin bind to ct-AChBP with high affinity, with K(D) values of 28.7 microM, 209 nM, and 110 nM, respectively. Choline bound with a lower affinity (K(D) = 163 microM). Our finding of a functional AChBP in a marine annelid demonstrates that AChBPs may exhibit variations in hallmark motifs such as ligand-binding residues and Cys loop length and shows conclusively that this neurotransmitter binding protein is not limited to the phylum Mollusca.
ESTHER : McCormack_2010_Biochemistry_49_2279
PubMedSearch : McCormack_2010_Biochemistry_49_2279
PubMedID: 20136097

Title : Covalent inhibitors of human monoacylglycerol lipase: ligand-assisted characterization of the catalytic site by mass spectrometry and mutational analysis - Zvonok_2008_Chem.Biol_15_854
Author(s) : Zvonok N , Pandarinathan L , Williams J , Johnston M , Karageorgos I , Janero DR , Krishnan SC , Makriyannis A
Ref : Chemical Biology , 15 :854 , 2008
Abstract : The active site of recombinant hexa-histidine-tagged human monoacylglycerol lipase (hMGL) is characterized by mass spectrometry using the inhibitors 5-((biphenyl-4-yl)methyl)-N,N-dimethyl-2H-tetrazole-2-carboxamide (AM6701), and N-arachidonylmaleimide (NAM) as probes. Carbamylation of Ser(129) by AM6701 in the putative hMGL catalytic triad demonstrates this residue's essential role in catalysis. Partial NAM alkylation of hMGL cysteine residues 215 and/or 249 was sufficient to achieve approximately 80% enzyme inhibition. Although Cys(215) and/or Cys(249) mutations to alanine(s) did not affect hMGL hydrolytic activity as compared with nonmutated hMGL, the C215A displayed heightened NAM sensitivity, whereas the C249A evidenced reduced NAM sensitivity. These data conclusively demonstrate a sulfhydryl-based mechanism for NAM inhibition of hMGL in which Cys(249) is of paramount importance. Identification of amino acids critical to the catalytic activity and pharmacological modulation of hMGL informs the design of selective MGL inhibitors as potential drugs.
ESTHER : Zvonok_2008_Chem.Biol_15_854
PubMedSearch : Zvonok_2008_Chem.Biol_15_854
PubMedID: 18721756

Title : The genome of Aeromonas salmonicida subsp. salmonicida A449: insights into the evolution of a fish pathogen - Reith_2008_BMC.Genomics_9_427
Author(s) : Reith ME , Singh RK , Curtis B , Boyd JM , Bouevitch A , Kimball J , Munholland J , Murphy C , Sarty D , Williams J , Nash JH , Johnson SC , Brown LL
Ref : BMC Genomics , 9 :427 , 2008
Abstract : BACKGROUND: Aeromonas salmonicida subsp. salmonicida is a Gram-negative bacterium that is the causative agent of furunculosis, a bacterial septicaemia of salmonid fish. While other species of Aeromonas are opportunistic pathogens or are found in commensal or symbiotic relationships with animal hosts, A. salmonicida subsp. salmonicida causes disease in healthy fish. The genome sequence of A. salmonicida was determined to provide a better understanding of the virulence factors used by this pathogen to infect fish. RESULTS: The nucleotide sequences of the A. salmonicida subsp. salmonicida A449 chromosome and two large plasmids are characterized. The chromosome is 4,702,402 bp and encodes 4388 genes, while the two large plasmids are 166,749 and 155,098 bp with 178 and 164 genes, respectively. Notable features are a large inversion in the chromosome and, in one of the large plasmids, the presence of a Tn21 composite transposon containing mercury resistance genes and an In2 integron encoding genes for resistance to streptomycin/spectinomycin, quaternary ammonia compounds, sulphonamides and chloramphenicol. A large number of genes encoding potential virulence factors were identified; however, many appear to be pseudogenes since they contain insertion sequences, frameshifts or in-frame stop codons. A total of 170 pseudogenes and 88 insertion sequences (of ten different types) are found in the A. salmonicida genome. Comparison with the A. hydrophila ATCC 7966T genome reveals multiple large inversions in the chromosome as well as an approximately 9% difference in gene content indicating instances of single gene or operon loss or gain.A limited number of the pseudogenes found in A. salmonicida A449 were investigated in other Aeromonas strains and species. While nearly all the pseudogenes tested are present in A. salmonicida subsp. salmonicida strains, only about 25% were found in other A. salmonicida subspecies and none were detected in other Aeromonas species. CONCLUSION: Relative to the A. hydrophila ATCC 7966T genome, the A. salmonicida subsp. salmonicida genome has acquired multiple mobile genetic elements, undergone substantial rearrangement and developed a significant number of pseudogenes. These changes appear to be a consequence of adaptation to a specific host, salmonid fish, and provide insights into the mechanisms used by the bacterium for infection and avoidance of host defence systems.
ESTHER : Reith_2008_BMC.Genomics_9_427
PubMedSearch : Reith_2008_BMC.Genomics_9_427
PubMedID: 18801193
Gene_locus related to this paper: aerpu-PEP , aers4-a4sh70 , aers4-a4sjf3 , aers4-a4sjy5 , aers4-a4smh7 , aers4-a4sqe9 , aers4-a4sqw3 , aers4-a4st97 , aers4-bioh , aers4-a4sqk8 , aers4-a4sjb7 , aerhh-a0kle4 , aersa-g7ctj0

Title : Full mass spectrometric characterization of human monoacylglycerol lipase generated by large-scale expression and single-step purification - Zvonok_2008_J.Proteome.Res_7_2158
Author(s) : Zvonok N , Williams J , Johnston M , Pandarinathan L , Janero DR , Li J , Krishnan SC , Makriyannis A
Ref : J Proteome Res , 7 :2158 , 2008
Abstract : The serine hydrolase monoacylglycerol lipase (MGL) modulates endocannabinoid signaling in vivo by inactivating 2-arachidonoylglycerol (2-AG), the main endogenous agonist for central CB1 and peripheral CB2 cannabinoid receptors. To characterize this key endocannabinoid enzyme by mass spectrometry-based proteomics, we first overexpressed recombinant hexa-histidine-tagged human MGL (hMGL) in Escherichia coli and purified it in a single chromatographic step with high yield (approximately 30 mg/L). With 2-AG as substrate, hMGL displayed an apparent V max of 25 micromol/(microg min) and K m of 19.7 microM, an affinity for 2-AG similar to that of native rat-brain MGL (rMGL) (Km=33.6 microM). hMGL also demonstrated a comparable affinity (Km approximately 8-9 microM) for the novel fluorogenic substrate, arachidonoyl, 7-hydroxy-6-methoxy-4-methylcoumarin ester (AHMMCE), in a sensitive, high-throughput fluorometric MGL assay. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) unequivocably demonstrated the mass (34,126 Da) and purity of this hMGL preparation. After in-solution tryptic digestion, hMGL full proteomic characterization was carried out, which showed (1) an absence of intramolecular disulfide bridges in the functional, recombinant enzyme and (2) the post-translational removal of the enzyme's N-terminal methionine. Availability of sufficient quantities of pure, well-characterized hMGL will enable further molecular and structural profiling of this key endocannabinoid-system enzyme.
ESTHER : Zvonok_2008_J.Proteome.Res_7_2158
PubMedSearch : Zvonok_2008_J.Proteome.Res_7_2158
PubMedID: 18452279

Title : Pseudocholinesterase deficiency and electroconvulsive therapy - Williams_2007_J.ECT_23_198
Author(s) : Williams J , Rosenquist P , Arias L , McCall WV
Ref : J Ect , 23 :198 , 2007
Abstract : Clinically significant pseudocholinesterase deficiency is a relatively uncommon disorder, but when present, it presents clinicians with challenges regarding medication administration. This is especially true in cases of patients receiving electroconvulsive therapy (ECT), as the presence of pseudocholinesterase deficiency limits the use of certain muscle relaxants. The authors describe a patient receiving ECT for treatment of his depression, who also possessed an unsuspected pseudocholinesterase deficiency. This was diagnosed after the patient was given succinylcholine, did not spontaneously recover motor function, and eventually required intubation. Subsequent ECT treatments were then managed with an alternative muscle relaxant which was not dependent on pseudocholinesterase for termination of action.
ESTHER : Williams_2007_J.ECT_23_198
PubMedSearch : Williams_2007_J.ECT_23_198
PubMedID: 17805000

Title : A single nucleotide polymorphism in CHAT influences response to acetylcholinesterase inhibitors in Alzheimer's disease - Harold_2006_Pharmacogenet.Genomics_16_75
Author(s) : Harold D , Macgregor S , Patterson CE , Hollingworth P , Moore P , Owen MJ , Williams J , O'Donovan M , Passmore P , McIlroy S , Jones L
Ref : Pharmacogenet Genomics , 16 :75 , 2006
Abstract : BACKGROUND: Alzheimer's disease (AD) is a devastating neurodegeneration with a characteristic deficit in cholinergic neurotransmission. Treatment with acetylcholinesterase (AChE) inhibitors aims to reverse this deficit and does ameliorate the decline in cognition in some AD patients, although response is variable. OBJECTIVE: To examine whether sequence variation in the gene encoding choline acetyltransferase (CHAT), which encodes the major catalytic enzyme of the cholinergic pathway, predicts response to AChE inhibitors.
METHODS: Alzheimer's disease patients (121) were treated with cholinesterase inhibitors and the effect of treatment on cognition was measured using the Mini Mental State Examination (MMSE). Six polymorphisms in CHAT were analysed for association with change in MMSE score.
RESULTS: After correction for multiple testing, we found one SNP, rs733722, in a promoter region of CHAT, is associated with response of AD patients to cholinesterase inhibitors (P = 0.03) and accounts for 6% of the variance in response to AChE inhibitors. CONCLUSION: Rs733722 represents a putative marker of response to AChE inhibitors in AD patients.
ESTHER : Harold_2006_Pharmacogenet.Genomics_16_75
PubMedSearch : Harold_2006_Pharmacogenet.Genomics_16_75
PubMedID: 16424819

Title : The genome of the social amoeba Dictyostelium discoideum - Eichinger_2005_Nature_435_43
Author(s) : Eichinger L , Pachebat JA , Glockner G , Rajandream MA , Sucgang R , Berriman M , Song J , Olsen R , Szafranski K , Xu Q , Tunggal B , Kummerfeld S , Madera M , Konfortov BA , Rivero F , Bankier AT , Lehmann R , Hamlin N , Davies R , Gaudet P , Fey P , Pilcher K , Chen G , Saunders D , Sodergren E , Davis P , Kerhornou A , Nie X , Hall N , Anjard C , Hemphill L , Bason N , Farbrother P , Desany B , Just E , Morio T , Rost R , Churcher C , Cooper J , Haydock S , van Driessche N , Cronin A , Goodhead I , Muzny D , Mourier T , Pain A , Lu M , Harper D , Lindsay R , Hauser H , James K , Quiles M , Madan Babu M , Saito T , Buchrieser C , Wardroper A , Felder M , Thangavelu M , Johnson D , Knights A , Loulseged H , Mungall K , Oliver K , Price C , Quail MA , Urushihara H , Hernandez J , Rabbinowitsch E , Steffen D , Sanders M , Ma J , Kohara Y , Sharp S , Simmonds M , Spiegler S , Tivey A , Sugano S , White B , Walker D , Woodward J , Winckler T , Tanaka Y , Shaulsky G , Schleicher M , Weinstock G , Rosenthal A , Cox EC , Chisholm RL , Gibbs R , Loomis WF , Platzer M , Kay RR , Williams J , Dear PH , Noegel AA , Barrell B , Kuspa A
Ref : Nature , 435 :43 , 2005
Abstract : The social amoebae are exceptional in their ability to alternate between unicellular and multicellular forms. Here we describe the genome of the best-studied member of this group, Dictyostelium discoideum. The gene-dense chromosomes of this organism encode approximately 12,500 predicted proteins, a high proportion of which have long, repetitive amino acid tracts. There are many genes for polyketide synthases and ABC transporters, suggesting an extensive secondary metabolism for producing and exporting small molecules. The genome is rich in complex repeats, one class of which is clustered and may serve as centromeres. Partial copies of the extrachromosomal ribosomal DNA (rDNA) element are found at the ends of each chromosome, suggesting a novel telomere structure and the use of a common mechanism to maintain both the rDNA and chromosomal termini. A proteome-based phylogeny shows that the amoebozoa diverged from the animal-fungal lineage after the plant-animal split, but Dictyostelium seems to have retained more of the diversity of the ancestral genome than have plants, animals or fungi.
ESTHER : Eichinger_2005_Nature_435_43
PubMedSearch : Eichinger_2005_Nature_435_43
PubMedID: 15875012
Gene_locus related to this paper: dicdi-abhd , dicdi-ACHE , dicdi-apra , dicdi-cinbp , dicdi-CMBL , dicdi-crysp , dicdi-DPOA , dicdi-P90528 , dicdi-ppme1 , dicdi-Q8MYE7 , dicdi-q54cf7 , dicdi-q54cl7 , dicdi-q54cm0 , dicdi-q54ct5 , dicdi-q54cu1 , dicdi-q54d54 , dicdi-q54d66 , dicdi-q54dj5 , dicdi-q54dy7 , dicdi-q54ek1 , dicdi-q54eq6 , dicdi-q54et1 , dicdi-q54et7 , dicdi-q54f01 , dicdi-q54g24 , dicdi-q54g47 , dicdi-q54gi7 , dicdi-q54gw5 , dicdi-q54gx3 , dicdi-q54h23 , dicdi-q54h73 , dicdi-q54i38 , dicdi-q54ie5 , dicdi-q54in4 , dicdi-q54kz1 , dicdi-q54l36 , dicdi-q54li1 , dicdi-q54m29 , dicdi-q54n21 , dicdi-q54n35 , dicdi-q54n85 , dicdi-q54qe7 , dicdi-q54qi3 , dicdi-q54qk2 , dicdi-q54rl3 , dicdi-q54rl8 , dicdi-q54sy6 , dicdi-q54sz3 , dicdi-q54t49 , dicdi-q54t91 , dicdi-q54th2 , dicdi-q54u01 , dicdi-q54vc2 , dicdi-q54vw1 , dicdi-q54xe3 , dicdi-q54xl3 , dicdi-q54xu1 , dicdi-q54xu2 , dicdi-q54y48 , dicdi-q54yd0 , dicdi-q54ye0 , dicdi-q54yl1 , dicdi-q54yr8 , dicdi-q54z90 , dicdi-q55bx3 , dicdi-q55d01 , dicdi-q55d81 , dicdi-q55du6 , dicdi-q55eu1 , dicdi-q55eu8 , dicdi-q55fk4 , dicdi-q55gk7 , dicdi-Q54ZA6 , dicdi-q86h82 , dicdi-Q86HC9 , dicdi-Q86HM5 , dicdi-Q86HM6 , dicdi-q86iz7 , dicdi-q86jb6 , dicdi-Q86KU7 , dicdi-q550s3 , dicdi-q552c0 , dicdi-q553t5 , dicdi-q555e5 , dicdi-q555h0 , dicdi-q555h1 , dicdi-q557k5 , dicdi-q558u2 , dicdi-Q869Q8 , dicdi-u554 , dicdi-y9086 , dicdi-q54r44 , dicdi-f172a

Title : Candidate gene association studies of genes involved in neuronal cholinergic transmission in Alzheimer's disease suggests choline acetyltransferase as a candidate deserving further study - Cook_2005_Am.J.Med.Genet.B.Neuropsychiatr.Genet_132B_5
Author(s) : Cook LJ , Ho LW , Wang L , Terrenoire E , Brayne C , Evans JG , Xuereb J , Cairns NJ , Turic D , Hollingworth P , Moore PJ , Jehu L , Archer N , Walter S , Foy C , Edmondson A , Powell J , Lovestone S , Williams J , Rubinsztein DC
Ref : American Journal of Medicine Genet B Neuropsychiatr Genet , 132B :5 , 2005
Abstract : Consistent deficits in the cholinergic system are evident in the brains of Alzheimer's Disease (AD) patients, including reductions in the activities of acetylcholine, acetylcholinesterase (AChE), and choline acetyltransferase (ChAT), increased butyrylcholinesterase (BChE) activity, and a selective loss of nicotinic acetylcholine receptors (nAChRs). Accordingly, we have analyzed polymorphisms in the genes encoding AChE, ChAT, BChE, and several of the subunit genes from neuronal nAChRs, for genetic associations with late-onset AD. A significant association for disease was detected for a non-coding polymorphism in ChAT (allele chi(1) (2) = 12.84, P = 0.0003; genotype chi(2) (2) = 11.89, P = 0.0026). Although replication analysis did not confirm the significance of this finding when the replication samples were considered alone (allele chi(1) (2) = 1.02, P = 0.32; genotype chi(2) (2) = 1.101, P = 0.58) the trends were in the correct direction and a significant association remained when the two sample sets were pooled (allele chi(1) (2) = 12.37, P = 0.0004; genotype chi(2) (2) = 11.61, P = 0.003). Previous studies have reported significant disease associations for both the K-variant of BChE and the coding ChAT rs3810950 polymorphism with AD. Replication analyses of these two loci failed to detect any significant association for disease in our case-control samples.
ESTHER : Cook_2005_Am.J.Med.Genet.B.Neuropsychiatr.Genet_132B_5
PubMedSearch : Cook_2005_Am.J.Med.Genet.B.Neuropsychiatr.Genet_132B_5
PubMedID: 15690550

Title : Pseudocholinesterase polymorphism in an Irish population - Adebayo_2005_Eur.J.Intern.Med_16_492
Author(s) : Adebayo GI , Williams J , Healy S
Ref : Eur J Intern Med , 16 :492 , 2005
Abstract : BACKGROUND: Pseudocholinesterase polymorphism, as an example of pharmacogenetics with important clinical implications, has been widely studied and documented. However, data on a sample Irish population is lacking. We sought to provide this. METHOD: In an assay involving Ellman's reaction, pseudocholinesterase activity, alone and with dibucaine or fluoride as an inhibitor, was quantified using propionylthiocholine iodide as substrate.
RESULTS: Pseudocholinesterase activities of 1.13-12.71 U/ml (mean +/- SD 6.74 +/- 2.04 U/ml) showed a normal distribution among our 116 healthy, non-medicated volunteers, aged 11-80 years (30.7 +/- 10.5 years) and weighing 46-114.6 kg (66.8 +/- 11.4 kg). However, dibucaine numbers from an inhibition study yielded a trimodal pattern consistent with the hypothesis of two allelic genes. Using an established nomenclature, 92 (79.3%) of our volunteers were homozygous for the usual form of the enzyme (E1uE1u). Of the 13 genotyped as E1uE1a, it is possible that 3 were misclassified and are probably E1kE1a. Only one volunteer was homozygous for the atypical form of the enzyme, with activity of 1.13 U/ml and dibucaine and fluoride number of 18.2 and 82.8, respectively. CONCLUSION: The continuous variation in pseudocholinesterase activity and the trimodal pattern of dibucaine numbers are both in accord with observations in other population groups. Although dibucaine number yields a trimodal pattern, its use could lead to misclassification of some E1kE1a as E1uE1a.
ESTHER : Adebayo_2005_Eur.J.Intern.Med_16_492
PubMedSearch : Adebayo_2005_Eur.J.Intern.Med_16_492
PubMedID: 16275543

Title : Fluorous Boc ((F)Boc) carbamates: new amine protecting groups for use in fluorous synthesis - Luo_2001_J.Org.Chem_66_4261
Author(s) : Luo Z , Williams J , Read RW , Curran DP
Ref : J Org Chem , 66 :4261 , 2001
Abstract : The first fluorous variants of the Boc (tert-butyloxycarbonyl) group have been prepared and tested for their suitability as nitrogen protecting groups. A group with two fluorous chains and an ethylene spacer, (RfCH2CH2)2(CH3)COC(O)-, was readily attached to a representative amine but was difficult to cleave. In contrast, groups with two fluorous chains and a propylene spacer, (RfCH2CH2CH2)2(CH3)COC(O)-, or one fluorous chain and an ethylene spacer, (RfCH2CH2)(CH3)2COC(O)-, were readily formed and cleaved. The fluorous alcohol component of the (F)Boc group can be removed by evaporation and can be recovered and reused. The utility of the new (F)Boc group (C8F17CH2CH2)(CH3)2COC(O)- was demonstrated in 16 and 96 compound library synthesis exercises. Separations can be achieved either by manual, parallel fluorous solid-phase extraction, or automated, serial fluorous chromatography. The results provide additional confirmation of the value of "light" fluorous synthesis techniques, and the new fluorous Boc groups expand the applicability of fluorous synthesis techniques to many classes of nitrogen-containing organic compounds.
ESTHER : Luo_2001_J.Org.Chem_66_4261
PubMedSearch : Luo_2001_J.Org.Chem_66_4261
PubMedID: 11397162

Title : Using meta-analysis to explain the diversity of results in genetic studies of late-onset Alzheimer's disease and to identify high-risk subgroups - Lehmann_2001_Neurosci_108_541
Author(s) : Lehmann DJ , Williams J , McBroom J , Smith AD
Ref : Neuroscience , 108 :541 , 2001
Abstract : In late-onset Alzheimer's disease, there is a puzzling inconsistency between the findings of case-control studies of most proposed risk genes, except apolipoprotein E epsilon4. This inconsistency may stem from the failure to define the genetic and non-genetic interactions that affect the disease association of each particular susceptibility gene. Such interactions will limit the influence of the gene to a 'relevant subset' of vulnerable people. The relevant subsets for many risk genes will be narrow, compared to that of apolipoprotein E epsilon4. Studies may therefore miss the association or even suggest that a risk gene is protective. In these circumstances, the precise composition of a cohort is critical and defining the relevant subset is crucial. We illustrate how such definition may be achieved through meta-analysis. We take as an example the butyrylcholinesterase K variant, whose association with Alzheimer's disease may now be provisionally defined. This analysis leads to the identification of a potentially high-risk group: over 75 year old male carriers of both apolipoprotein E epsilon4 and butyrylcholinesterase K variant.
ESTHER : Lehmann_2001_Neurosci_108_541
PubMedSearch : Lehmann_2001_Neurosci_108_541
PubMedID: 11738493

Title : DNA polymorphisms at the lipoprotein lipase gene and their association with quantitative variation in plasma high-density lipoproteins and triacylglycerides - Mitchell_1994_Hum.Biol_66_383
Author(s) : Mitchell RJ , Earl L , Bray P , Fripp YJ , Williams J
Ref : Hum Biol , 66 :383 , 1994
Abstract : Lipoprotein lipase (LPL) plays a critical role in the metabolism of lipoproteins because this enzyme hydrolyzes the triacylglycerides in chylomicrons and very low density lipoproteins. This process influences the production of high-density lipoprotein (HDL), which takes up tissue cholesterol for transport to the liver for excretion. Accordingly, LPL qualifies as a candidate gene for understanding lipid metabolic disorders and atherosclerosis. Studies on the relationship between genetic variation at the LPL locus and lipid phenotypes have produced equivocal results to date. To help clarify this issue, we investigated 144 outwardly healthy male Mediterranean migrants (from Italy and Greece), age between 40 and 70 years and resident in Australia, for associations between two common LPL restriction site polymorphisms and the following lipid and lipoprotein phenotypes: total plasma cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triacylglycerides. A series of analysis of variance tests, controlling for age, body mass index, and ethnicity, showed that the HindIII polymorphism at the LPL locus is significantly associated with both triacylglyceride and HDL cholesterol concentrations in this sample. The PvUII polymorphism, however, showed no association with any lipid. Kruskal-Wallis tests confirmed the significance of the associations between the HindIII RFLP and both HDL (p = 0.008) and triacylglycerides (p = 0.03). When the sample was subdivided into subjects who exhibited primary hypertriacylglyceridemia and normolipidemics, a significant difference was observed in the frequency of HindIII (p < 0.05) but not PvuII genotypes. HindIII heterozygotes (H1,H2) were least and H2,H2 individuals were most at risk for triacylglyceridemia. Examination of the normolipidemic sample revealed some evidence for an independent effect of the PvuII polymorphism on both LDL cholesterol and total cholesterol levels.
ESTHER : Mitchell_1994_Hum.Biol_66_383
PubMedSearch : Mitchell_1994_Hum.Biol_66_383
PubMedID: 8026810