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61.
62.
—The convulsant action of methyldithiocarbazinate (MDTC), thiocarbohydrazide (TCH) and thiosemicarbazide (TSC) has been studied in mice. The relationship between dose and time to convulsions indicated that MDTC has a dual action and is more potent than TSC. Pretreatment of mice with pyridoxal phosphate (0.25 mmol/kg) protected against convulsions and death produced by low doses of MDTC or TCH, and low or high doses of TSC. Pretreatment with pyridoxine hydrochloride (0.25 mmol/kg) protected mice against TSC but not against TCH. It protected against low doses of MDTC (0.12 mmol/kg), but shortened the latency to convulsions after intermediate doses of MDTC (0.37 mmol/kg). Glutamate decarboxylase activity (GAD, EC 4.1.1.15) in whole brain homogenates from mice killed at the onset of seizures, was significantly reduced by all 3 drugs at all doses. This inhibition did not exceed 30% after any dose of TSC or TCH, but was 64% in mice killed 4 min after the injection of MDTC (0.98 mmol/kg). The addition of pyridoxal phosphate to brain homogenates abolished GAD inhibition after MDTC but not after TCH. In vitro brain GAD was 50% inhibited by 10−4m -MDTC, 18% by 10−4m -TSC and 8% by 10 −4m -TCH. Kinetic studies suggested that at low concentrations MDTC inhibits by competing with pyridoxal phosphate. At the onset of convulsions the cerebral content of pyridoxal phosphate was reduced after low or high doses of TSC (0.27 and 2.2 mmol/kg) and after high doses of MDTC (0.98 mmol/kg). All three drugs (at 10−5−10−4m ) inhibited pyridoxal phosphokinase (EC 2.7.1.35) in vitro. Short latency convulsions after MDTC (0.37–0.98 mmol/kg) very probably arise from inhibition of cerebral GAD, due to competition for coenzymic sites and/or unavailability of coenzyme. Long-latency convulsions after MDTC (0.12–0.37 mmol/kg) are comparable to those seen after TSC (0.27–2.2 mmol/kg) and may depend on a mechanism additional to inhibition of GAD. 相似文献
63.
64.
Minehira K Young SG Villanueva CJ Yetukuri L Oresic M Hellerstein MK Farese RV Horton JD Preitner F Thorens B Tappy L 《Journal of lipid research》2008,49(9):2038-2044
The liver secretes triglyceride-rich VLDLs, and the triglycerides in these particles are taken up by peripheral tissues, mainly heart, skeletal muscle, and adipose tissue. Blocking hepatic VLDL secretion interferes with the delivery of liver-derived triglycerides to peripheral tissues and results in an accumulation of triglycerides in the liver. However, it is unclear how interfering with hepatic triglyceride secretion affects adiposity, muscle triglyceride stores, and insulin sensitivity. To explore these issues, we examined mice that cannot secrete VLDL [due to the absence of microsomal triglyceride transfer protein (Mttp) in the liver]. These mice exhibit markedly reduced levels of apolipoprotein B-100 in the plasma, along with reduced levels of triglycerides in the plasma. Despite the low plasma triglyceride levels, triglyceride levels in skeletal muscle were unaffected. Adiposity and adipose tissue triglyceride synthesis rates were also normal, and body weight curves were unaffected. Even though the blockade of VLDL secretion caused hepatic steatosis accompanied by increased ceramides and diacylglycerols in the liver, the mice exhibited normal glucose tolerance and were sensitive to insulin at the whole-body level, as judged by hyperinsulinemic euglycemic clamp studies. Normal hepatic glucose production and insulin signaling were also maintained in the fatty liver induced by Mttp deletion. Thus, blocking VLDL secretion causes hepatic steatosis without insulin resistance, and there is little effect on muscle triglyceride stores or adiposity. 相似文献
65.
Focused glycomic analysis of the N-linked glycan biosynthetic pathway in ovarian cancer 总被引:1,自引:0,他引:1
Abbott KL Nairn AV Hall EM Horton MB McDonald JF Moremen KW Dinulescu DM Pierce M 《Proteomics》2008,8(16):3210-3220
66.
Lineke Begeman Richard Suu-Ire Ashley C. Banyard Christian Drosten Elisa Eggerbauer Conrad M. Freuling Louise Gibson Hooman Goharriz Daniel L. Horton Daisy Jennings Denise A. Marston Yaa Ntiamoa-Baidu Silke Riesle Sbarbaro David Selden Emma L. Wise Thijs Kuiken Anthony R. Fooks Thomas Müller James L. N. Wood Andrew A. Cunningham 《PLoS neglected tropical diseases》2020,14(12)
Rabies is a fatal neurologic disease caused by lyssavirus infection. Bats are important natural reservoir hosts of various lyssaviruses that can be transmitted to people. The epidemiology and pathogenesis of rabies in bats are poorly understood, making it difficult to prevent zoonotic transmission. To further our understanding of lyssavirus pathogenesis in a natural bat host, an experimental model using straw-colored fruit bats (Eidolon helvum) and Lagos bat virus, an endemic lyssavirus in this species, was developed. To determine the lowest viral dose resulting in 100% productive infection, bats in five groups (four bats per group) were inoculated intramuscularly with one of five doses, ranging from 100.1 to 104.1 median tissue culture infectious dose (TCID50). More bats died due to the development of rabies after the middle dose (102.1 TCID50, 4/4 bats) than after lower (101.1, 2/4; 101.1, 2/4) or higher (103.1, 2/4; 104.1, 2/4) doses of virus. In the two highest dose groups, 4/8 bats developed rabies. Of those bats that remained healthy 3/4 bats seroconverted, suggesting that high antigen loads can trigger a strong immune response that abrogates a productive infection. In contrast, in the two lowest dose groups, 3/8 bats developed rabies, 1/8 remained healthy and seroconverted and 4/8 bats remained healthy and did not seroconvert, suggesting these doses are too low to reliably induce infection. The main lesion in all clinically affected bats was meningoencephalitis associated with lyssavirus-positive neurons. Lyssavirus antigen was detected in tongue epithelium (5/11 infected bats) rather than in salivary gland epithelium (0/11), suggesting viral excretion via the tongue. Thus, intramuscular inoculation of 102.1 TCID50 of Lagos bat virus into straw-colored fruit bats is a suitable model for lyssavirus associated bat rabies in a natural reservoir host, and can help with the investigation of lyssavirus infection dynamics in bats. 相似文献
67.
The chemical-ionization (ci) mass spectra of the carbohydrate antibiotic lincomycin (1), its 7(S)-chloro analog clindamycin (2), and its N-deacylated derivative methyl 1-thiolincosaminide (3), produced with isobutane or ammonia as the reagent gas, display in each instance the protonated molecular-ion as the most abundant species. Only a few fragment-ions are observed, and these arise largely from low-energy, nonskeletal cleavage-reactions of the major ion, or through thermal breakdown of the original molecule; characteristic differences in the patterns of charge capture are observed as a function of the reagent gas. The spectra contrast sharply with those obtained by electron-impact (ei) mass spectrometry, wherein extreme fragmentation occurs and few prominent fragments of high mass are observed. The ci-ms technique offers considerable potential as a micro method for determining the purity of antibiotics, for analyzing them in admixture, and for monitoring reactions performed by chemical or biochemical methods to effect structural modification of antibiotics. 相似文献
68.
Horton R Gibson R Coggill P Miretti M Allcock RJ Almeida J Forbes S Gilbert JG Halls K Harrow JL Hart E Howe K Jackson DK Palmer S Roberts AN Sims S Stewart CA Traherne JA Trevanion S Wilming L Rogers J de Jong PJ Elliott JF Sawcer S Todd JA Trowsdale J Beck S 《Immunogenetics》2008,60(1):1-18
The human major histocompatibility complex (MHC) is contained within about 4 Mb on the short arm of chromosome 6 and is recognised
as the most variable region in the human genome. The primary aim of the MHC Haplotype Project was to provide a comprehensively
annotated reference sequence of a single, human leukocyte antigen-homozygous MHC haplotype and to use it as a basis against
which variations could be assessed from seven other similarly homozygous cell lines, representative of the most common MHC
haplotypes in the European population. Comparison of the haplotype sequences, including four haplotypes not previously analysed,
resulted in the identification of >44,000 variations, both substitutions and indels (insertions and deletions), which have
been submitted to the dbSNP database. The gene annotation uncovered haplotype-specific differences and confirmed the presence
of more than 300 loci, including over 160 protein-coding genes. Combined analysis of the variation and annotation datasets
revealed 122 gene loci with coding substitutions of which 97 were non-synonymous. The haplotype (A3-B7-DR15; PGF cell line)
designated as the new MHC reference sequence, has been incorporated into the human genome assembly (NCBI35 and subsequent
builds), and constitutes the largest single-haplotype sequence of the human genome to date. The extensive variation and annotation
data derived from the analysis of seven further haplotypes have been made publicly available and provide a framework and resource
for future association studies of all MHC-associated diseases and transplant medicine.
Horton and Gibson contributed equally to this work. 相似文献
69.
Liu He Rebecca Lever Andrew Cubbon Muhammad Tehseen Tabitha Jenkins Alice
O Nottingham Anya Horton Hannah Betts Martin Fisher Samir
M Hamdan Panos Soultanas Edward
L Bolt 《Nucleic acids research》2023,51(4):1740
DNA strand breaks are repaired by DNA synthesis from an exposed DNA end paired with a homologous DNA template. DNA polymerase delta (Pol δ) catalyses DNA synthesis in multiple eukaryotic DNA break repair pathways but triggers genome instability unless its activity is restrained. We show that human HelQ halts DNA synthesis by isolated Pol δ and Pol δ-PCNA-RPA holoenzyme. Using novel HelQ mutant proteins we identify that inhibition of Pol δ is independent of DNA binding, and maps to a 70 amino acid intrinsically disordered region of HelQ. Pol δ and its POLD3 subunit robustly stimulated DNA single-strand annealing by HelQ, and POLD3 and HelQ interact physically via the intrinsically disordered HelQ region. This data, and inability of HelQ to inhibit DNA synthesis by the POLD1 catalytic subunit of Pol δ, reveal a mechanism for limiting DNA synthesis and promoting DNA strand annealing during human DNA break repair, which centres on POLD3. 相似文献
70.
James H. Horton 《Brittonia》1963,15(3):177-203