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111.
112.
Citrate, pyruvate, and lactate contaminants of commercial serum albumin 总被引:13,自引:0,他引:13
Commercial serum albumin was found to contain lactate, pyruvate, and especially citrate in addition to fatty acids. Glucose, aspartate, and alpha-ketoglutarate were also present but at lower concentrations. Charcoal treatment followed by prolonged dialysis was effective in removing most of these contaminants. 相似文献
113.
Steven J. Milner John A. Carver F. John Ballard Geoffrey L. Francis 《Biotechnology and bioengineering》1999,62(6):693-703
The crucial step of folding of recombinant proteins presents serious challenges to obtaining the native structure. This problem is exemplified by insulin‐like growth factor (IGF)‐I which when refolded in vitro produces the native three‐disulfide structure, an alternative structure with mispaired disulfide bonds and other isomeric forms. To investigate this phenomenon we have examined the refolding properties of an analog of IGF‐I which contains a 13‐amino acid N‐terminal extension and a charge mutation at position 3 (Long‐ [Arg3]IGF‐I). Unlike IGF‐I, which yields 45% of the native structure and 24% of the alternative structure when refolded in vitro, Long‐[Arg3]GF‐I yields 85% and 10% of these respective forms. To investigate the interactions that affect the refolding of Long‐[Arg3]IGF‐I and IGF‐I, we acid‐trapped folding intermediates and products for inclusion in a kinetic analysis of refolding. In addition to non‐native intermediates, three native‐like intermediates were identified, that appear to have a major role in the in vitro refolding pathway of Long‐[Arg3]IGF‐I; a single‐disulfide Cys18–Cys61 intermediate, an intermediate with Cys18–Cys61 and Cys6–Cys48 disulfide bonds and another with Cys18–Cys61 and Cys47–Cys52 disulfide bonds. Furthermore, from our kinetic analysis we propose that the Cys18‐Cys61, Cys6‐Cys48 intermediate forms the native structure, not by the direct formation of the last (Cys47‐Cys52) disulfide bond, but by rearrangement via the Cys18–Cys61 intermediate and a productive Cys18–Cys61, Cys47–Cys52 intermediate. In this pathway, the last disulfide bond to form involves Cys6 and Cys48. Finally, we apply this pathway to IGF‐I and conclude that the divergence in the in vitro folding pathway of IGF‐I is caused by non‐native interactions involving Glu3 that stabilize the alternative structure. © 1999 John Wiley & Sons, Inc. Biotechnol Bioeng 62: 693–703, 1999. 相似文献
114.
Ballard C Lana MM Theodoulou M Douglas S McShane R Jacoby R Kossakowski K Yu LM Juszczak E;Investigators DART AD 《PLoS medicine》2008,5(4):e76
Background
There have been increasing concerns regarding the safety and efficacy of neuroleptics in people with dementia, but there are very few long-term trials to inform clinical practice. The aim of this study was to determine the impact of long-term treatment with neuroleptic agents upon global cognitive decline and neuropsychiatric symptoms in patients with Alzheimer disease.Methods and Findings
Design: Randomised, blinded, placebo-controlled parallel two-group treatment discontinuation trial.Setting: Oxfordshire, Newcastle and Gateshead, London and Edinburgh, United Kingdom.Participants: Patients currently prescribed the neuroleptics thioridazine, chlorpromazine, haloperidol trifluoperazine or risperidone for behavioural or psychiatric disturbance in dementia for at least 3 mo.Interventions: Continue neuroleptic treatment for 12 mo or switch to an identical placebo.Outcome measures: Primary outcome was total Severe Impairment Battery (SIB) score. Neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory (NPI).Results: 165 patients were randomised (83 to continue treatment and 82 to placebo, i.e., discontinue treatment), of whom 128 (78%) commenced treatment (64 continue/64 placebo). Of those, 26 were lost to follow-up (13 per arm), resulting in 51 patients per arm analysed for the primary outcome. There was no significant difference between the continue treatment and placebo groups in the estimated mean change in SIB scores between baseline and 6 mo; estimated mean difference in deterioration (favouring placebo) −0.4 (95% confidence interval [CI] −6.4 to 5.5), adjusted for baseline value (p = 0.9). For neuropsychiatric symptoms, there was no significant difference between the continue treatment and placebo groups (n = 56 and 53, respectively) in the estimated mean change in NPI scores between baseline and 6 mo; estimated mean difference in deterioration (favouring continue treatment) −2.4 (95% CI −8.2 to 3.5), adjusted for baseline value (p = 0.4). Both results became more pronounced at 12 mo. There was some evidence to suggest that those patients with initial NPI ≥ 15 benefited on neuropsychiatric symptoms from continuing treatment.Conclusions
For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this benefit must be weighed against the side effects of therapy.Trial registration: Cochrane Central Registry of Controlled Trials/National Research Register (#ISRCTN33368770). 相似文献115.
Barlaam B Acton DG Ballard P Bradbury RH Cross D Ducray R Germain H Hudson K Klinowska T Magnien F Ogilvie DJ Olivier A Ross HS Smith R Trigwell CB Vautier M Wright L 《Bioorganic & medicinal chemistry letters》2008,18(6):1799-1803
We have identified a new series of C-5 substituted indazolylaminoquinazolines as potent erbB2 kinase inhibitors. The lead compound 22 showed excellent in vitro potency, good physical properties, acceptable oral pharmacokinetics in rat and dog, and low human in vitro clearance. It showed at least equivalent activity dose for dose compared to lapatinib in various erbB2- or EGFR-driven xenograft models after chronic oral administration. 相似文献
116.
Guido Achermann Theresa M. Ballard Francesca Blasco Pierre-Emmanuel Broutin Bernd Büttelmann Holger Fischer Martin Graf Maria-Clemencia Hernandez Peter Hilty Frédéric Knoflach Andreas Koblet Henner Knust Anke Kurt James R. Martin Raffaello Masciadri Richard H.P. Porter Heinz Stadler Andrew W. Thomas Gerhard Trube Jürgen Wichmann 《Bioorganic & medicinal chemistry letters》2009,19(19):5746-5752
Through iterative design cycles we have discovered a number of novel new classes where the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine was deemed the most promising GABAA α5 inverse agonist class with potential for cognitive enhancement. This class combines a modest subtype binding selectivity with inverse agonism and has the most favourable molecular properties for further lead optimisation towards a central nervous system (CNS) acting medicine. 相似文献
117.
118.
Hoffmann T Bös M Stadler H Schnider P Hunkeler W Godel T Galley G Ballard TM Higgins GA Poli SM Sleight AJ 《Bioorganic & medicinal chemistry letters》2006,16(5):1362-1365
The discovery of a novel, achiral pyridine class of potent and orally active neurokinin-1 (NK(1)) receptor antagonists is described. The evaluation of this class is briefly outlined, leading to the identification of netupitant 21 and befetupitant 29, two new proprietary chemical entities with high affinity and excellent CNS penetration. 相似文献
119.
Ohrfelt A Zetterberg H Andersson K Persson R Secic D Brinkmalm G Wallin A Mulugeta E Francis PT Vanmechelen E Aarsland D Ballard C Blennow K Westman-Brinkmalm A 《Neurochemical research》2011,36(11):2029-2042
Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are neurodegenerative diseases that are characterized by intra-neuronal inclusions of Lewy bodies in distinct brain regions. These inclusions consist mainly of aggregated α-synuclein (α-syn) protein. The present study used immunoprecipitation combined with nanoflow liquid chromatography (LC) coupled to high resolution electrospray ionization Fourier transform ion cyclotron resonance tandem mass spectrometry (ESI-FTICR-MS/MS) to determine known and novel isoforms of α-syn in brain tissue homogenates. N-terminally acetylated full-length α-syn (Ac-α-syn?????) and two N-terminally acetylated C-terminally truncated forms of α-syn (Ac-α-syn????? and Ac-α-syn?????) were found. The different forms of α-syn were further studied by Western blotting in brain tissue homogenates from the temporal cortex Brodmann area 36 (BA36) and the dorsolateral prefrontal cortex BA9 derived from controls, patients with DLB and PD with dementia (PDD). Quantification of α-syn in each brain tissue fraction was performed using a novel enzyme-linked immunosorbent assay (ELISA). 相似文献
120.
Phillip Edward Kunkler Carrie Jo Ballard Jessica Joan Pellman LuJuan Zhang Gerry Stephen Oxford Joyce Harts Hurley 《PloS one》2014,9(7)
Headache is the most common symptom associated with air pollution, but little is understood about the underlying mechanism. Nasal administration of environmental irritants activates the trigeminovascular system by a TRPA1-dependent process. This report addresses questions about the anatomical pathway involved and the function of TRP channels in this pathway. TRPV1 and TRPA1 are frequently co-localized and interact to modulate function in sensory neurons. We demonstrate here that resiniferatoxin ablation of TRPV1 expressing neurons significantly reduces meningeal blood flow responses to nasal administration of both TRPV1 and TRPA1 agonists. Accordingly resiniferatoxin also significantly reduces TRPV1 and CGRP immunostaining and TRPV1 and TRPA1 message levels in trigeminal ganglia. Sensory neurons of the trigeminal ganglia innervate the nasal epithelium and the meninges, but the mechanism and anatomical route by which nasal administration evokes meningeal vasodilatation is unclear. Double retrograde labeling from the nose and meninges reveals no co-localization of fluorescent label, however nasal and meningeal labeled cells are located in close proximity to each other within the trigeminal ganglion. Our data demonstrate that TRPV1 expressing neurons are important for TRPA1 responses in the nasal-meningeal pathway. Our data also suggest that the nasal-meningeal pathway is not primarily by axon reflex, but may instead result from intraganglionic transmission. 相似文献