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991.
Leblais V Demolombe S Vallette G Langin D Baró I Escande D Gauthier C 《The Journal of biological chemistry》1999,274(10):6107-6113
In human cardiac myocytes, we have previously identified a functional beta3-adrenoceptor in which stimulation reduces action potential duration. Surprisingly, in cardiac biopsies obtained from cystic fibrosis patients, beta3-adrenoceptor agonists produced no effects on action potential duration. This result suggests the involvement of cystic fibrosis transmembrane conductance regulator (CFTR) chloride current in the electrophysiological effects of beta3-adrenoceptor stimulation in non-cystic fibrosis tissues. We therefore investigated the control of CFTR activity by human beta3-adrenoceptors in a recombinant system: A549 human cells were intranuclearly injected with plasmids encoding CFTR and beta3-adrenoceptors. CFTR activity was functionally assayed using the 6-methoxy-N-(3-sulfopropyl)quinolinium fluorescent probe and the patch-clamp technique. Injection of CFTR-cDNA alone led to the expression of a functional CFTR protein activated by cAMP or cGMP. Co-expression of CFTR (but not of mutated DeltaF508-CFTR) with high levels of beta3-adrenoceptor produced an increased halide permeability under base-line conditions that was not further sensitive to cAMP or beta3-adrenoceptor stimulation. Patch-clamp experiments confirmed that CFTR channels were permanently activated in cells co-expressing CFTR and a high level of beta3-adrenoceptor. Permanent CFTR activation was not associated with elevated intracellular cAMP or cGMP levels. When the expression level of beta3-adrenoceptor was lowered, CFTR was not activated under base-line conditions but became sensitive to beta3-adrenoceptor stimulation (isoproterenol plus nadolol, SR 58611, or CGP 12177). This later effect was not prevented by protein kinase A inhibitors. Our results provide molecular evidence that CFTR but not mutated DeltaF508-CFTR is regulated by beta3-adrenoceptors expression through a protein kinase A-independent pathway. 相似文献
992.
Cells in the rat hippocampus fire as a function of the animal's location in space. Thus, a rat moving through the world produces a statistically reproducible sequence of place cell firings. With this perspective, spatial navigation can be viewed as a sequence learning problem for the hippocampus. That is, learning entails associating the relationships among a sequence of places that are represented by a sequence of place cell firing. Recent experiments by McNaughton and colleagues suggest the hippocampus can recall a sequence of place cell firings at a faster rate than it was experienced. This speedup, which occurs during slow-wave sleep, is called temporal compression. Here, we show that a simplified model of hippocampal area CA3, based on integrate-and-fire cells and unsupervised Hebbian learning, reproduces this temporal compression. The amount of compression is proportional to the activity level during recall and to the relative timespan of associativity during learning. Compression seems to arise from an alteration of network dynamics between learning and recall. During learning, the dynamics are paced by external input and slowed by a low overall level of activity. During recall, however, external input is absent, and the dynamics are controlled by intrinsic network properties. Raising the activity level by lowering inhibition increases the rate at which the network can transition between previously learned states and thereby produces temporal compression. The tendency for speeding up future activations, however, is limited by the temporal range of associations that were present during learning. 相似文献
993.
Roujeinikova A Levy CW Rowsell S Sedelnikova S Baker PJ Minshull CA Mistry A Colls JG Camble R Stuitje AR Slabas AR Rafferty JB Pauptit RA Viner R Rice DW 《Journal of molecular biology》1999,294(2):527-535
Molecular genetic studies with strains of Escherichia coli resistant to triclosan, an ingredient of many anti-bacterial household goods, have suggested that this compound works by acting as an inhibitor of enoyl reductase (ENR) and thereby blocking lipid biosynthesis. We present structural analyses correlated with inhibition data, on the complexes of E. coli and Brassica napus ENR with triclosan and NAD(+) which reveal how triclosan acts as a site-directed, picomolar inhibitor of the enzyme by mimicking its natural substrate. Elements of both the protein and the nucleotide cofactor play important roles in triclosan recognition, providing an explanation for the factors controlling its tight binding to the enzyme and for the emergence of triclosan resistance. 相似文献
994.
Modified purines are found in all organisms in the tRNA, rRNA, and even DNA, raising the possibility of an early role for
these compounds in the evolution of life. These include N
6-methyladenine, 1-methyladenine, N
6,N
6-dimethyladenine, 1-methylhypoxanthine, 1-methylguanine, and N
2-methylguanine. We find that these bases as well as a number of nonbiological modified purines can be synthesized from adenine
and guanine by the simple reaction of an amine or an amino group with adenine and guanine under the concentrated conditions
of the drying-lagoon or drying-beach model of prebiotic synthesis with yields as high as 50%. These compounds are therefore
as prebiotic as adenine and guanine and could have played an important role in the RNA world by providing additional functional
groups in ribozymes, especially for the construction of hydrophobic binding pockets.
Received: 7 August 1998 / Accepted: 31 December 1998 相似文献
995.
We investigated in a randomized double-blind placebo-controlled study the effects of zinc supplementation (2 mg/kg/day) for 12 weeks on growth, serum insulin-like growth factor-I (IGF-I) and insulin-like factor binding protein-3 (IGFBP-3) on 3- to 9-month-old infants with nonorganic failure to thrive (NOFTT). 25 infants completed the study, 14 received zinc supplementation (group A), and 11 received placebo (group B). The control group for baseline measurements was composed of 10 age-matched normal growing infants. There were no significant changes in weight for age, length for age, or weight for length during the entire study period in either group A or B. Serum IGF-I levels at baseline were similar in all the groups. After 12 weeks of therapy, serum IFG-I levels increased significantly only in the zinc-supplemented group, from 40.3 +/- 7 ng/ml at baseline to 65 +/- 8 ng/ml (p < 0.05). There was a marked difference in serum IGF-I levels between the zinc-supplemented group and the placebo group after 12 weeks: 65 +/- 8 vs. 49.4 +/- 5 ng/ml (p = 0.058, 95% CI of difference 9.88-21.31). No change was demonstrated in serum IGFBP-3 levels in either study group. We conclude that although zinc supplementation increased serum IGF-I levels, it did not improve the growth parameters of infants with NOFTT. 相似文献
996.
997.
Chorea-acanthocytosis (CHAC) (OMIM 200150) is a rare neurological syndrome characterized by neurodegeneration in combination with morphologically abnormal red cells (acanthocytosis). A partial yeast artificial chromosome contig of the CHAC critical region on chromosome 9q21 has been constructed, and 21 expressed sequence tags have been mapped. We have subsequently cloned Galpha14, a member of the G-protein alpha-subunit multigene family, and have identified Galphaq in the contig. The genomic structure of both genes has been established after construction of a bacterial artificial chromosome contig that showed Galphaq and Galpha14 to be in a head-to-tail arrangement (Cen-Galphaq-Galpha14-qter). Northern analysis found Galphaq to be ubiquitously expressed and Galpha14 to display a more restricted pattern of expression. Mutation analysis of the coding regions and splice sites for Galphaq and Galpha14 in 10 affected individuals from different families identified no changes likely to cause disease; however, two distinct single nucleotide polymorphisms in the coding region of Galpha14 have been identified. This study has excluded two plausible candidate genes from involvement in CHAC and has provided a solid platform for a positional cloning initiative. 相似文献
998.
Transport of proteins along the exocytotic pathway is primarily achieved by vesicular intermediates. Two proteins, Golgi SNAREs of 27 kDa, GS27, and of 28 kDa, GS28 (HGMW-approved nomenclature GOSR2 and GOSR1, respectively), are important trafficking membrane proteins between the endoplasmic reticulum and the Golgi and between Golgi subcompartments. Here, we present the human GS27 and GS28 cDNA sequences. They encode predicted proteins of 212 and 250 amino acids, respectively. Chromosomal mapping analyses reveal that human GS27 is located on chromosome 17q21 and GS28 on approximately 17q11. The chromosomal location of GS27 near a locus implicated in familial essential hypertension and its known function in trafficking indicate that it is a potential candidate gene for this disease. 相似文献
999.
John W Ely Jerome A Osheroff Mark H Ebell George R Bergus Barcey T Levy M Lee Chambliss Eric R Evans 《BMJ (Clinical research ed.)》1999,319(7206):358-361
ObjectivesTo characterise the information needs of family doctors by collecting the questions they asked about patient care during consultations and to classify these in ways that would be useful to developers of knowledge bases.DesignObservational study in which investigators visited doctors for two half days and collected their questions. Taxonomies were developed to characterise the clinical topic and generic type of information sought for each question.SettingEastern Iowa.ParticipantsRandom sample of 103 family doctors.ResultsParticipants asked a total of 1101 questions. Questions about drug prescribing, obstetrics and gynaecology, and adult infectious disease were most common and comprised 36% of all questions. The taxonomy of generic questions included 69 categories; the three most common types, comprising 24% of all questions, were “What is the cause of symptom X?” “What is the dose of drug X?” and “How should I manage disease or finding X?” Answers to most questions (702, 64%) were not immediately pursued, but, of those pursued, most (318, 80%) were answered. Doctors spent an average of less than 2 minutes pursuing an answer, and they used readily available print and human resources. Only two questions led to a formal literature search.ConclusionsFamily doctors in this study did not pursue answers to most of their questions. Questions about patient care can be organised into a limited number of generic types, which could help guide the efforts of knowledge base developers.
Key messages
- Questions that doctors have about the care of their patients could help guide the content of medical information sources and medical training
- In this study of US family doctors, participants frequently had questions about patient care but did not pursue answers to most questions (64%)
- On average, participants spent less than 2 minutes seeking an answer to a question
- The most common resources used to answer questions included textbooks and colleagues; formal literature searches were rarely performed
- The most common generic questions were “What is the cause of symptom X?” “What is the dose of drug X?” and “How should I manage disease or finding X?”
1000.
Joint analysis of the DRD5 marker concludes association with attention-deficit/hyperactivity disorder confined to the predominantly inattentive and combined subtypes 总被引:15,自引:0,他引:15
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Lowe N Kirley A Hawi Z Sham P Wickham H Kratochvil CJ Smith SD Lee SY Levy F Kent L Middle F Rohde LA Roman T Tahir E Yazgan Y Asherson P Mill J Thapar A Payton A Todd RD Stephens T Ebstein RP Manor I Barr CL Wigg KG Sinke RJ Buitelaar JK Smalley SL Nelson SF Biederman J Faraone SV Gill M 《American journal of human genetics》2004,74(2):348-356
Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable, heterogeneous disorder of early onset, consisting of a triad of symptoms: inattention, hyperactivity, and impulsivity. The disorder has a significant genetic component, and theories of etiology include abnormalities in the dopaminergic system, with DRD4, DAT1, SNAP25, and DRD5 being implicated as major susceptibility genes. An initial report of association between ADHD and the common 148-bp allele of a microsatellite marker located 18.5 kb from the DRD5 gene has been followed by several studies showing nonsignificant trends toward association with the same allele. To establish the postulated association of the (CA)(n) repeat with ADHD, we collected genotypic information from 14 independent samples of probands and their parents, analyzed them individually and, in the absence of heterogeneity, analyzed them as a joint sample. The joint analysis showed association with the DRD5 locus (P=.00005; odds ratio 1.24; 95% confidence interval 1.12-1.38). This association appears to be confined to the predominantly inattentive and combined clinical subtypes. 相似文献