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101.
The Effects of Hemin and Double-Stranded RNA on α and β Globin Synthesis in Reticulocyte and Krebs II Ascites Cell-Free Systems and the Relationship of These Effects to an Initiation Factor Preparation 下载免费PDF全文
Yves Beuzard Irving M. London 《Proceedings of the National Academy of Sciences of the United States of America》1974,71(7):2863-2866
Protein synthesis in reticulocyte lysates ceases abruptly in the absence of added hemin or in the presence of double-stranded RNA. A similar effect of double-stranded RNA is observed in Krebs II ascites cell-free systems translating exogenous globin mRNA. The shut-off of protein synthesis is due to inhibition of initiation and can be prevented or reversed by addition of the initiation factor preparation M(3). Preparations of M(1), M(2), and dissociation factor are ineffective under these conditions. The effects of added hemin, M(3), and globin mRNA on the synthesis of alpha and beta globin chains have been studied in the reticulocyte and ascites cell extracts. When the concentration of M(3) is rate limiting, the synthesis of beta chains exceeds that of alpha chains. When the concentration of mRNA is rate limiting, synthesis of alpha and beta chains is more nearly equal. 相似文献
102.
Regulation of protein synthesis in rabbit reticulocyte lysates by the heme-regulated protein kinase: Inhibition of interaction of Met-tRNAfMet binding factor with another initiation factor in formation of Met-tRNAfMet·40S ribosomal subunit complexes 下载免费PDF全文
R. S. Ranu I. M. London A. Das A. Dasgupta A. Majumdar R. Ralston R. Roy N. K. Gupta 《Proceedings of the National Academy of Sciences of the United States of America》1978,75(2):745-749
Protein synthesis in reticulocytes and their lysates is regulated by heme. In heme deficiency a heme-regulated translational inhibitor (HRI) that blocks initiation of polypeptide chains is activated. HRI is a protein kinase (ATP: protein phosphotransferase, EC 2.7.1.37) that specifically phosphorylates the 38,000-dalton subunit of the Met-tRNA(f) (Met) binding factor (IF), which forms a ternary complex with Met-tRNA(f) (Met) and GTP, a finding that suggests that the inhibition by HRI involves the phosphorylation of IF.We have investigated the effect of HRI in the partial reactions of protein chain initiation in which the IF-promoted binding of Met-tRNA(f) (Met) to 40S ribosomal subunits is enhanced by another initiation factor [ternary complex dissociation factor (TDF)] and AUG. The results show that HRI at very low concentrations markedly inhibits the binding of Met-tRNA(f) (Met) to 40S subunits. The inhibitory effect of HRI requires ATP. Under these conditions HRI phosphorylates only the 38,000-dalton subunit of IF.The TDF preparations not only promote the binding of the ternary complex to 40S subunits but also promote the dissociation of the ternary complex in the presence of 5 mM Mg(2+) at 0 degrees . The preincubation of purified IF alone with low concentrations of HRI and ATP does not significantly affect its capacity to form the ternary complex; however, the TDF-promoted dissociation of the ternary complex is inhibited. The nonhydrolyzable analog adenosine 5'-[beta,gamma-imido]triphosphate does not substitute for ATP. These findings suggest that phosphorylation causes a conformational modification in IF, which results in inhibition of the interaction between the ternary complex and TDF that is required for the binding of the ternary complex to 40S subunits. 相似文献
103.
Regulation of protein synthesis: Activation by double-stranded RNA of a protein kinase that phosphorylates eukaryotic initiation factor 2 总被引:14,自引:15,他引:14
Daniel Levin Irving M. London 《Proceedings of the National Academy of Sciences of the United States of America》1978,75(3):1121-1125
Incubation of reticulocyte lysates or isolated crude ribosomes with low levels of double-stranded RNA (0.1-10 ng/ml) induces the formation of an inhibitor of protein synthesis initiation similar to that observed in heme deficiency. The inhibitor is associated with a cyclic AMP-independent protein kinase activity (ATP:protein phosphotransferase, EC 2.7.1.37) that phosphorylates the small polypeptide (38,000 daltons) of the eukaryotic initiation factor eIF-2. Activation of the inhibitor requires ATP in addition to double-stranded RNA and is accompanied by the phosphorylation of a 67,000-dalton polypeptide of unknown function. The inhibitor remains associated with the ribosomes during high-speed sedimentation. Once formed, the ribosome-associated inhibitor phosphorylates eIF-2 and inhibits protein synthesis in the absence of double-stranded RNA. Inhibition is prevented by exogenous eIF-2. The bound inhibitor can be solubilized by extraction with 0.5 M KCl. The soluble inhibitor preparation retains the ability to phosphorylate the small polypeptide of eIF-2 and to inhibit protein synthesis. Untreated crude ribosomes also contain cyclic AMP-independent protein kinase activities that phosphorylate the middle polypeptide (49,000 daltons) of eIF-2 and several polypeptide subunits of eIF-3 (160,000, 125,000, and 65,000 daltons); these kinase activities are not affected by double-stranded RNA and do not inhibit protein synthesis. 相似文献
104.
105.
Annette Rid Abha Saxena Abdhullah H. Baqui Anant Bhan Julie Bines Marie-Charlotte Bouesseau Arthur Caplan James Colgrove Ames Dhai Rita Gomez-Diaz Shane K. Green Gagandeep Kang Rosanna Lagos Patricia Loh Alex John London Kim Mulholland Pieter Neels Punee Pitisuttithum Samba Cor Sarr Michael Selgelid Mark Sheehan Peter G. Smith 《Vaccine》2014
Vaccines are among the most cost-effective interventions against infectious diseases. Many candidate vaccines targeting neglected diseases in low- and middle-income countries are now progressing to large-scale clinical testing. However, controversy surrounds the appropriate design of vaccine trials and, in particular, the use of unvaccinated controls (with or without placebo) when an efficacious vaccine already exists. This paper specifies four situations in which placebo use may be acceptable, provided that the study question cannot be answered in an active-controlled trial design; the risks of delaying or foregoing an efficacious vaccine are mitigated; the risks of using a placebo control are justified by the social and public health value of the research; and the research is responsive to local health needs. The four situations are: (1) developing a locally affordable vaccine, (2) evaluating the local safety and efficacy of an existing vaccine, (3) testing a new vaccine when an existing vaccine is considered inappropriate for local use (e.g. based on epidemiologic or demographic factors), and (4) determining the local burden of disease. 相似文献
106.
McNamara DM Holubkov R Postava L Janosko K MacGowan GA Mathier M Murali S Feldman AM London B 《Journal of the American College of Cardiology》2004,44(10):2019-2026
OBJECTIVES: We evaluated the interaction of angiotensin-converting enzyme (ACE) inhibitor therapy with the effect of the ACE D/I polymorphism on heart failure survival. BACKGROUND: The ACE deletion allele, ACE-D, is associated with increased ACE activity. The utilization of ACE genotyping to predict the impact of ACE inhibitor dose has not been previously evaluated. METHODS: We prospectively studied 479 subjects with systolic dysfunction (left ventricular ejection fraction 0.25 +/- 0.08). Subjects were divided on the basis of ACE inhibitor therapy into low dose (50%, n = 201), or those receiving angiotensin receptor antagonists (n = 51). Patients were genotyped for the ACE D/I polymorphism, followed to the end point of death or cardiac transplantation, and transplant-free survival compared by genotype. RESULTS: The ACE-D allele was associated with an increased risk of events (p = 0.026). In analysis by ACE inhibitor dose, this effect was primarily in the low-dose group (1-year percent event-free survival: II/ID/DD = 86/77/71,2-year = 79/66/59, p = 0.032). In the standard-dose group, the impact was markedly diminished (1-year: II/ID/DD = 91/81/80, 2-year: 77/70/71, p = 0.64). The impact of beta-blockers and high dose ACE inhibitors was greatest in subjects with the ACE DD genotype (p = 0.001) and was less apparent with the II and ID genotypes (p = 0.38). CONCLUSIONS: Higher doses of ACE inhibitors diminished the impact of the ACE-D allele, and the benefits of beta-blockers and high-dose ACE inhibitors appeared maximal for DD patients. Determination of ACE genotype may help target therapy for patients with heart failure. 相似文献
107.
Alex John London 《The Hastings Center report》2018,48(3)
Following a boom in investment and overinflated expectations in the 1980s, artificial intelligence entered a period of retrenchment known as the “AI winter.” With advances in the field of machine learning and the availability of large datasets for training various types of artificial neural networks, AI is in another cycle of halcyon days. Although medicine is particularly recalcitrant to change, applications of AI in health care have professionals in fields like radiology worried about the future of their careers and have the public tittering about the prospect of soulless machines making life‐and‐death decisions. Medicine thus appears to be at an inflection point—a kind of Groundhog Day on which either AI will bring a springtime of improved diagnostic and predictive practices or the shadow of public and professional fear will lead to six more metaphorical weeks of winter in medical AI. 相似文献
108.
Alex John London 《The Hastings Center report》2019,49(1):15-21
Although decision‐making algorithms are not new to medicine, the availability of vast stores of medical data, gains in computing power, and breakthroughs in machine learning are accelerating the pace of their development, expanding the range of questions they can address, and increasing their predictive power. In many cases, however, the most powerful machine learning techniques purchase diagnostic or predictive accuracy at the expense of our ability to access “the knowledge within the machine.” Without an explanation in terms of reasons or a rationale for particular decisions in individual cases, some commentators regard ceding medical decision‐making to black box systems as contravening the profound moral responsibilities of clinicians. I argue, however, that opaque decisions are more common in medicine than critics realize. Moreover, as Aristotle noted over two millennia ago, when our knowledge of causal systems is incomplete and precarious—as it often is in medicine—the ability to explain how results are produced can be less important than the ability to produce such results and empirically verify their accuracy. 相似文献
109.
We describe an additional case of spastic paretic hemifacial contracture, an uncommon condition characterized by sustained unilateral contraction of the facial muscles associated with mild ipsilateral facial paresis. This entity has only rarely been associated with multiple sclerosis (MS) and can be mistaken for hemifacial spasm. Early consideration of MS in the differential diagnosis of young patients admitted with these symptoms is essential. 相似文献
110.
Guilmot Antoine Maldonado Slootjes Sofia Sellimi Amina Bronchain Maroussia Hanseeuw Bernard Belkhir Leila Yombi Jean Cyr De Greef Julien Pothen Lucie Yildiz Halil Duprez Thierry Fillée Catherine Anantharajah Ahalieyah Capes Antoine Hantson Philippe Jacquerye Philippe Raymackers Jean-Marc London Frederic El Sankari Souraya Ivanoiu Adrian Maggi Pietro van Pesch Vincent 《Journal of neurology》2021,268(3):751-757
Journal of Neurology - Evidence of immune-mediated neurological syndromes associated with the severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection is limited. We therefore... 相似文献