In Saccharomyces cerevisiae, more than 80% of the ∼6200 predicted genes are nonessential, implying that the genome is buffered from the phenotypic consequences of genetic perturbation. To evaluate ...function, we developed a method for systematic construction of double mutants, termed synthetic genetic array (SGA) analysis, in which a query mutation is crossed to an array of ∼4700 deletion mutants. Inviable double-mutant meiotic progeny identify functional relationships between genes. SGA analysis of genes with roles in cytoskeletal organization (BNI1, ARP2, ARC40, BIM1), DNA synthesis and repair (SGS1, RAD27), or uncharacterized functions (BBC1, NBP2) generated a network of 291 interactions among 204 genes. Systematic application of this approach should produce a global map of gene function.
1. Permanent therapy with oral anticoagulants offers the most consistent protection in patients with mechanical heart valves. 2. Antiplatelet agents alone do not consistently protect patients with ...mechanical prosthetic heart valves, including patients in sinus rhythm with St. Jude Medical valves in the aortic position. 3. Levels of oral anticoagulants that prolong the INR to 2.0 to 3.0 appear satisfactory for patients with St. Jude Medical bileaflet and Medtronic-Hall tilting disk mechanical valves in the aortic position, provided they are in sinus rhythm and the left atrium is not enlarged. Presumably, this is also true for the CarboMedics bileaflet valve, based on the observation of no clinically important difference in the rate of systemic embolism with this valve and the St. Jude Medical bileaflet valve. 4. Levels of oral anticoagulants that prolong the INR to 2.5 to 3.5 are satisfactory for tilting disk valves and bileaflet prosthetic valves in the mitral position. 5. Experience in patients with caged ball valves who had prothrombin time ratios reported in terms of the INR is sparse, because few such valves have been inserted in recent years. The number of surviving patients with caged ball valves continues to decrease. It has been suggested that the most advantageous level of the INR in patients with caged ball or caged disk valves should be as high as 4.0 to 4.9. However, others have shown a high rate of major hemorrhage with an INR that is even somewhat lower, 3.0-4.5. The problem is self-limited, however, because few such valves are being inserted. 6. In patients with mechanical heart valves, aspirin, in addition to oral anticoagulants, has been shown to diminish the frequency of thromboemboli. The risk of bleeding is somewhat increased if the INR is 2.0 to 3.0 or 2.5 to 3.5. However, if the INR is 3.0 to 4.5, the risk of bleeding becomes excessive with aspirin. There are no investigations in which aspirin 80 mg/d in combination with oral anticoagulants was evaluated. 7. Data are insufficient to recommend dipyridamole over low doses of aspirin in combination with warfarin. Whether dipyridamole plus aspirin is more effective than aspirin alone when used with warfarin is undetermined. 8. Patients with bioprosthetic valves in the mitral position as well as patients with bioprosthetic valves in the aortic position may be at risk for thromboemboli during the first 3 months after operation. 9. Among patients with bioprosthetic valves in the mitral position, oral anticoagulants at an INR of 2.0 to 2.3 were as effective as an INR of 2.5 to 4.0 and were associated with fewer bleeding complications during the first 3 months after operation.10. Aspirin may reduce the long-term frequency of thromboembolism in patients with bioprosthetic valves.
Life with 6000 genes Goffeau, A. (Universite Catholique de Louvain, Louvain-la-Neuve, Belgium.); Barrell, B.G; Bussey, H ...
Science (American Association for the Advancement of Science),
10/1996, Letnik:
274, Številka:
5287
Journal Article
Recenzirano
The genome of the yeast Saccharomyces cerevisiae has been completely sequenced through a worldwide collaboration. The sequence of 12,068 kilobases defines 5885 potential protein-encoding genes, ...approximately 140 genes specifying ribosomal RNA, 40 genes for small nuclear RNA molecules, and 275 transfer RNA genes. In addition, the complete sequence provides information about the higher order organization of yeast's 16 chromosomes and allows some insight into their evolutionary history. The genome shows a considerable amount of apparent genetic redundancy, and one of the major problems to be tackled during the next stage of the yeast genome project is to elucidate the biological functions of all of these genes
The sequenced yeast genome offers a unique resource for the analysis of eukaryotic cell function and enables genome-wide screens for genes involved in cellular processes. We have identified genes ...involved in cell surface assembly by screening transposon-mutagenized cells for altered sensitivity to calcofluor white, followed by supplementary screens to further characterize mutant phenotypes. The mutated genes were directly retrieved from genomic DNA and then matched uniquely to a gene in the yeast genome database. Eighty-two genes with apparent perturbation of the cell surface were identified, with mutations in 65 of them displaying at least one further cell surface phenotype in addition to their modified sensitivity to calcofluor. Fifty of these genes were previously known, 17 encoded proteins whose function could be anticipated through sequence homology or previously recognized phenotypes and 15 genes had no previously known phenotype.
Colorectal cancer is the second most common cancer in the United Kingdom and other developed countries in the West. Although it is usually not familial, there is a rare dominantly inherited ...susceptibility to colon cancer, familial adenomatous polyposis (FAP; also often previously called familial polyposis coli). During adolescence affected individuals develop from a few hundred to over a thousand adenomatous polyps in their large bowel. These are sufficiently likely to give rise to adenocarcinomas to make prophylactic removal of the colon usual in diagnosed FAP individuals. Adenomas may occur elsewhere in the gastrointestinal tract and the condition is often associated with other extracolonic lesions, such as epidermoid cysts, jaw osteomata and fibrous desmoid tumours. Adenomata have been suggested to be precancerous states for most colorectal tumours. Knudson has suggested that the mutation for a dominantly inherited cancer susceptibility may be the first step in a recessive change in the tumour cells, and that the same gene may be involved in both familial and non-familial cases of a given tumour. Following up a case report of an interstitial deletion of chromosome 5 in a mentally retarded individual with multiple developmental abnormalities and FAP, we have now shown that the FAP gene is on chromosome 5, most probably near bands 5q21-q22.
K1 killer toxin is a secreted, pore-forming protein that kills sensitive yeast cells. The heterodimeric toxin is processed from a precursor in the Golgi, and has allowed identification of the KEX2- ...and KEX1-encoded proteases. The toxin binds to a glucan receptor on the cell wall of target yeast, and mutational analysis implicates both the alpha- and beta-toxin subunits in receptor binding. Toxin-resistant mutants with altered cell-wall glucans have helped to outline a pathway of assembly of these polysaccharides. Patch-clamp technology has demonstrated the nature of the lethal channel in toxin-treated plasma membranes. The hydrophobic alpha-subunit-encoding region is the site of all mutations affecting channel formation. Immunity to the toxin is conferred by the toxin precursor, and immunity mutations map to the region encoding the alpha subunit. The precursor probably competes with the toxin to prevent channel formation in toxin-producing cells, but the basis of this remains unknown. This toxin/immunity system has a domain structure that differs from that of other characterized toxins and has no known homologues.
This article concerning the pharmacokinetics and pharmacodynamics of vitamin K antagonists (VKAs) is part of the Seventh American College of Chest Physicians Conference on Antithrombotic and ...Thrombolytic Therapy: Evidence-Based Guidelines. The article describes the antithrombotic effect of VKAs, the monitoring of anticoagulation intensity, the clinical applications of VKA therapy, and the optimal therapeutic range of VKAs, and provides specific management recommendations. Grade 1 recommendations are strong, and indicate that the benefits do, or do not, outweigh the risks, burdens, and costs. Grade 2 suggests that individual patient's values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S–187S). Among the key recommendations in this article are the following: for dosing of VKAs, we suggest the initiation of oral anticoagulation therapy with doses between 5 and 10 mg for the first 1 or 2 days for most individuals, with subsequent dosing based on the international normalized ratio (INR) response (Grade 2B). In the elderly and in other patient subgroups with an elevated bleeding risk, we suggest a starting dose at ≤ 5 mg (Grade 2C). We recommend basing subsequent doses after the initial two or three doses on the results of INR monitoring (Grade 1C). The article also includes several specific recommendations for the management of patients with INRs above the therapeutic range and for patients requiring invasive procedures. For example, in patients with mild to moderately elevated INRs without major bleeding, we suggest that when vitamin K is to be given it be administered orally rather than subcutaneously (Grade 1A). For the management of patients with a low risk of thromboembolism, we suggest stopping warfarin therapy approximately 4 days before they undergo surgery (Grade 2C). For patients with a high risk of thromboembolism, we suggest stopping warfarin therapy approximately 4 days before surgery, to allow the INR to return to normal, and beginning therapy with full-dose unfractionated heparin or full-dose low-molecular-weight heparin as the INR falls (Grade 2C). In patients undergoing dental procedures, we suggest the use of tranexamic acid mouthwash (Grade 2B) or epsilon amino caproic acid mouthwash without interrupting anticoagulant therapy (Grade 2B) if there is a concern for local bleeding. For most patients who have a lupus inhibitor, we suggest a therapeutic target INR of 2.5 (range, 2.0 to 3.0) Grade 2B. In patients with recurrent thromboembolic events with a therapeutic INR or other additional risk factors, we suggest a target INR of 3.0 (range, 2.5 to 3.5) Grade 2C. As models of anticoagulation monitoring and management, we recommend that clinicians incorporate patient education, systematic INR testing, tracking, and follow-up, and good communication with patients concerning results and dosing decisions (Grade 1C+).
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