Mutator genes for suppression of gross chromosomal rearrangements identified by a genome-wide screening in Saccharomyces cerevisiae

Different types of gross chromosomal rearrangements (GCRs), including translocations, interstitial deletions, terminal deletions with de novo telomere additions, and chromosome fusions, are observed in many cancers. Multiple pathways, such as S-phase checkpoints, DNA replication, recombination, chromatin remodeling, and telomere maintenance that suppress GCRs have been identified. To experimentally expand our knowledge of other pathway(s) that suppress GCRs, we developed a generally applicable genome-wide screening method. In this screen, we identified 10 genes (ALO1, CDC50, CSM2, ELG1, ESC1, MMS4, RAD5, RAD18, TSA1, and UFO1) that encode proteins functioning in the suppression of GCRs. Moreover, the breakpoint junctions of GCRs from these GCR mutator mutants were determined with modified breakpoint-mapping methods. We also identified nine genes (AKR1, BFR1, HTZ1, IES6, NPL6, RPL13B, RPL27A, RPL35A, and SHU2) whose mutations generated growth defects with the pif1Delta mutation. In addition, we found that some of these mutations changed the telomere size.     

Cyclic GMP formation of resistance vessel in the development of hypertension in spontaneously hypertensive rats.

We investigated the basal levels and responses of cyclic GMP (cGMP) derived from perfused mesenteric arteries to acetylcholine (ACh) and sodium nitroprusside (SNP) in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) at different ages, in order to evaluate the basal and stimulated release of endothelium-derived relaxing factor (EDRF) from the resistance vessel during the development of hypertension. The mesenteric arteries were removed from 8-, 12- and 20-week-old WKY and SHR, and were perfused with Krebs-Henseleit solution containing 0.2 mM isobutyl methyl xanthine. The effluents from the perfused arteries were corrected before and after infusions of graded doses of ACh or SNP, and the levels of cGMP were measured. The basal levels of cGMP from the mesenteric arteries in the 12- and 20-week-old SHR were significantly lower than those in age-matched WKY. A negative correlation was observed between the basal levels of cGMP and the systolic blood pressure in SHR, but not in WKY, among all ages. On the other hand, there were no differences in the responses of cGMP to infusion of ACh between the WKY and SHR at each age. Moreover, the responsiveness of cGMP to infusion of SNP in the 12-week-old SHR was much higher than that in age-matched WKY. These data suggest that the basal cGMP formation in the arteries which may reflect the basal release of EDRF is reduced in older SHR and is associated with the development of hypertension, and that the stimulated release of EDRF is not associated with the development of hypertension.     

Low doses of endothelin-3 elicit endothelium dependent vasodilation which accompanies with elevation of cyclic GMP.

Low doses (10(-16)-10(-10) M) of endothelin-3 (ET-3) elicited continuous vasodilations of mesenteric arteries preconstricted with norepinephrine (NE) but not with KCl. In arteries perfused with Ca2+ free solution, ET-3 did not affect the perfusion pressure. In endothelium-denuded arteries preconstricted with NE, ET-3 significantly elevated the perfusion pressure in a dose-related manner. The levels of cyclic GMP and cyclic AMP from the intact arteries were significantly elevated by ET-3; the cyclic GMP elevasion disappeared with methylene blue. Following endothelium-denudation, cyclic GMP elevation was abolished, but cyclic AMP elevation was unaffected. Levels of 6-Keto-PGF1 alpha in the arteries were not changed appreciably by ET-3. These data indicate that the vasodilating effects of ET-3 depend on the presence of extracellular Ca2+ and the existence of endothelium. They are accompanied by elevations of cyclic nucleotides and the elevation of cyclic GMP depends on the endothelium. It is possible that the vasodilating effects of low doses of ET-3 are associated with endothelium-derived relaxing factor.     

Assessment of human health risk for heavy metals in fish and shrimp collected from Subarnarekha river,India

Five fish species and one shrimp species from the Subarnarekha river were analyzed for heavy metals using inductively coupled plasma-mass spectrometry. The geometric mean concentration of As, Cd, Cu, Fe, Pb, Ni, Zn, Cr, Co, and Sr for all the samples was found to be 0.248, 0.031, 5.16, 104.9, 0.121, 4.68, 52.2, 0.784, 0.207, and 42.86 mg kg^?1_fresh, respectively. The concentrations of metals in the fish and shrimp exceed the limits of Indian and FAO standards for food for As, Cu, Ni, Cd, and Zn in many samples. The mean target hazard quotient (THQ) values for the 10 metals were below one for all the samples; however, the maximum THQ was more than one for shrimp in case of As, Cu, and Cr. The results indicate that the concentration of metals in some species, especially shrimp, at some locations is alarming and do present an appreciable hazard risk on human health.     

Design,Synthesis, and Optimization of Balanced Dual NK1/NK3 Receptor Antagonists

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Therapeutic strategy using extracorporeal life support,including appropriate indication,management, limitation and timing of switch to ventricular assist device in patients with acute myocardial infarction

The appropriate indication for, management of and limitations to extracorporeal life support (ECLS) and the timing of a switch to a ventricular assist device (VAD) remain controversial issues in patients with acute myocardial infarction (AMI) complicated with cardiogenic shock or cardiopulmonary arrest. To evaluate and discuss these issues, we studied patients with AMI treated with ECLS and compared deceased and discharged patients. Thirty-eight patients with AMI who needed ECLS [35 men (92.1 %), aged 59.9 ± 13.5 years] were enrolled in this study. Of these 38 patients, 34 subsequently underwent percutaneous coronary intervention (PCI), and four subsequently received coronary artery bypass grafting (CABG). Fourteen patients (36.8 %) were discharged from the hospital. The outcome was not favorable for those patients with deteriorating low output syndrome (LOS) and the development of leg ischemia, hemolysis and multiple organ failure during ECLS. Levels of creatine kinase, creatine kinase-MB (CK-MB), lactate dehydrogenase, serum creatinine (Cr) and amylase after the patient had been put on ECLS and fluctuation of the cardiac index, blood pressure, arterial blood gas analysis and CK-MB and Cr levels during ECLS were indicators to switch from the ECLS to VAD. In the case of patients with no complication associated with ECLS, 4.6–5.6 days after initiation of ECLS was assumed to be the threshold to decide whether to switch from ECLS to VAD. Patients with AMI who suddenly developed refractory pulseless ventricular tachycardia or ventricular fibrillation without deteriorating LOS and who underwent successful PCI or CABG, and who prevented the complications associated with ECLS, showed a high probability of recovering with ECLS.     

Myocardial infarction with acute insulin poisoning--a case report

A 36-year-old woman without overt coronary risk factors was admitted to hospital with coma about 9 hours after mass self-injection of insulin (1,500 units). Laboratory investigation revealed severe hypoglycemia and hyperinsulinemia. During the treatment of her hypoglycemia, circulatory collapse occurred. The ECG, echocardiogram, and elevation in troponin T suggested a diagnosis of myocardial infarction. Although the patient became apallic and developed systemic spasticity due to hypoglycemic brain damage, her hemodynamics improved with supportive care alone. Coronary angiography and myocardial scintigraphy performed later demonstrated a broad area of myocardial damage despite intact coronary artery circulation. The authors hypothesize that temporary coronary arterial narrowing or coronary arterial vasospasm induced by severe hyperinsulinemia contributed to the pathogenesis of the myocardial infarction. The possibility of myocardial infarction should be considered in patients with acute insulin poisoning.     

Soluble interleukin-2 receptor level on day 7 as a predictor of graft-versus-host disease after HLA-haploidentical stem cell transplantation using reduced-intensity conditioning

In the present study, we analyzed the kinetics of serum soluble interleukin-2 receptor (sIL-2R) using data from 77 patients undergoing HLA-haploidentical transplantation using reduced-intensity conditioning (RIC), who were at an advanced stage or at high risk for relapse, to clarify the usefulness of sIL-2R as a biomarker of acute graft-versus-host disease (GVHD). Anti-T-lymphocyte globulin and methylprednisolone were used as GVHD prophylaxis. While the median sIL-2R in 38 patients not developing GVHD was suppressed at levels <740 U/ml, sIL-2R in 25 patients developing severe GVHD peaked on day 11 (1,663 U/ml), and thereafter decreased to <1,000 U/ml after day 30. The occurrence of GVHD was not limited to times of high sIL-2R level, but occurred at any time point on the sIL-2R curve. Most patients developing GVHD, however, experienced a higher sIL-2R level early in their transplant course. The combination of RIC and glucocorticoids sufficiently suppressed sIL-2R levels after HLA-haploidentical transplantation. In a multivariate analysis to identify factors associated with GVHD, day 7 sIL-2R >810 U/ml was the only factor significantly associated with the occurrence of severe GVHD (p = 0.0101).