The integrity of chromosomes during cell division is ensured by both trans-acting factors and cis-acting chromosomal sites. Failure of either these chromosome integrity determinants (CIDs) can cause chromosomes to be broken and subsequently misrepaired to form gross chromosomal rearrangements (GCRs). We developed a simple and rapid assay for GCRs, exploiting yeast artificial chromosomes (YACs) in Saccharomyces cerevisiae. We used this assay to screen a genome-wide pool of mutants for elevated rates of GCR. The analyses of these mutants define new CIDs (Orc3p, Orc5p, and Ycs4p) and new pathways required for chromosome integrity in DNA replication elongation (Dpb11p), DNA replication initiation (Orc3p and Orc5p), and mitotic condensation (Ycs4p). We show that the chromosome integrity function of Orc5p is associated with its ATP-binding motif and is distinct from its function in controlling the efficiency of initiation of DNA replication. Finally, we used our YAC assay to assess the interplay of trans and cis factors in chromosome integrity. Increasing the number of origins on a YAC suppresses GCR formation in our dpb11 mutant but enhances it in our orc mutants. This result provides potential insights into the counterbalancing selective pressures necessary for the evolution of origin density on chromosomes.

A low-cost second generation single crystal (SC) superalloy, designated DD6, has been developed for aeroengine turbine blade applications. DD6 contains 2 wt. % rhenium, which is about 2/3 of that of the second generation single crystal superalloys such as PWA1484, CMSX-4 and Rene N5. The alloy system employs the relatively high additive refractory element (tungsten molybdenum, tantalum, rhenium and niobium) content of about 19.5 wt. %. A cost reduction of about 25% is expected for this alloy.DD6 alloy has an approximate 40 "C improvement of creep strength relative to the fast generation single crystal superalloys such as DD3, a Chinese first generation single crystal alloy whose creep rupture properties are comparable with PWA1480 alloy. The tensile properties and creep rupture properties of the alloy are comparable to those of the second generation single crystal alloys such as SC180, Rene NS, CMSX-4 and PWA1484. Most notably, the alloy provides superior oxidation resistance and good hot corrosion resistance. The advantage shown in the creep rupture properties over DD3 also generally hold for fatigue properties.DD6 also has good microskucture stability, heat treatment characteristics and environmental properties.Casting trials have been conducted on DD6 involving a great number of bars and some complex shaped hollow turbine blades. These trials demonstrated that DD6 possesses excellent single crystal castability. Table 1 presents the compositions of first, second and third generation single crystal alloys, including DD6 and DD3. A main distinction of the chemical compositions of the fast, second and third generation single crystal superalloys is rhenium-free, 3 wt. % Re and 6 wt. % Re, respectively -. I1 *II The effects of Re on the mechanical properties of single crystal superalloys are very significanf especially in improving the creep rupture life. However, Re is a rare element and the price of Re is very expensive. The aeroengine manufacturers all consider Re as a strategic element. Therefore, the development of low-Re second generation single crystal alloy is important. The goals of the present research were as follows: 1) develop a low cost second generation single crystal alloy, using low Re; 2) maintain the mechanical properties of the alloy at levels equivalent to those of the second generation single crystal alloys, such as SC180, Rene N5, CMSX-4 and PWA1484; 3) design a alloy combining high strengths with good environmental properties, microstructural stability, heat treatment characteristics and castability.A low-cost second gene&ion Single crystal alloy, designated DD6, has been developed by Beijing Institute of Aeronautical Materials for aeroengine blade applications. Based on the study of single crystal superalloys for many years, with the help of the computer aided design of alloy compositions, the contents of tungsten, molybdenum, tantalum, rhenium and alumimun were judiciously balanced with the predominating rhenium requirement. A large number of trials were carried out, and the composition f...

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Birt-Hogg-Dube (BHD) disease is an autosomal dominant cancer syndrome characterized by benign skin tumors, renal cancer and spontaneous pneumothorax and is caused by mutations in the Folliculin (FLCN) gene. Benign skin tumors and pneumothorax occur in the majority of patients affected by BHD syndrome, but only 30-45% of them develop renal cell carcinoma (RCC) with a median age of diagnosis at 48. The earliest onset of RCC in a BHD patient has been reported at age 20. Here we report a case of a 14 year-old patient with germline FLCN mutation leading to an early-onset bulky RCC that could not be classified strictly according to existing histological types. Germline genetic testing revealed a deletion at FLCN exon 5. The father of the patient was identified as the asymptomatic carrier. We report the youngest patient with BHD-related RCC. This early onset presentation supports genetic testing of at-risk patients and initiation of imaging surveillance for RCC in early adolescence. In addition, future studies are necessary to understand the determinants of reduced penetrance in BHD disease.