DNA sequence level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders

Psychiatric disorders are a group of genetically related diseases with highly polygenic architectures. Genome-wide association analyses have made substantial progress towards understanding the genetic architecture of these disorders. More recently, exome- and whole-genome sequencing of cases and families have identified rare, high penetrant variants that provide direct functional insight. There remains, however, a gap in the heritability explained by these complementary approaches. To understand how multiple genetic variants combine to modify both severity and penetrance of a highly penetrant variant, we sequenced 48 whole genomes from a family with a high loading of psychiatric disorder linked to a balanced chromosomal translocation. The (1;11)(q42;q14.3) translocation directly disrupts three genes: DISC1, DISC2, DISC1FP and has been linked to multiple brain imaging and neurocognitive outcomes in the family. Using DNA sequence-level linkage analysis, functional annotation and population-based association, we identified common and rare variants in GRM5 (minor allele frequency (MAF) > 0.05), PDE4D (MAF > 0.2) and CNTN5 (MAF < 0.01) that may help explain the individual differences in phenotypic expression in the family. We suggest that whole-genome sequencing in large families will improve the understanding of the combined effects of the rare and common sequence variation underlying psychiatric phenotypes

Ordered and deterministic cancer genome evolution after p53 loss

Although p53 inactivation promotes genomic instability1 and presents a route to malignancy for more than half of all human cancers2,3, the patterns through which heterogenous TP53 (encoding human p53) mutant genomes emerge and influence tumorigenesis remain poorly understood. Here, in a mouse model of pancreatic ductal adenocarcinoma that reports sporadic p53 loss of heterozygosity before cancer onset, we find that malignant properties enabled by p53 inactivation are acquired through a predictable pattern of genome evolution. Single-cell sequencing and in situ genotyping of cells from the point of p53 inactivation through progression to frank cancer reveal that this deterministic behaviour involves four sequential phases-Trp53 (encoding mouse p53) loss of heterozygosity, accumulation of deletions, genome doubling, and the emergence of gains and amplifications-each associated with specific histological stages across the premalignant and malignant spectrum. Despite rampant heterogeneity, the deletion events that follow p53 inactivation target functionally relevant pathways that can shape genomic evolution and remain fixed as homogenous events in diverse malignant populations. Thus, loss of p53-the 'guardian of the genome'-is not merely a gateway to genetic chaos but, rather, can enable deterministic patterns of genome evolution that may point to new strategies for the treatment of TP53-mutant tumours

Different Aspects of Cavitation Damages in Some Stainless Steels

Cavitation is an important factor in many areas of science and engineering, including acoustics, chemistry and hydraulics. In this paper the authors analyze the manner of cavitation damages in different samples of stainless steels. Cavitation destruction was performed in a magnetostrictive vibrating apparatus in Laboratory of Polytechnic University of Timisoara, Romania. Cavitation erosion behaviour was appreciated considering macrostructural analysis (both quantitative and qualitative) made at stereomicroscope type OLYMPUS equipped with QuickMicrophoto 2.2 software and structural analysis at scaning electron microscope (SEM) at Philips SEM microscope. Finally conclusions regarding specific structural features of cavitation at stainless steels were revealed

Structural Analysis of Cavitation for Different Stainless Steels

The cavitation phenomenon is currently approaching all areas of technology and modern industry, where are fluid in motion. In this paper cavitational erosion was conducted on different samples of stainless steels. The cavitation were performed in magnetostrictive vibrating apparatus at Cavitation Laboratory (Polytechnic University of Timisoara). The present paper intends to identify specific structural features in stainless steels. Several investigations were done: macrostructural analysis (Olympus SZX57), scaning electron microscope (Philips SEM) and X-ray diffraction (D8 ADVANCE). After quantitative and qualitative investigations structural features were put in evidence on experimental stainless steels