Different molecular mechanisms causing 9p21 deletions in acute lymphoblastic leukemia of childhood

Deletion of chromosome 9p21 is a crucial event for the development of several cancers including acute lymphoblastic leukemia (ALL). Double strand breaks (DSBs) triggering 9p21 deletions in ALL have been reported to occur at a few defined sites by illegitimate action of the V(D)J recombination activating protein complex. We have cloned 23 breakpoint junctions for a total of 46 breakpoints in 17 childhood ALL (9 B- and 8 T-lineages) showing different size deletions at one or both homologous chromosomes 9 to investigate which particular sequences make the region susceptible to interstitial deletion. We found that half of 9p21 deletion breakpoints were mediated by ectopic V(D)J recombination mechanisms whereas the remaining half were associated to repeated sequences, including some with potential for non-B DNA structure formation. Other mechanisms, such as microhomology-mediated repair, that are common in other cancers, play only a very minor role in ALL. Nucleotide insertions at breakpoint junctions and microinversions flanking the breakpoints have been detected at 20/23 and 2/23 breakpoint junctions, respectively, both in the presence of recombination signal sequence (RSS)-like sequences and of other unspecific sequences. The majority of breakpoints were unique except for two cases, both T-ALL, showing identical deletions. Four of the 46 breakpoints coincide with those reported in other cases, thus confirming the presence of recurrent deletion hotspots. Among the six cases with heterozygous 9p deletions, we found that the remaining CDKN2A and CDKN2B alleles were hypermethylated at CpG islands

Host Genetic Background Strongly Influences the Response to Influenza A Virus Infections

The genetic make-up of the host has a major influence on its response to combat pathogens. For influenza A virus, several single gene mutations have been described which contribute to survival, the immune response and clearance of the pathogen by the host organism. Here, we have studied the influence of the genetic background to influenza A H1N1 (PR8) and H7N7 (SC35M) viruses. The seven inbred laboratory strains of mice analyzed exhibited different weight loss kinetics and survival rates after infection with PR8. Two strains in particular, DBA/2J and A/J, showed very high susceptibility to viral infections compared to all other strains. The LD50 to the influenza virus PR8 in DBA/2J mice was more than 1000-fold lower than in C57BL/6J mice. High susceptibility in DBA/2J mice was also observed after infection with influenza strain SC35M. In addition, infected DBA/2J mice showed a higher viral load in their lungs, elevated expression of cytokines and chemokines, and a more severe and extended lung pathology compared to infected C57BL/6J mice. These findings indicate a major contribution of the genetic background of the host to influenza A virus infections. The overall response in highly susceptible DBA/2J mice resembled the pathology described for infections with the highly virulent influenza H1N1-1918 and newly emerged H5N1 viruses

Competitive Tendering In The Netherlands: Central Planning Or Functional Specifications?

Institute of Transport and Logistics Studies. Faculty of Economics and Business. The University of Sydne

Vernetzung in Altenarbeit und Altenpolitik Probleme und Perspektiven in der neuen Bundesrepublik

UuStB Koeln(38)-14A2694 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Influence of Dynamic Field of View Restrictions on Rotation Gain Perception in Virtual Environments

International audienceThe perception of rotation gain, defined as a modification of the virtual rotation with respect to the real rotation, has been widely studied to determine detection thresholds and widely applied to redirected navigation techniques. In contrast, Field of View (FoV) restrictions have been explored in virtual reality as a mitigation strategy for motion sickness, although they can alter user's perception and navigation performance in virtual environments. This paper explores whether the use of dynamic FoV manipulations, referred also as vignetting, could alter the perception of rotation gains during virtual rotations in virtual environments (VEs). We conducted a study to estimate and compare perceptual thresholds of rotation gains while varying the vignetting type (no vignetting, horizontal and global vignetting) and the vignetting effect (luminance or blur). 24 Participants performed 60 or 90 degrees virtual rotations in a virtual forest, with different rotation gains applied. Participants have to choose whether or not the virtual rotation was greater than the physical one. Results showed that the point of subjective equality was different across the vignetting types, but not across the vignetting effect or the turns. Subjective questionnaires indicated that vignetting seems less comfortable than the baseline condition to perform the task. We discuss the applications of such results to improve the design of vignetting for redirection techniques