Laser Induced Non-Sequential Double Ionization Investigated at and Below the Threshold for Electron Impact Ionization

We use correlated electron–ion momentum measurements to investigate laserinduced non-sequential double ionization of Ar and Ne. Light intensities are chosen in a regime at and below the threshold where, within the rescattering model, electron impact ionization of the singly charged ion core is expected to become energetically forbidden. Yet we find Ar2+ ion momentum distributions and an electron–electron momentum correlation indicative of direct impactionization. Within the quasistatic model this may be understood by assuming that the electric field of the light wave reduces the ionization potential of the singly charged ion core at the instant of scattering. The width of the projection of the ion momentum distribution onto an axis perpendicular to the light beam polarization vector is found to scalewiththe square root of the peak electric field strength in the light pulse. A scaling like this is not expected from the phase space available after electron impact ionization. It may indicate that the electric field at the instant of scattering is usually different fromzero and determines the transverse momentum distribution. A comparison of our experimental results with several theoretical results is give

Different molecular patterns in glioblastoma multiforme subtypes upon recurrence

One of the hallmarks of glioblastoma is its inherent tendency to recur. At this point patients with relapsed GBM show a survival time of only few months. The molecular basis of the recurrence process in GBM is still poorly understood. The aim of the present study was to investigate the genetic profile of relapsed GBM compared to their respective primary tumors. We have included 20 paired GBMs. In all tumor samples, we have analyzed p53 and PTEN status by sequencing analysis, EGFR amplification by semiquantitative PCR and a wide-genome fingerprinting was performed by microsatellite analysis. Among primary GBM, we observed twelve type 2 GBM, four type 1 GBM and four further GBM showing neither p53 mutations nor EGFR amplification (non-type 1–non-type 2 GBM). Upon recurrence, we have detected two molecular patterns of tumor progression: GBM initially showing either type 1 or type 2 profiles conserved them at the time of relapse. In contrast, non-type 1–non-type 2 GBM acquired the typical pattern of type 2 GBM and harbor EGFR amplification without p53 mutation. New PTEN mutations upon relapse were only detected in type 2 GBM. Additional LOH were more frequently identified in relapses of type 2 GBM than in those showing the type 1 signature. Taken together, our results strongly suggest that recurrences of GBM may display two distinct pattern of accumulation of molecular alterations depending on the profile of the original tumor

Evidence for a Pathogenic Role of Different Mutations at Codon 188 of PRNP

Clinical and pathological changes in familial Creutzfeldt-Jakob disease (CJD) cases may be similar or indistinguishable from sporadic CJD. Therefore determination of novel mutations in PRNP remains of major importance

Early Onset Prion Disease from Octarepeat Expansion Correlates with Copper Binding Properties

Insertional mutations leading to expansion of the octarepeat domain of the prion protein (PrP) are directly linked to prion disease. While normal PrP has four PHGGGWGQ octapeptide segments in its flexible N-terminal domain, expanded forms may have up to nine additional octapeptide inserts. The type of prion disease segregates with the degree of expansion. With up to four extra octarepeats, the average onset age is above 60 years, whereas five to nine extra octarepeats results in an average onset age between 30 and 40 years, a difference of almost three decades. In wild-type PrP, the octarepeat domain takes up copper (Cu2+) and is considered essential for in vivo function. Work from our lab demonstrates that the copper coordination mode depends on the precise ratio of Cu2+ to protein. At low Cu2+ levels, coordination involves histidine side chains from adjacent octarepeats, whereas at high levels each repeat takes up a single copper ion through interactions with the histidine side chain and neighboring backbone amides. Here we use both octarepeat constructs and recombinant PrP to examine how copper coordination modes are influenced by octarepeat expansion. We find that there is little change in affinity or coordination mode populations for octarepeat domains with up to seven segments (three inserts). However, domains with eight or nine total repeats (four or five inserts) become energetically arrested in the multi-histidine coordination mode, as dictated by higher copper uptake capacity and also by increased binding affinity. We next pooled all published cases of human prion disease resulting from octarepeat expansion and find remarkable agreement between the sudden length-dependent change in copper coordination and onset age. Together, these findings suggest that either loss of PrP copper-dependent function or loss of copper-mediated protection against PrP polymerization makes a significant contribution to early onset prion disease

N-Glycans and Glycosylphosphatidylinositol-Anchor Act on Polarized Sorting of Mouse PrPC in Madin-Darby Canine Kidney Cells

The cellular prion protein (PrPC) plays a fundamental role in prion disease. PrPC is a glycosylphosphatidylinositol (GPI)-anchored protein with two variably occupied N-glycosylation sites. In general, GPI-anchor and N-glycosylation direct proteins to apical membranes in polarized cells whereas the majority of mouse PrPC is found in basolateral membranes in polarized Madin-Darby canine kidney (MDCK) cells. In this study we have mutated the first, the second, and both N-glycosylation sites of PrPC and also replaced the GPI-anchor of PrPC by the Thy-1 GPI-anchor in order to investigate the role of these signals in sorting of PrPC in MDCK cells. Cell surface biotinylation experiments and confocal microscopy showed that lack of one N-linked oligosaccharide leads to loss of polarized sorting of PrPC. Exchange of the PrPC GPI-anchor for the one of Thy-1 redirects PrPC to the apical membrane. In conclusion, both N-glycosylation and GPI-anchor act on polarized sorting of PrPC, with the GPI-anchor being dominant over N-glycans

Computational Refinement of Functional Single Nucleotide Polymorphisms Associated with ATM Gene

gene are the most common forms of genetic variations that account for various forms of cancer. However, the extent to which SNPs interferes with the gene regulation and affects cancer susceptibility remains largely unknown. gene. gene function can aid in better understanding of genetic differences in disease susceptibility