Functional analysis of the mismatch repair system in bladder cancer

In bladder cancer the observed microsatellite instability indicates that mismatch repair deficiency could be a frequently involved factor in bladder cancer progression. To investigate this hypothesis we analysed extracts of seven bladder cancer cell lines and, as a novel approach, five clinical cancer samples for mismatch repair activity. We found that one cell line (T24) and three of the clinical samples had a reduced repair capacity, measured to ~20% or less. The T24 cell extract was unable to repair a G-G mismatch and showed reduced repair of a 2-base loop, consistent with diminished function of the MSH2-MSH6 heterodimer. The functional assay was combined with measurement for mutation frequency, microsatellite analysis, sequencing, MTT assay, immunohistochemical analysis and RT-PCR analysis of the mismatch repair genes MSH2, MSH3, MSH6, PMS1, PMS2 and MLH1. A >7-fold relative increase in mutation frequency was observed for T24 compared to a bladder cancer cell line with a fully functional mismatch repair system. Neither microsatellite instability, loss of repair nor mismatch repair gene mutations were detected. However, RT-PCR analysis of mRNA levels did detect changes in the ratio of expression of the Mut S and Mut L homologues. The T24 cell line had the lowest MSH6 expression level of the cell lines tested. Identical RT-PCR analysis of seventeen clinical samples (normal urothelium, 7; pTa low stage, 5; and pT1-4 high stage, 5) indicated a significant change in the expression ratio between MSH3/MSH6 (P< 0.004), MSH2/MSH3 (P< 0.012) and PMS2/MLH1 P< 0.005, in high stage bladder tumours compared to normal urothelium and low stage tumours. Collectively, the data suggest that imbalanced expression of mismatch repair genes could lead to partial loss of mismatch repair activity that is associated with invasive bladder cancer. © 2001 Cancer Research Campaign http://www.bjcancer.co

Study of charge state of polarization domain walls in organic ferroelectric 2-methylbenzimidazole crystals

The work is supported by the RFBR grant № 16-02-00399

Re-entrant Layer-by-Layer Etching of GaAs(001)

We report the first observation of re-entrant layer-by-layer etching based on {\it in situ\/} reflection high-energy electron-diffraction measurements. With AsBr$_3$ used to etch GaAs(001), sustained specular-beam intensity oscillations are seen at high substrate temperatures, a decaying intensity with no oscillations at intermediate temperatures, but oscillations reappearing at still lower temperatures. Simulations of an atomistic model for the etching kinetics reproduce the temperature ranges of these three regimes and support an interpretation of the origin of this phenomenon as the site-selectivity of the etching process combined with activation barriers to interlayer adatom migration.Comment: 11 pages, REVTeX 3.0. Physical Review Letters, in press

Progressive multifocal leukoencephalopathy in a multiple Sclerosis patient diagnosed after switching from natalizumab to fingolimod

Background: Natalizumab- (NTZ-) associated progressive multifocal leukoencephalopathy (PML) is a severe and often disabling infectious central nervous system disease that can become evident in multiple sclerosis (MS) patients after NTZ discontinuation. Recently, novel diagnostic biomarkers for the assessment of PML risk in NTZ treated MS patients such as the anti-JC virus antibody index have been reported, and the clinical relevance of milky-way lesions detectable by MRI has been discussed. Case Presentation and Conclusion: We report a MS patient in whom PML was highly suspected solely based on MRI findings after switching from NTZ to fingolimod despite repeatedly negative (ultrasensitive) polymerase chain reaction (PCR) testing for JC virus DNA in cerebrospinal fluid. The PML diagnosis was histopathologically confirmed by brain biopsy. The occurrence of an immune reconstitution inflammatory syndrome (IRIS) during fingolimod therapy, elevated measures of JCV antibody indices, and the relevance of milky-way-like lesions detectable by (7 T) MRI are discussed

Trend Identification in Twentieth-Century U.S. Snowfall: The Challenges

There is an increasing interest in examining long-term trends in measures of snow climatology. An examination of the U.S. daily snowfall records for 1900–2004 revealed numerous apparent inconsistencies. For example, long-term snowfall trends among neighboring lake-effect stations differ greatly from insignificant to +100% century -1. Internal inconsistencies in the snow records, such as a lack of upward trends in maximum seasonal snow depth at stations with large upward trends in snowfall, point to inhomogeneities. Nationwide, the frequency of daily observations with a 10:1 snowfall-to-liquid-equivalent ratio declined from 30% in the 1930s to a current value of around 10%, a change that is clearly due to observational practice. There then must be biases in cold-season liquid-equivalent precipitation, or snowfall, or both. An empirical adjustment of snow-event, liquid-equivalent precipitation indicates that the potential biases can be statistically significant. Examples from this study show that there are nonclimatic issues that complicate the identification of and significantly change the trends in snow variables. Thus, great care should be taken in interpretation of time series of snow-related variables from the Cooperative Observer Program (COOP) network. Furthermore, full documentation of optional practices should be required of network observers so that future users of these data can properly account for such practices

Chapter 8: Droughts, Floods, and Wildfires

Recent droughts and associated heat waves have reached record intensity in some regions of the United States; however, by geographical scale and duration, the Dust Bowl era of the 1930s remains the benchmark drought and extreme heat event in the historical record (very high confidence). While by some measures drought has decreased over much of the continental United States in association with long-term increases in precipitation, neither the precipitation increases nor inferred drought decreases have been confidently attributed to anthropogenic forcing. The human effect on recent major U.S. droughts is complicated. Little evidence is found for a human influence on observed precipitation deficits, but much evidence is found for a human influence on surface soil moisture deficits due to increased evapotranspiration caused by higher temperatures. Future decreases in surface (top 10 cm) soil moisture from anthropogenic forcing over most of the United States are likely as the climate warms under higher scenarios. Substantial reductions in western U.S. winter and spring snowpack are projected as the climate warms. Earlier spring melt and reduced snow water equivalent have been formally attributed to human-induced warming (high confidence) and will very likely be exacerbated as the climate continues to warm (very high confidence). Under higher scenarios, and assuming no change to current water resources management, chronic, long-duration hydrological drought is increasingly possible by the end of this century. Detectable changes in some classes of flood frequency have occurred in parts of the United States and are a mix of increases and decreases. Extreme precipitation, one of the controlling factors in flood statistics, is observed to have generally increased and is projected to continue to do so across the United States in a warming atmosphere. However, formal attribution approaches have not established a significant connection of increased riverine flooding to human-induced climate change, and the timing of any emergence of a future detectable anthropogenic change in flooding is unclear. The incidence of large forest fires in the western United States and Alaska has increased since the early 1980s and is projected to further increase in those regions as the climate warms, with profound changes to certain ecosystems

Selective substitution in orbital domains of a low doped manganite : an investigation from Griffiths phenomenon and modification of glassy features

An effort is made to study the contrast in magnetic behavior resulting from minimal disorder introduced by substitution of 2.5% Ga or Al in Mn-site of La${_{0.9}}$Sr$_{0.1}$MnO${_3}$. It is considered that Ga or Al selectively creates disorder within the orbital domains or on its walls, causing enhancement of Griffiths phase (GP) singularity for the former and disappearance of it in the later case. It is shown that Ga replaces Mn$^{3+}$ which is considered to be concentrated within the domains, whereas Al replaces Mn$^{4+}$ which is segregated on the hole-rich walls, without causing any significant effect on structure or ferromagnetic transition temperatures. Thus, it is presumed that the effect of disorder created by Ga extend across the bulk of the domain having correlation over similar length-scale resulting in enhancement of GP phenomenon. On the contrary, effect of disorder created by Al remains restricted to the walls resulting in the modification of the dynamics arising from the domain walls and suppresses the GP. Moreover contrasting features are observed in the low temperature region of the compounds; a re-entrant spin glass like behavior is observed in the Ga doped sample, while the observed characteristics for the Al doped sample is ascribed only to modified domain wall dynamics with the absence of any glassy phase. Distinctive features in third order susceptibility measurements reveals that the magnetic ground state of the entire series comprises of orbital domain states. These observations bring out the role of the nature of disorder on GP phenomenon and also reconfirms the character of self-organization in low-doped manganites

Dark Matter and the Chemical Evolution of Irregular Galaxies

We present three types of chemical evolution models for irregular galaxies: closed-box with continuous star formation rates (SFRs), closed-box with bursting SFRs, and O-rich outflow with continuous SFRs. We discuss the chemical evolution of the irregular galaxies NGC 1560 and II Zw 33, and a ``typical'' irregular galaxy. The fraction of low-mass stars needed by our models is larger than that derived for the solar vicinity, but similar to that found in globular clusters. For our typical irregular galaxy we need a mass fraction of about 40% in the form of substellar objects plus non baryonic dark matter inside the Holmberg radius, in good agreement with the results derived for NGC 1560 and II Zw 33 where we do have an independent estimate of the mass fraction in non baryonic dark matter. Closed-box models are better than O-rich outflow models in explaining the C/O and Z/O observed values for our typical irregular galaxy.Comment: 14 pages, 2 figure, uses emulateapj.sty package. ApJ in press. New models were added. The order of Tables has been correcte