Calpain-mediated degradation of p35 to p25 in postmortem human and rat brains

AbstractTau in Alzheimer neurofibrillary tangles has been shown to be hyperphosphorylated and CDK5, GSK3, MAP kinase and SAP kinases are the candidate kinases for the phosphorylation of tau. Recently, it was reported that the conversion of p35, the activator of CDK5, to p25 was upregulated in Alzheimer’s disease (AD) brains, and that p35 is cleaved to yield p25 by calpain. Here we show that p35 is rapidly cleaved to p25 in rat and human brains within a short postmortem delay and that the conversion of p35 to p25 is partially dependent on calpain activity. Immunoblot analysis of brains prepared from patients with AD or age-matched control individuals with a short postmortem delay revealed no specific increase in the levels of p25 in AD brains, whereas the levels of active form of calpain were increased in AD brains compared to the those in controls. These observations suggest that the conversion of p35 to p25 is a postmortem degradation event and may not be upregulated in AD brains

Correlation effects during liquid infiltration into hydrophobic nanoporous mediums

Correlation effects arising during liquid infiltration into hydrophobic porous medium are considered. On the basis of these effects a mechanism of energy absorption at filling porous medium by nonwetting liquid is suggested. In accordance with this mechanism, the absorption of mechanical energy is a result expenditure of energy for the formation of menisci in the pores on the shell of the infinite cluster and expenditure of energy for the formation of liquid-porous medium interface in the pores belonging to the infinite cluster of filled pores. It was found that in dependences on the porosity and, consequently, in dependences on the number of filled pores neighbors, the thermal effect of filling can be either positive or negative and the cycle of infiltration-defiltration can be closed with full outflow of liquid. It can occur under certain relation between percolation properties of porous medium and the energy characteristics of the liquid-porous medium interface and the liquid-gas interface. It is shown that a consecutive account of these correlation effects and percolation properties of the pores space during infiltration allow to describe all experimental data under discussion

Factors affecting the mesothelioma detection rate within national and international epidemiological studies: insights from Scottish linked cancer registry-mortality data

ICD-9 code 163 (malignant neoplasm of pleura) listed as underlying cause of death detected only 40% of Scottish mesothelioma cases (all body sites) from the cancer registry in 1981–1999. This is lower than both the previously published 55% figure, derived from UK mesothelioma register data 1986–1991, which is based on any mention of mesothelioma on death certificates, cross-referenced to cancer registry data, and the 44% figure derived from Scottish mortality data 1981–1999, which captured any mention of mesothelioma on the death certificate. Detection from cancer registry data increased to 75% under ICD-10 in Scotland, confirming earlier predictions of the benefit of ICD-10's more specific mesothelioma codes. Including the accidental poisoning codes E866.4 (ICD-9) and X49 (ICD-10), covering poisoning by ‘unspecified' and ‘other' causes, which appear to have been used as coding surrogates for mesothelioma when asbestos exposure was explicitly mentioned in deaths suggestive of a mesothelioma, and which are recorded as the underlying cause of death in 4–7% of mesotheliomas, may improve the mesothelioma detection rate in future epidemiological studies

Occupational, domestic and environmental mesothelioma risks in the British population: a case–control study

We obtained lifetime occupational and residential histories by telephone interview with 622 mesothelioma patients (512 men, 110 women) and 1420 population controls. Odds ratios (ORs) were converted to lifetime risk (LR) estimates for Britons born in the 1940s. Male ORs (95% confidence interval (CI)) relative to low-risk occupations for >10 years of exposure before the age of 30 years were 50.0 (25.8–96.8) for carpenters (LR 1 in 17), 17.1 (10.3–28.3) for plumbers, electricians and painters, 7.0 (3.2–15.2) for other construction workers, 15.3 (9.0–26.2) for other recognised high-risk occupations and 5.2 (3.1–8.5) in other industries where asbestos may be encountered. The LR was similar in apparently unexposed men and women (∼1 in 1000), and this was approximately doubled in exposed workers' relatives (OR 2.0, 95% CI 1.3–3.2). No other environmental hazards were identified. In all, 14% of male and 62% of female cases were not attributable to occupational or domestic asbestos exposure. Approximately half of the male cases were construction workers, and only four had worked for more than 5 years in asbestos product manufacture

P301S Mutant Human Tau Transgenic Mice Manifest Early Symptoms of Human Tauopathies with Dementia and Altered Sensorimotor Gating

Tauopathies are neurodegenerative disorders characterized by the accumulation of abnormal tau protein leading to cognitive and/or motor dysfunction. To understand the relationship between tau pathology and behavioral impairments, we comprehensively assessed behavioral abnormalities in a mouse tauopathy model expressing the human P301S mutant tau protein in the early stage of disease to detect its initial neurological manifestations. Behavioral abnormalities, shown by open field test, elevated plus-maze test, hot plate test, Y-maze test, Barnes maze test, Morris water maze test, and/or contextual fear conditioning test, recapitulated the neurological deficits of human tauopathies with dementia. Furthermore, we discovered that prepulse inhibition (PPI), a marker of sensorimotor gating, was enhanced in these animals concomitantly with initial neuropathological changes in associated brain regions. This finding provides evidence that our tauopathy mouse model displays neurofunctional abnormalities in prodromal stages of disease, since enhancement of PPI is characteristic of amnestic mild cognitive impairment, a transitional stage between normal aging and dementia such as Alzheimer's disease (AD), in contrast with attenuated PPI in AD patients. Therefore, assessment of sensorimotor gating could be used to detect the earliest manifestations of tauopathies exemplified by prodromal AD, in which abnormal tau protein may play critical roles in the onset of neuronal dysfunctions

Pleural cancer mortality in Spain: time-trends and updating of predictions up to 2020

Background A total of 2,514,346 metric tons (Mt) of asbestos were imported into Spain from 1906 until the ban on asbestos in 2002. Our objective was to study pleural cancer mortality trends as an indicator of mesothelioma mortality and update mortality predictions for the periods 2011–2015 and 2016–2020 in Spain.Methods Log-linear Poisson models were fitted to study the effect of age, period of death and birth cohort (APC) on mortality trends. Change points in cohort- and period-effect curvatures were assessed using segmented regression. Fractional power-link APC models were used to predict mortality until 2020. In addition, an alternative model based on national asbestos consumption figures was also used to perform long-term predictions.Results Pleural cancer deaths increased across the study period, rising from 491 in 1976–1980 to 1,249 in 2006–2010. Predictions for the five-year period 2016–2020 indicated a total of 1,319 pleural cancer deaths (264 deaths/year). Forecasts up to 2020 indicated that this increase would continue, though the age-adjusted rates showed a levelling-off in male mortality from 2001 to 2005, corresponding to the lower risk in post-1960 generations. Among women, rates were lower and the mortality trend was also different, indicating that occupational exposure was possibly the single factor having most influence on pleural cancer mortality.Conclusion The cancer mortality-related consequences of human exposure to asbestos are set to persist and remain in evidence until the last surviving members of the exposed cohorts have disappeared. It can thus be assumed that occupationally-related deaths due to pleural mesothelioma will continue to occur in Spain until at least 2040.The study was partially supported by a research grant from the Spanish Health Research Fund (FIS PI11/00871) and the HAR2009-07543 project of the Ministry of Science and Innovation. The Department of Labour of the Government of Catalonia provided the asbestos consumption data

Alzheimer's Aβ Peptides with Disease-Associated N-Terminal Modifications: Influence of Isomerisation, Truncation and Mutation on Cu2+ Coordination

coordination of various Aβ peptides has been widely studied. A number of disease-associated modifications involving the first 3 residues are known, including isomerisation, mutation, truncation and cyclisation, but are yet to be characterised in detail. In particular, Aβ in plaques contain a significant amount of truncated pyroglutamate species, which appear to correlate with disease progression. coordination modes between pH 6–9 with nominally the same first coordination sphere, but with a dramatically different pH dependence arising from differences in H-bonding interactions at the N-terminus. coordination of Aβ, which may be critical for alterations in aggregation propensity, redox-activity, resistance to degradation and the generation of the Aβ3–× (× = 40/42) precursor of disease-associated Aβ3[pE]–x species

The links between health-related behaviors and life satisfaction in elderly individuals who prefer institutional living

BACKGROUND: Life satisfaction among residents of institutions is becoming an important issue in a rapidly aging population. The aim of this cross-sectional study was to investigate the links between life satisfaction and health-related behaviors amongst functionally independent elderly people who prefer institutional living in İstanbul, Turkey. METHODS: The socio-demographic characteristics, health-related behaviors, leisure-time activities and fall histories of 133 residents of an institution in Istanbul were assessed by a structured questionnaire during face-to-face interviews. A validated life-satisfaction index questionnaire (LSI-A) was completed. RESULTS: The mean age of the study group was 73.9 ± 8.0 (range 60–90 years). Within the group, 22.6% had never married and 14.3% had university degrees. The majority (71.4%) were in the low income bracket. The overall mean LSI-A score was 20.3 ± 5.9. Participants who declared moderate/high income levels had a significantly higher mean LSI-A score than those in the low-income bracket (p = 0.009). Multivariate analysis of the data suggested that leisure-time activities and participation in regular physical activities are significant predictors of LSI-A scores (R(2): 0.112; p = 0.005 and p = 0.02, respectively). CONCLUSION: The findings imply that regular physical activity and leisure-time activities are significantly related to life satisfaction among residents in institutions. Participation in physical activity and leisure-time activity programs may help to improve the life satisfaction of elderly people living in institutions