Metabolism, Genomics, and DNA Repair in the Mouse Aging Liver

The liver plays a pivotal role in the metabolism of nutrients, drugs, hormones, and metabolic waste products, thereby maintaining body homeostasis. The liver undergoes substantial changes in structure and function within old age. Such changes are associated with significant impairment of many hepatic metabolic and detoxification activities, with implications for systemic aging and age-related disease. It has become clear, using rodent models as biological tools, that genetic instability in the form of gross DNA rearrangements or point mutations accumulate in the liver with age. DNA lesions, such as oxidized bases or persistent breaks, increase with age and correlate well with the presence of senescent hepatocytes. The level of DNA damage and/or mutation can be affected by changes in carcinogen activation, decreased ability to repair DNA, or a combination of these factors. This paper covers some of the DNA repair pathways affecting liver homeostasis with age using rodents as model systems

An Ab Initio Approach to the Solar Coronal Heating Problem

We present an ab initio approach to the solar coronal heating problem by modelling a small part of the solar corona in a computational box using a 3D MHD code including realistic physics. The observed solar granular velocity pattern and its amplitude and vorticity power spectra, as reproduced by a weighted Voronoi tessellation method, are used as a boundary condition that generates a Poynting flux in the presence of a magnetic field. The initial magnetic field is a potential extrapolation of a SOHO/MDI high resolution magnetogram, and a standard stratified atmosphere is used as a thermal initial condition. Except for the chromospheric temperature structure, which is kept fixed, the initial conditions are quickly forgotten because the included Spitzer conductivity and radiative cooling function have typical timescales much shorter than the time span of the simulation. After a short initial start up period, the magnetic field is able to dissipate 3-4 10^6 ergs cm^{-2} s^{-1} in a highly intermittent corona, maintaining an average temperature of $\sim 10^6$ K, at coronal density values for which emulated images of the Transition Region And Coronal Explorer(TRACE) 171 and 195 pass bands reproduce observed photon count rates.Comment: 12 pages, 14 figures. Submitted to Ap

Does biological maturity actually confound gender-related differences in physical activity in preadolescence?

Aim To examine: (i) if maturity-related gender differences in moderate-to-vigorous physical activity (MVPA) depend on how maturity status is defined and measured; and (ii) the influence of maturity level on compliance with PA recommendations. Methods The study involved 253 children (139 boys) aged 9.9 ± 0.9 years, with mean stature and weight of 1.39 ± 0.08 m and 35.8 ± 8.8 kg respectively. Their PA was evaluated using an Actigraph accelerometer (Model 7164). Maturity was assessed using the estimated age at peak height velocity (APHV) and a standardized APHV by gender (i.e. centred APHV). Results Boys engaged in significantly more MVPA than girls (P < 0.0001). There was a significant correlation between the centred APHV and MVPA in boys (r = 0.20; P = 0.016), but not in girls (r = 0.13; P = 0.155). An ancova controlling for the estimated APHV showed no significant interactions between gender and APHV, and the main effect of gender on MVPA was negated. Conversely, there was a significant main effect of APHV on MVPA (F 1,249 = 6.12; P = 0.014; η p 2 = 0.024). Only 9.1% of children met the PA recommendations, including 14.4% of boys and 2.6% of girls (P < 0.01). This observation also applies in both pre-APHV (12.7% of boys vs. 2.4% of girls, P < 0.001) and post-APHV children (23.8% of boys vs. 3.4% of girls, P < 0.0001). No differences in PA guidelines were observed between pre-APHV and post-APHV children. Conclusions Among prepubescent children, the influence of biological maturity on gender differences in PA may be a function of how maturity status is determined. The most physically active prepubescent children were those who were on time according to APHV

Termination Casts: A Flexible Approach to Termination with General Recursion

This paper proposes a type-and-effect system called Teqt, which distinguishes terminating terms and total functions from possibly diverging terms and partial functions, for a lambda calculus with general recursion and equality types. The central idea is to include a primitive type-form "Terminates t", expressing that term t is terminating; and then allow terms t to be coerced from possibly diverging to total, using a proof of Terminates t. We call such coercions termination casts, and show how to implement terminating recursion using them. For the meta-theory of the system, we describe a translation from Teqt to a logical theory of termination for general recursive, simply typed functions. Every typing judgment of Teqt is translated to a theorem expressing the appropriate termination property of the computational part of the Teqt term.Comment: In Proceedings PAR 2010, arXiv:1012.455

Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment

Oxidative stress is thought to play a role in the pathogenesis of Alzheimer's disease (AD) and increased oxidative DNA damage has been observed in brain tissue from AD patients. Base excision repair (BER) is the primary DNA repair pathway for small base modifications such as alkylation, deamination and oxidation. In this study, we have investigated alterations in the BER capacity in brains of AD patients. We employed a set of functional assays to measure BER activities in brain tissue from short post-mortem interval autopsies of 10 sporadic AD patients and 10 age-matched controls. BER activities were also measured in brain samples from 9 amnestic mild cognitive impairment (MCI) subjects. We found significant BER deficiencies in brains of AD patients due to limited DNA base damage processing by DNA glycosylases and reduced DNA synthesis capacity by DNA polymerase β. The BER impairment was not restricted to damaged brain regions and was also detected in the brains of amnestic MCI patients, where it correlated with the abundance of neurofibrillary tangles. These findings suggest that BER dysfunction is a general feature of AD brains which could occur at the earliest stages of the disease. The results support the hypothesis that defective BER may play an important role in the progression of AD

Step-Indexed Normalization for a Language with General Recursion

The Trellys project has produced several designs for practical dependently typed languages. These languages are broken into two fragments-a_logical_fragment where every term normalizes and which is consistent when interpreted as a logic, and a_programmatic_fragment with general recursion and other convenient but unsound features. In this paper, we present a small example language in this style. Our design allows the programmer to explicitly mention and pass information between the two fragments. We show that this feature substantially complicates the metatheory and present a new technique, combining the traditional Girard-Tait method with step-indexed logical relations, which we use to show normalization for the logical fragment.Comment: In Proceedings MSFP 2012, arXiv:1202.240

Equality, Quasi-Implicit Products, and Large Eliminations

This paper presents a type theory with a form of equality reflection: provable equalities can be used to coerce the type of a term. Coercions and other annotations, including implicit arguments, are dropped during reduction of terms. We develop the metatheory for an undecidable version of the system with unannotated terms. We then devise a decidable system with annotated terms, justified in terms of the unannotated system. Finally, we show how the approach can be extended to account for large eliminations, using what we call quasi-implicit products.Comment: In Proceedings ITRS 2010, arXiv:1101.410

The predictive effect of fear-avoidance beliefs on low back pain among newly qualified health care workers with and without previous low back pain: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Health care workers have a high prevalence of low back pain (LBP). Although physical exposures in the working environment are linked to an increased risk of LBP, it has been suggested that individual coping strategies, for example fear-avoidance beliefs, could also be important in the development and maintenance of LBP. Accordingly, the main objective of this study was to examine (1) the association between physical work load and LBP, (2) the predictive effect of fear-avoidance beliefs on the development of LBP, and (3) the moderating effect of fear-avoidance beliefs on the association between physical work load and LBP among cases with and without previous LBP.</p> <p>Methods</p> <p>A questionnaire survey among 5696 newly qualified health care workers who completed a baseline questionnaire shortly before completing their education and a follow-up questionnaire 12 months later. Participants were selected on the following criteria: (a) being female, (b) working in the health care sector (n = 2677). Multinomial logistic regression analysis was used to evaluate the effect of physical work load and fear-avoidance beliefs on the severity of LBP.</p> <p>Results</p> <p>For those with previous LBP, physical work load has an importance, but not among those without previous LBP. In relation to fear-avoidance beliefs, there is a positive relation between it and LBP of than 30 days in both groups, i.e. those without and with previous LBP. No moderating effect of fear-avoidance beliefs on the association between physical work load and LBP was found among cases with and without LBP.</p> <p>Conclusion</p> <p>Both physical work load and fear-avoidance beliefs matters in those with previous LBP. Only fear-avoidance beliefs matters in those without previous LBP. The study did not find a moderating effect of fear-avoidance beliefs on the association between physical work load and LBP.</p