Analysis of a mechanistic Markov model for gene duplicates evolving under subfunctionalization

Background Gene duplication has been identified as a key process driving functional change in many genomes. Several biological models exist for the evolution of a pair of duplicates after a duplication event, and it is believed that gene duplicates can evolve in different ways, according to one process, or a mix of processes. Subfunctionalization is one such process, under which the two duplicates can be preserved by dividing up the function of the original gene between them. Analysis of genomic data using subfunctionalization and related processes has thus far been relatively coarse-grained, with mathematical treatments usually focusing on the phenomenological features of gene duplicate evolution. Results Here, we develop and analyze a mathematical model using the mechanics of subfunctionalization and the assumption of Poisson rates of mutation. By making use of the results from the literature on the Phase-Type distribution, we are able to derive exact analytical results for the model. The main advantage of the mechanistic model is that it leads to testable predictions of the phenomenological behavior (instead of building this behavior into the model a priori), and allows for the estimation of biologically meaningful parameters. We fit the survival function implied by this model to real genome data (Homo sapiens, Mus musculus, Rattus norvegicus and Canis familiaris), and compare the fit against commonly used phenomenological survival functions. We estimate the number of regulatory regions, and rates of mutation (relative to silent site mutation) in the coding and regulatory regions. We find that for the four genomes tested the subfunctionalization model predicts that duplicates most-likely have just a few regulatory regions, and the rate of mutation in the coding region is around 5-10 times greater than the rate in the regulatory regions. This is the first model-based estimate of the number of regulatory regions in duplicates. Conclusions Strong agreement between empirical results and the predictions of our model suggest that subfunctionalization provides a consistent explanation for the evolution of many gene duplicates

Intelligence and memory outcomes within 10 years of childhood convulsive status epilepticus

Long-term intelligence and memory outcomes of children post convulsive status epilepticus (CSE) have not been systematically investigated despite evidence of short-term impairments in CSE. The present study aimed to describe intelligence and memory outcomes in children within 10 years of CSE and identify potential risk factors for adverse outcomes. In this cohort study, children originally identified by the population-based North London Convulsive Status Epilepticus in Childhood Surveillance Study (NLSTEPSS) were prospectively recruited between July 2009 and February 2013 and invited for neuropsychological assessments and magnetic resonance imaging (MRI) scans. Full-scale intelligence quotients (FSIQs) were measured using the Wechsler Abbreviated Scales of Intelligence (WASI), and global memory scores (GMS) was assessed using the Children's Memory Scale (CMS). The cohort was analyzed as a whole and stratified into a prolonged febrile seizures (PFS) and non-PFS group. Their performance was compared with population norms and controls. Regression models were fitted to identify predictors of outcomes. With a mean of 8.9 years post-CSE, 28.5% of eligible participants were unable to undertake testing because of their severe neurodevelopmental deficits. Children with CSE who undertook formal testing (N = 94) were shown to have significantly lower FSIQ (p = 0.001) and GMS (p = 0.025) from controls; the PFS group (N = 34) had lower FSIQs (p = 0.022) but similar memory quotients (p = 0.88) with controls. Intracranial volume (ICV), developmental delay at baseline, and active epilepsy at follow-up were predictive of longterm outcomes in the non-PFS group. The relationship between ICV and outcomes was absent in the PFS group despite its presence in the control and non-PFS groups. Post-CSE, survivors reveal significant intelligence and memory impairments, but prognosis differs by CSE type; memory scores are uncompromised in the PFS group despite evidence of their lower FSIQ whereas both are compromised in the non-PFS group. Correlations between brain volumes and outcomes differ in the PFS, non-PFS, and control groups and require further investigatio

A Cross-Sectional Survey on Knowledge and Perceptions of Health Risks Associated with Arsenic and Mercury Contamination from Artisanal Gold mining in Tanzania.

An estimated 0.5 to 1.5 million informal miners, of whom 30-50% are women, rely on artisanal mining for their livelihood in Tanzania. Mercury, used in the processing gold ore, and arsenic, which is a constituent of some ores, are common occupational exposures that frequently result in widespread environmental contamination. Frequently, the mining activities are conducted haphazardly without regard for environmental, occupational, or community exposure. The primary objective of this study was to assess community risk knowledge and perception of potential mercury and arsenic toxicity and/or exposure from artisanal gold mining in Rwamagasa in northwestern Tanzania. A cross-sectional survey of respondents in five sub-villages in the Rwamagasa Village located in Geita District in northwestern Tanzania near Lake Victoria was conducted. This area has a history of artisanal gold mining and many of the population continue to work as miners. Using a clustered random selection approach for recruitment, a total of 160 individuals over 18 years of age completed a structured interview. The interviews revealed wide variations in knowledge and risk perceptions concerning mercury and arsenic exposure, with 40.6% (n=65) and 89.4% (n=143) not aware of the health effects of mercury and arsenic exposure respectively. Males were significantly more knowledgeable (n=59, 36.9%) than females (n=36, 22.5%) with regard to mercury (x²=3.99, p<0.05). An individual's occupation category was associated with level of knowledge (x²=22.82, p=<0.001). Individuals involved in mining (n=63, 73.2%) were more knowledgeable about the negative health effects of mercury than individuals in other occupations. Of the few individuals (n=17, 10.6%) who knew about arsenic toxicity, the majority (n=10, 58.8%) were miners. The knowledge of individuals living in Rwamagasa, Tanzania, an area with a history of artisanal gold mining, varied widely with regard to the health hazards of mercury and arsenic. In these communities there was limited awareness of the threats to health associated with exposure to mercury and arsenic. This lack of knowledge, combined with minimal environmental monitoring and controlled waste management practices, highlights the need for health education, surveillance, and policy changes

Feasibility of using quadriceps-strengthening exercise to improve pain and sleep in a severely demented elder with osteoarthritis – a case report

BACKGROUND: Osteoarthritis (OA) of the knee, which is prevalent among older adults in nursing homes, causes significant pain and suffering, including disturbance of nocturnal sleep. One nonpharmacologic treatment option is quadriceps-strengthening exercise, however, the feasibility of such a treatment for reducing pain from OA in severely demented elders has not been studied. This report describes our test of the feasibility of such an exercise program, together with its effects on pain and sleep, in a severely demented nursing home resident. CASE PRESENTATION: The subject was an elderly man with severe cognitive impairment (Mini-Mental Status Exam score 4) and knee OA (Kellgren-Lawrence radiographic grade 4). He was enrolled in a 5-week, 10-session standardized progressive-resistance training program to strengthen the quadriceps, and completed all sessions. Pain was assessed with the Western Ontario and MacMaster OA Index (WOMAC) pain subscale, and sleep was assessed by actigraphy. The patient was able to perform the exercises, with a revision to the protocol. However, the WOMAC OA pain subscale proved inadequate for measuring pain in a patient with low cognitive functioning, and therefore the effects on pain were inconclusive. Although his sleep improved after the intervention, the influence of his medications and the amount of daytime sleep on his nighttime sleep need to be considered. CONCLUSIONS: A quadriceps-strengthening exercise program for treating OA of the knee is feasible in severely demented elders, although a better outcome measure is needed for pain

VEGF receptors on PC12 cells mediate transient activation of ERK1/2 and Akt: comparison of nerve growth factor and vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) and endostatin are angiogenic and anti-angiogenic molecules, respectively, that have been implicated in neurogenesis and neuronal survival. Using alkaline phosphatase fusion proteins, we show that the PC12 neuronal cell line contains cell membrane receptors for VEGF but not for endostatin and the collagen XV endostatin homologue. Immunocytochemistry confirmed that proliferating and differentiated PC12 cells express VEGF receptors 1, 2 and neuropilin-1. While no functional effects of VEGF on PC12 cell proliferation and differentiation could be observed, a slight VEGF-induced reduction of caspase-3 activity in differentiated apoptotic PC12 cells was paralleled by transient activation of ERK1/2 and Akt. In direct comparison, nerve growth factor proved to be a strikingly more potent neuroprotective agent than VEGF

A Study of D0 --> K0(S) K0(S) X Decay Channels

Using data from the FOCUS experiment (FNAL-E831), we report on the decay of $D^0$ mesons into final states containing more than one $K^0_S$. We present evidence for two Cabibbo favored decay modes, $D^0\to K^0_SK^0_S K^- \pi^+$ and $D^0\to K^0_SK^0_S K^+ \pi^-$, and measure their combined branching fraction relative to $D^0\to \bar{K} ^0\pi^+\pi^-$ to be $\frac{\Gamma(D^0\to K^0_SK^0_SK^{\pm}\pi^{\mp})}{\Gamma(D^0\to \bar{K} ^0\pi^+\pi^-)}$ = 0.0106 $\pm$ 0.0019 $\pm$ 0.0010. Further, we report new measurements of $\frac{\Gamma(D^0\to K^0_SK^0_SK^0_S)}{\Gamma(D^0\to \bar{K} ^0\pi^+\pi^-)}$ = 0.0179 $\pm$ 0.0027 $\pm$ 0.0026, $\frac{\Gamma(D^0\to K^0\bar{K} ^0)}{\Gamma(D^0\to \bar{K} ^0\pi^+\pi^-)}$ = 0.0144 $\pm$ 0.0032 $\pm$ 0.0016, and $\frac{\Gamma(D^0\to K^0_SK^0_S\pi^+\pi^-)}{\Gamma(D^0\to \bar{K} ^0\pi^+\pi^-)}$ = 0.0208 $\pm$ 0.0035 $\pm$ 0.0021 where the first error is statistical and the second is systematic.Comment: 11 pages, 3 figures, typos correcte