MLML2R: an R package for maximum likelihood estimation of DNA methylation and hydroxymethylation proportions.

Accurately measuring epigenetic marks such as 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) at the single-nucleotide level, requires combining data from DNA processing methods including traditional (BS), oxidative (oxBS) or Tet-Assisted (TAB) bisulfite conversion. We introduce the R package MLML2R, which provides maximum likelihood estimates (MLE) of 5-mC and 5-hmC proportions. While all other available R packages provide 5-mC and 5-hmC MLEs only for the oxBS+BS combination, MLML2R also provides MLE for TAB combinations. For combinations of any two of the methods, we derived the pool-adjacent-violators algorithm (PAVA) exact constrained MLE in analytical form. For the three methods combination, we implemented both the iterative method by Qu et al. [Qu, J., M. Zhou, Q. Song, E. E. Hong and A. D. Smith (2013): "Mlml: consistent simultaneous estimates of dna methylation and hydroxymethylation," Bioinformatics, 29, 2645-2646.], and also a novel non iterative approximation using Lagrange multipliers. The newly proposed non iterative solutions greatly decrease computational time, common bottlenecks when processing high-throughput data. The MLML2R package is flexible as it takes as input both, preprocessed intensities from Infinium Methylation arrays and counts from Next Generation Sequencing technologies. The MLML2R package is freely available at https://CRAN.R-project.org/package=MLML2R.

Correlation between Mitochondrial Reactive Oxygen and Severity of Atherosclerosis.

Atherosclerosis has been associated with mitochondria dysfunction and damage. Our group demonstrated previously that hypercholesterolemic mice present increased mitochondrial reactive oxygen (mtROS) generation in several tissues and low NADPH/NADP+ ratio. Here, we investigated whether spontaneous atherosclerosis in these mice could be modulated by treatments that replenish or spare mitochondrial NADPH, named citrate supplementation, cholesterol synthesis inhibition, or both treatments simultaneously. Robust statistical analyses in pooled group data were performed in order to explain the variation of atherosclerosis lesion areas as related to the classic atherosclerosis risk factors such as plasma lipids, obesity, and oxidative stress, including liver mtROS. Using three distinct statistical tools (univariate correlation, adjusted correlation, and multiple regression) with increasing levels of stringency, we identified a novel significant association and a model that reliably predicts the extent of atherosclerosis due to variations in mtROS. Thus, results show that atherosclerosis lesion area is positively and independently correlated with liver mtROS production rates. Based on these findings, we propose that modulation of mitochondrial redox state influences the atherosclerosis extent.

Social support of low-income Brazilian mothers related to time to completion of childhood vaccinations.

Our study objective was to examine how maternal social support and depressive symptoms are associated with time to completion of childhood vaccinations. We used cross-sectional data from 582 randomly-selected, low-income Brazilian children. Adjusted Cox Proportional Hazard models were used to estimate time to completing the first three recommended oral polio and diphtheria, pertussis and tetanus (DPT) vaccinations as well as their booster doses. Among only the women with low social support, each ten-point increase on the Medical Outcomes Study - Social Support Scale was associated with a 20% increased chance of completing the first three recommended vaccinations for polio and DPT at any given time (HR = 1.20, 95% CI 1.02-1.42). Although falling short of statistical significance, also among mothers with low social support, we found a suggestive finding of increased social support associated with 25% greater chance of completing polio and DPT booster vaccines at any given time (HR = 1.25, 95% CI 0.98-1.60). There was no association between maternal depressive symptoms and vaccination completion. Among mothers with little social support, increased social support may be important for timely completion of vaccinations in low-income Brazilian children. Longitudinal studies and research on mechanisms explaining associations between maternal social support and childhood vaccination are needed.

Manganese exposure induces microglia activation and dystrophy in the substantia nigra of non-human primates.

Chronic manganese (Mn) exposure produces neurological deficits including a form of parkinsonism that is different from Parkinson's disease (PD). In chronic Mn exposure, dopamine neurons in the substantia nigra (SN) do not degenerate but they appear to be dysfunctional. Further, previous studies have suggested that the substantia nigra pars reticulata (SNr) is affected by Mn. In the present study, we investigated whether chronic Mn exposure induces microglia activation in the substantia nigra pars compacta (SNc) and SNr in Cynomolgus macaques. Animals were exposed to different weekly doses of Mn (3.3-5.0, 5.0-6.7, 8.3-10 mg Mn/kg body weight) and microglia were examined in the substantia nigra using LN3 immunohistochemistry. We observed that in control animals, LN3 labeled microglia were characterized by a resting phenotype. However, in Mn-treated animals, microglia increased in number and displayed reactive changes with increasing Mn exposure. This effect was more prominent in the SNr than in the SNc. In the SNr of animals administered the highest Mn dose, microglia activation was the most advanced and included dystrophic changes. Reactive microglia expressed increased iNOS, L-ferritin, and intracellular ferric iron which were particularly prominent in dystrophic compartments. Our observations indicate that moderate Mn exposure produces structural changes on microglia, which may have significant consequences on their function.

Asymptotic behavior of the scaled mutation rate estimators.

Important aspects of population evolution have been investigated using nucleotide sequences. Under the neutral Wright-Fisher model, the scaled mutation rate represents twice the average number of new mutations per generations and it is one of the key parameters in population genetics. In this study, we present various methods of estimation of this parameter, analytical studies of their asymptotic behavior as well as comparisons of the distribution's behavior of these estimators through simulations. As knowledge of the genealogy is needed to estimate the maximum likelihood estimator (MLE), an application with real data is also presented, using jackknife to correct the bias of the MLE, which can be generated by the estimation of the tree. We proved analytically that the Waterson's estimator and the MLE are asymptotically equivalent with the same rate of convergence to normality. Furthermore, we showed that the MLE has a better rate of convergence than Waterson's estimator for values of the parameter greater than one and this relationship is reversed when the parameter is less than one.