Gene expression profiling is proving to be a powerful approach for the identification of molecular mechanisms underlying complex cellular functions such as the dynamic early embryonic development. ...The objective of this study was to perform a transcript abundance profiling analysis of bovine early embryonic development in vivo using a bovine developmental array. The molecular description of the first week of life at the mRNA level is particularly challenging when considering the important fluctuations in RNA content that occur between developmental stages. Accounting for the different intrinsic RNA content between developmental stages was achieved by restricting the reaction time during the global amplification steps and by using spiked controls and reference samples. Analysis based on intensity values revealed that most of the transcripts on the array were present at some point during in vivo bovine early embryonic development, while the varying number of genes detected in each developmental stage confirmed the dynamic profile of gene expression occurring during embryonic development. Pair-wise comparison of gene expression showed a marked difference between oocytes and blastocysts profiles, and principal component analysis revealed that the majority of the transcripts could be regrouped into three main clusters representing distinct RNA abundance profiles. Overall, these data provide a detailed temporal profile of the abundance of mRNAs revealing the richness of signaling processes in early mammalian development. Results presented here provide better knowledge of bovine in vivo embryonic development and contribute to the progression of our current knowledge regarding the first week of life in mammals.
Several lines of evidence suggest the involvement of neuroinflammatory changes in Alzheimer's disease (AD) pathophysiology such as amyloidosis and neurodegeneration. In fact, genome-wide association ...studies (GWAS) have shown a link between genes involved in neuroinflammation and AD. In order to further investigate whether interactions between candidate genetic variances coding for neuroinflammatory molecules are associated with brain amyloid β (Aβ) fibrillary accumulation, we conducted an epistasis analysis on a pool of genes associated with molecular mediators of inflammation.
(18)FFlorbetapir positron emission tomography (PET) imaging was employed to assess brain Aβ levels in 417 participants from ADNI-GO/2 and posteriorly 174 from ADNI-1. IL-1β, IL4, IL6, IL6r, IL10, IL12, IL18, C5, and C9 genes were chosen based on previous studies conducted in AD patients. Using the (18)Fflorbetapir standardized uptake value ratio (SUVR) as a quantitative measure of fibrillary Aβ, epistasis analyses were performed between two sets of markers of immune-related genes using gender, diagnosis, and apolipoprotein E (APOE) as covariates. Voxel-based analyses were also conducted. The results were corrected for multiple comparison tests. Cerebrospinal fluid (CSF) Aβ1-42/phosphorylated tau (p-tau) ratio concentrations were used to confirm such associations.
Epistasis analysis unveiled two significant single nucleotide polymorphism (SNP)-SNP interactions (false discovery rate (FDR) threshold 0.1), both interactions between C9 gene (rs261752) and IL6r gene (rs4240872, rs7514452). In a combined sample, the interactions were confirmed (p ≤ 10-5) and associated with amyloid accumulation within cognitively normal and AD spectrum groups. Voxel-based analysis corroborated initial findings. CSF biomarker (Aβ1-42/p-tau) confirmed the genetic interaction. Additionally, rs4240872 and rs7514452 SNPs were shown to be associated with CSF and plasma concentrations of IL6r protein.
Certain allele combinations involving IL6r and C9 genes are associated with Aβ burden in the brain. Hypothesis-driven search for epistasis is a valuable strategy for investigating imaging endophenotypes in complex neurodegenerative diseases.
Motivated by a DNA methylation application, this article addresses the problem of fitting and inferring a multivariate binomial regression model for outcomes that are contaminated by errors and ...exhibit extra‐parametric variations, also known as dispersion. While dispersion in univariate binomial regression has been extensively studied, addressing dispersion in the context of multivariate outcomes remains a complex and relatively unexplored task. The complexity arises from a noteworthy data characteristic observed in our motivating dataset: non‐constant yet correlated dispersion across outcomes. To address this challenge and account for possible measurement error, we propose a novel hierarchical quasi‐binomial varying coefficient mixed model, which enables flexible dispersion patterns through a combination of additive and multiplicative dispersion components. To maximize the Laplace‐approximated quasi‐likelihood of our model, we further develop a specialized two‐stage expectation‐maximization (EM) algorithm, where a plug‐in estimate for the multiplicative scale parameter enhances the speed and stability of the EM iterations. Simulations demonstrated that our approach yields accurate inference for smooth covariate effects and exhibits excellent power in detecting non‐zero effects. Additionally, we applied our proposed method to investigate the association between DNA methylation, measured across the genome through targeted custom capture sequencing of whole blood, and levels of anti‐citrullinated protein antibodies (ACPA), a preclinical marker for rheumatoid arthritis (RA) risk. Our analysis revealed 23 significant genes that potentially contribute to ACPA‐related differential methylation, highlighting the relevance of cell signaling and collagen metabolism in RA. We implemented our method in the R Bioconductor package called “SOMNiBUS.”
Ranking a group of candidate sites and selecting from it the high-risk locations or hotspots for detailed engineering study and countermeasure evaluation is the first step in a transport safety ...improvement program. Past studies have however mainly focused on the task of applying appropriate methods for ranking locations, with few focusing on the issue of how to define selection methods or threshold rules for hotspot identification. The primary goal of this paper is to introduce a multiple testing-based approach to the problem of selecting hotspots. Following the recent developments in the literature, two testing procedures are studied under a Bayesian framework: Bayesian test with weights (BTW) and a Bayesian test controlling for the posterior false discovery rate (FDR) or false negative rate (FNR). The hypotheses tests are implemented on the basis of two random effect or Bayesian models, namely, the hierarchical Poisson/Gamma or Negative Binomial model and the hierarchical Poisson/Lognormal model. A dataset of highway–railway grade crossings is used as an application example to illustrate the proposed procedures incorporating both the posterior distribution of accident frequency and the posterior distribution of ranks. Results on the effects of various decision parameters used in hotspot identification procedures are discussed.
Gene expression analysis performed through comparative abundance of transcripts is facing a new challenge with the increasing need to compare samples of known cell number, such as early embryos or ...laser microbiopsies, where the RNA contents of identical cellular inputs can by nature be variable. When working with scarce tissues, the success of microarray profiling largely depends on the efficiency of the amplification step as determined by its ability to preserve the relative abundance of transcripts in the resulting amplified sample. Maintaining this initial relative abundance across samples is paramount to the generation of physiologically relevant data when comparing samples of different RNA content. The T7 RNA polymerase (T7-IVT) amplification is widely used for microarray sample preparation. Characterization of the reaction's kinetics has clearly indicated that its true linear phase is of short duration and is followed by a nonlinear phase. This second phase leads to modifications in transcript abundance that biases comparison between samples of different types. The impact assessment performed in this study has shown that the standard amplification protocol significantly lowers the quality of microarray data, rendering more than half of differentially expressed candidates undetected and distorting the true proportional differences of all candidates analyzed.
Several reports have described cortical thickness (CTh) developmental trajectories, with conflicting results. Some studies have reported inverted-U shape curves with peaks of CTh in late childhood to ...adolescence, while others suggested predominant monotonic decline after age 6. In this study, we reviewed CTh developmental trajectories in the NIH MRI Study of Normal Brain Development, and in a second step, evaluated the impact of post-processing quality control (QC) procedures on identified trajectories. The quality-controlled sample included 384 individual subjects with repeated scanning (1–3 per subject, total scans n=753) from 4.9 to 22.3years of age. The best-fit model (cubic, quadratic, or first-order linear) was identified at each vertex using mixed-effects models. The majority of brain regions showed linear monotonic decline of CTh. There were few areas of cubic trajectories, mostly in bilateral temporo-parietal areas and the right prefrontal cortex, in which CTh peaks were at, or prior to, age 8. When controlling for total brain volume, CTh trajectories were even more uniformly linear. The only sex difference was faster thinning of occipital areas in boys compared to girls. The best-fit model for whole brain mean thickness was a monotonic decline of 0.027mm per year. QC procedures had a significant impact on identified trajectories, with a clear shift toward more complex trajectories (i.e., quadratic or cubic) when including all scans without QC (n=954). Trajectories were almost exclusively linear when using only scans that passed the most stringent QC (n=598). The impact of QC probably relates to decreasing the inclusion of scans with CTh underestimation secondary to movement artifacts, which are more common in younger subjects. In summary, our results suggest that CTh follows a simple linear decline in most cortical areas by age 5, and all areas by age 8. This study further supports the crucial importance of implementing post-processing QC in CTh studies of development, aging, and neuropsychiatric disorders.
•Cortical thickness follows mostly a monotonic linear decline after 5years of age.•Areas with cubic developmental trajectories have peaks of cortical thickness prior to age 8.•The only sex difference in maturation is faster occipital thinning in males.•Mean cortical thickness follows a monotonic linear decline of 0.027mm per year.•Quality control processes have a significant impact on identified trajectories.•A post-processing quality control should be applied in all cortical thickness studies.
In this study, the stable isotope ratios of δ13C and δ15N of bridled terns’ (Onychoprion anaethetus) tail feathers were used to investigate changes in the food sources assimilated by the birds on ...Penguin Island, Western Australia, during different phases of the breeding season. Samples were taken immediately after they arrived on the island returning from migration (BM), before egg-laying (BEL), after egg-laying (AEL), after hatching (AH) and from fledglings (F). A one-way MANOVA (excluding the BM phase) and two one-way ANOVAs (including all phases), showed that the δ13C and δ15N values differed significantly between the stages of the breeding season, with the greatest differences between the BM and BEL stages. The mean δ13C values were higher and those for δ15N were lower for BM birds than all other stages, indicating that the food source assimilated by the birds, and their foraging locations, changed during the breeding season. These results support the hypothesis of the Central Place Foraging Theory, i.e. that adult breeding birds adjust their foraging strategies when they are bound to a central place to care for their young. Induced feathers were regenerated over ~70 days and their regrowth rates were similar before and after egg-laying.
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