Hic et Runx: new insights into T cell tissue residency.

Tissue-resident memory T cells (Trm), which typically do not enter the blood or lymphatic circulation at steady-state, are considered crucial for controlling pathogen entry at skin and mucosal barriers. Two recent studies (Fonseca et al. and Crowl et al.) shed light on the mechanisms of Trm cell differentiation.

A Bayesian network approach incorporating imputation of missing data enables exploratory analysis of complex causal biological relationships.

Bayesian networks can be used to identify possible causal relationships between variables based on their conditional dependencies and independencies, which can be particularly useful in complex biological scenarios with many measured variables. Here we propose two improvements to an existing method for Bayesian network analysis, designed to increase the power to detect potential causal relationships between variables (including potentially a mixture of both discrete and continuous variables). Our first improvement relates to the treatment of missing data. When there is missing data, the standard approach is to remove every individual with any missing data before performing analysis. This can be wasteful and undesirable when there are many individuals with missing data, perhaps with only one or a few variables missing. This motivates the use of imputation. We present a new imputation method that uses a version of nearest neighbour imputation, whereby missing data from one individual is replaced with data from another individual, their nearest neighbour. For each individual with missing data, the subsets of variables to be used to select the nearest neighbour are chosen by sampling without replacement the complete data and estimating a best fit Bayesian network. We show that this approach leads to marked improvements in the recall and precision of directed edges in the final network identified, and we illustrate the approach through application to data from a recent study investigating the causal relationship between methylation and gene expression in early inflammatory arthritis patients. We also describe a second improvement in the form of a pseudo-Bayesian approach for upweighting certain network edges, which can be useful when there is prior evidence concerning their directions.

Evolutionary pressures of aerial insectivory reflected in anurognathid pterosaurs.

Across the evolution of powered flight, the ecological niche of aerial insectivore has been occupied by members of the three volant vertebrate clades-Aves and Chiroptera, and the first known volant vertebrates, pterosaurs. However, morphological and quantitative evidence to support pterosaurs exhibiting this ecology remains scant. Anurognathids are an unusual group of pterosaurs in which the skull exhibits the unique morphology of being mediolaterally expanded, so much so that their skulls may be wider than rostrocaudally long. Here, we conduct quantitative comparative cranial measurements and dental morphology in anurognathids against extant avian and chiropteran taxa, respectively, with ecologies and behaviors that are similar to predicted putative behaviors of anurognathids. Comparative analyses of both skull and dental morphology suggest anurognathid specimens in similar morphospaces as insectivorous crepuscular and nocturnal extant volant taxa. Our results support that this unique group of pterosaurs likely occupied a niche of mid-flight insectivorous capture in low-light conditions.

Lymphocyte DNA methylation mediates genetic risk at shared immune-mediated disease loci.

BACKGROUND: Defining regulatory mechanisms through which noncoding risk variants influence the cell-mediated pathogenesis of immune-mediated disease (IMD) has emerged as a priority in the post-genome-wide association study era. OBJECTIVES: With a focus on rheumatoid arthritis, we sought new insight into genetic mechanisms of adaptive immune dysregulation to help prioritize molecular pathways for targeting in this and related immune pathologies. METHODS: Whole-genome methylation and transcriptional data from isolated CD4+ T cells and B cells of more than 100 genotyped and phenotyped patients with inflammatory arthritis, all of whom were naive to immunomodulatory treatments, were obtained. Analysis integrated these comprehensive data with genome-wide association study findings across IMDs and other publicly available resources. RESULTS: We provide strong evidence that disease-associated DNA variants regulate cis-CpG methylation in CD4+ T and/or B cells at 37% RA loci. Using paired, cell-specific transcriptomic data and causal inference testing, we identify examples where site-specific DNA methylation in turn mediates gene expression, including FCRL3 in both cell types and ORMDL3/GSDMB, IL6ST/ANKRD55, and JAZF1 in CD4+ T cells. A number of genes regulated in this way highlight mechanisms common to RA and other IMDs including multiple sclerosis and asthma, in turn distinguishing them from osteoarthritis, a primarily degenerative disease. Finally, we corroborate the observed effects experimentally. CONCLUSIONS: Our observations highlight important mechanisms of genetic risk in RA and the wider context of immune dysregulation. They confirm the utility of DNA methylation profiling as a tool for causal gene prioritization and, potentially, therapeutic targeting in complex IMD.

Reactive Oxygen Species in COPD-Related Vascular Remodeling.

The pathogenesis of chronic obstructive pulmonary disease (COPD) is a multifaceted process involving the alteration of pulmonary vasculature. Such vascular remodeling can be associated with inflammation, shear stress, and hypoxia-conditions commonly seen in patients with lung diseases. Particularly, the overproduction of reactive oxygen species (ROS) in the diseased lungs contributes greatly to pulmonary vascular remodeling. ROS play an important role in vascular homeostasis, yet excessive ROS can alter pulmonary vasculature and impair lung function, as implicated in COPD at all stages. Increased inflammatory cell infiltration and endothelial dysfunction both correspond to the severity of COPD. As a byproduct of vascular remodeling, pulmonary hypertension negatively affects the long-term survival rate of COPD patients. While there is currently no cure for COPD, several treatment options have focused on alleviating COPD symptoms. Interventions such as long-term oxygen therapy, endothelium-targeted treatment, and pharmacological therapies show promising results in improving the life span of COPD patients and attenuating the progression of pulmonary hypertension. In this chapter, we aim to discuss the contributing factors of pulmonary vascular remodeling in COPD with an emphasis on the ROS, as well as potential redox treatments for COPD-related vascular remodeling.

Reconstructing the dietary habits and trophic positions of the Longipterygidae (Aves: Enantiornithes) using neontological and comparative morphological methods.

The Longipterygidae are a unique clade among the enantiornithines in that they exhibit elongate rostra (≥60% total skull length) with dentition restricted to the distal tip of the rostrum, and pedal morphologies suited for an arboreal lifestyle (as in other enantiornithines). This suite of features has made interpretations of this group's diet and ecology difficult to determine due to the lack of analogous taxa that exhibit similar morphologies together. Many extant bird groups exhibit rostral elongation, which is associated with several disparate ecologies and diets (e.g., aerial insectivory, piscivory, terrestrial carnivory). Thus, the presence of rostral elongation in the Longipterygidae only somewhat refines trophic predictions of this clade. Anatomical morphologies do not function singularly but as part of a whole and thus, any dietary or ecological hypothesis regarding this clade must also consider other features such as their unique dentition. The only extant group of dentulous volant tetrapods are the chiropterans, in which tooth morphology and enamel thickness vary depending upon food preference. Drawing inferences from both avian bill proportions and variations in the dental morphology of extinct and extant taxa, we provide quantitative data to support the hypothesis that the Longipterygidae were animalivorous, with greater support for insectivory.

CD4+ and B Lymphocyte Expression Quantitative Traits at Rheumatoid Arthritis Risk Loci in Patients With Untreated Early Arthritis: Implications for Causal Gene Identification.

OBJECTIVE: Rheumatoid arthritis (RA) is a genetically complex disease of immune dysregulation. This study sought to gain further insight into the genetic risk mechanisms of RA by conducting an expression quantitative trait locus (eQTL) analysis of confirmed genetic risk loci in CD4+ T cells and B cells from carefully phenotyped patients with early arthritis who were naive to therapeutic immunomodulation. METHODS: RNA and DNA were isolated from purified B and/or CD4+ T cells obtained from the peripheral blood of 344 patients with early arthritis. Genotyping and global gene expression measurements were carried out using Illumina BeadChip microarrays. Variants in linkage disequilibrium (LD) with non-HLA RA single-nucleotide polymorphisms (defined as r2 ≥ 0.8) were analyzed, seeking evidence of cis- or trans-eQTLs according to whether the associated probes were or were not within 4 Mb of these LD blocks. RESULTS: Genes subject to cis-eQTL effects that were common to both CD4+ and B lymphocytes at RA risk loci were FADS1, FADS2, BLK, FCRL3, ORMDL3, PPIL3, and GSDMB. In contrast, those acting on METTL21B, JAZF1, IKZF3, and PADI4 were unique to CD4+ lymphocytes, with the latter candidate risk gene being identified for the first time in this cell subset. B lymphocyte-specific eQTLs for SYNGR1 and CD83 were also found. At the 8p23 BLK-FAM167A locus, adjacent genes were subject to eQTLs whose activity differed markedly between cell types; in particular, the FAM167A effect displayed striking B lymphocyte specificity. No trans-eQTLs approached experiment-wide significance, and linear modeling did not identify a significant influence of biologic covariates on cis-eQTL effect sizes. CONCLUSION: These findings further refine the understanding of candidate causal genes in RA pathogenesis, thus providing an important platform from which downstream functional studies, directed toward particular cell types, may be prioritized.