Expansion of extrafollicular B and T cell subsets in childhood-onset systemic lupus erythematosus.

Introduction: Most childhood-onset SLE patients (cSLE) develop lupus nephritis (cLN), but only a small proportion achieve complete response to current therapies. The prognosis of children with LN and end-stage renal disease is particularly dire. Mortality rates within the first five years of renal replacement therapy may reach 22%.

Multi-omics subtyping pipeline for chronic obstructive pulmonary disease.

Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of mortality in the United States; however, COPD has heterogeneous clinical phenotypes. This is the first large scale attempt which uses transcriptomics, proteomics, and metabolomics (multi-omics) to determine whether there are molecularly defined clusters with distinct clinical phenotypes that may underlie the clinical heterogeneity. Subjects included 3,278 subjects from the COPDGene cohort with at least one of the following profiles: whole blood transcriptomes (2,650 subjects); plasma proteomes (1,013 subjects); and plasma metabolomes (1,136 subjects).

Subjects at-risk for future development of rheumatoid arthritis demonstrate a PAD4-and TLR-dependent enhanced histone H3 citrullination and proinflammatory cytokine production in CD14 monocytes.

The presence of anti-citrullinated protein/peptide antibodies (ACPA) and epitope spreading across the target autoantigens is a unique feature of rheumatoid arthritis (RA). ACPA are present in the peripheral blood for several years prior to the onset of arthritis and clinical classification of RA. ACPA recognize multiple citrullinated proteins, including histone H3 (H3).

Minimizing Batch Effects in Mass Cytometry Data.

Cytometry by Time-Of-Flight (CyTOF) uses antibodies conjugated to isotopically pure metals to identify and quantify a large number of cellular features with single-cell resolution. A barcoding approach allows for 20 unique samples to be pooled and processed together in one tube, reducing the intra-barcode technical variability. However, with only 20 samples per barcode, multiple barcode sets (batches) are required to address questions in robustly powered study designs.

Chronic Liver Disease in Humans Causes Expansion and Differentiation of Liver Lymphatic Endothelial Cells.

Liver lymphatic vessels support liver function by draining interstitial fluid, cholesterol, fat, and immune cells for surveillance in the liver draining lymph node. Chronic liver disease is associated with increased inflammation and immune cell infiltrate. However, it is currently unknown if or how lymphatic vessels respond to increased inflammation and immune cell infiltrate in the liver during chronic disease.

gemBS: high throughput processing for DNA methylation data from bisulfite sequencing.

Motivation: DNA methylation is essential for normal embryogenesis and development in mammals and can be captured at single base pair resolution by whole genome bisulfite sequencing (WGBS). Current available analysis tools are becoming rapidly outdated as they lack sensible functionality and efficiency to handle large amounts of data now commonly created.

Results: We developed gemBS, a fast high-throughput bioinformatics pipeline specifically designed for large scale BS-Seq analysis that combines a high performance BS-mapper (GEM3) and a variant caller specifically for BS-Seq data (BScall).

Distinct Trends of DNA Methylation Patterning in the Innate and Adaptive Immune Systems.

DNA methylation and the localization and post-translational modification of nucleosomes are interdependent factors that contribute to the generation of distinct phenotypes from genetically identical cells. With 112 whole-genome bisulfite sequencing datasets from the BLUEPRINT Epigenome Project, we analyzed the global development of DNA methylation patterns during lineage commitment and maturation of a range of immune system effector cells and the cancers that arise from them. We show clear trends in methylation patterns that are distinct in the innate and adaptive arms of the human immune system, both globally and in relation to consistently positioned nucleosomes.

Whole-genome fingerprint of the DNA methylome during human B cell differentiation.

We analyzed the DNA methylome of ten subpopulations spanning the entire B cell differentiation program by whole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpG methylation disappeared upon B cell commitment, whereas CpG methylation changed extensively during B cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpG sites. Early differentiation stages mainly displayed enhancer demethylation, which was associated with upregulation of key B cell transcription factors and affected multiple genes involved in B cell biology.

Multiple HLA epitopes contribute to type 1 diabetes susceptibility.

Disease susceptibility for type 1 diabetes is strongly associated with the inheritance of specific HLA alleles. However, conventional allele frequency analysis can miss HLA associations because many alleles are rare. In addition, disparate alleles that have similar peptide-binding sites, or shared epitopes, can be missed.

Association of the HLA-DRB1 epitope LA(67, 74) with rheumatoid arthritis and citrullinated vimentin binding.

Objective: Although rheumatoid arthritis (RA) has long been associated with an HLA-DRB1 shared epitope, a systematic search for other epitopes has never been conducted. In addition, the relationship between these epitopes and the binding of citrullinated autoantigens has not been investigated. We developed a program that can analyze HLA data for all possible epitopes of up to 5 amino acids and used this program to assess the shared epitope hypothesis in RA.

Biomedical discovery acceleration, with applications to craniofacial development.

The profusion of high-throughput instruments and the explosion of new results in the scientific literature, particularly in molecular biomedicine, is both a blessing and a curse to the bench researcher. Even knowledgeable and experienced scientists can benefit from computational tools that help navigate this vast and rapidly evolving terrain. In this paper, we describe a novel computational approach to this challenge, a knowledge-based system that combines reading, reasoning, and reporting methods to facilitate analysis of experimental data.

Consistent visualizations of changing knowledge.

Networks are increasingly used in biology to represent complex data in uncomplicated symbolic form. However, as biological knowledge is continually evolving, so must those networks representing this knowledge. Capturing and presenting this type of knowledge change over time is particularly challenging due to the intimate manner in which researchers customize those networks they come into contact with.