The influence of HLA genetic variation on plasma protein expression.

Genetic variation in the human leukocyte antigen (HLA) loci is associated with risk of immune-mediated diseases, but the molecular effects of HLA polymorphism are unclear. Here we examined the effects of HLA genetic variation on the expression of 2940 plasma proteins across 45,330 Europeans in the UK Biobank, with replication analyses across multiple ancestry groups. We detected 504 proteins affected by HLA variants (HLA-pQTL), including widespread trans effects by autoimmune disease risk alleles.

Exploring Choke Holds in Brazilian Jiujitsu Athletes: A Demographic Study.

Introduction Brazilian jiujitsu is a relatively new sport that has grown exponentially in popularity along with the growth of the Ultimate Fighting Championship (UFC). In jiujitsu, there are a variety of submissions with a choke hold being one of the most popular. There is a subset of athletes in jiujitsu who believes chokes are safe.

Single-cell isolation from full-thickness human intestinal tissue resections for single-cell RNA sequencing.

Single-cell isolation techniques allow the investigation of physical and functional relationships between individual cells within a complex cell population. Here, we present a protocol for single-cell isolation from full-thickness intestinal tissue resections. We describe steps for pre-processing specimens, isolation of lamina propria and muscular layers, and red blood cell lysis.

Distinct use of super-enhancer elements controls cell type-specific CD25 transcription and function.

The IL-2 receptor α chain (IL-2Rα/CD25) is constitutively expressed on double-negative (DN2/DN3 thymocytes and regulatory T cells (T) but induced by IL-2 on T and natural killer (NK) cells, with expression regulated by a STAT5-dependent super-enhancer. We investigated CD25 regulation and function using a series of mice with deletions spanning STAT5-binding elements. Deleting the upstream super-enhancer region mainly affected constitutive CD25 expression on DN2/DN3 thymocytes and T, with these mice developing autoimmune alopecia, whereas deleting an intronic region decreased IL-2-induced CD25 on peripheral T and NK cells.

Stricturing Crohn's Disease Single-Cell RNA Sequencing Reveals Fibroblast Heterogeneity and Intercellular Interactions.

Background & Aims: Fibroblasts play a key role in stricture formation in Crohn's disease (CD) but understanding its pathogenesis requires a systems-level investigation to uncover new treatment targets. We studied full-thickness CD tissues to characterize fibroblast heterogeneity and function by generating the first single-cell RNA sequencing (scRNAseq) atlas of strictured bowel and providing proof of principle for therapeutic target validation.

Methods: We performed scRNAseq of 13 fresh full-thickness CD resections containing noninvolved, inflamed nonstrictured, and strictured segments as well as 7 normal non-CD bowel segments.

Stricturing Crohn's disease single-cell RNA sequencing reveals fibroblast heterogeneity and intercellular interactions.

Background: Fibroblasts play a key role in stricture formation in Crohn's disease (CD) but understanding it's pathogenesis requires a systems-level investigation to uncover new treatment targets. We studied full thickness CD tissues to characterize fibroblast heterogeneity and function by generating the first single cell RNA sequencing (scRNAseq) atlas of strictured bowel and providing proof of principle for therapeutic target validation.

Methods: We performed scRNAseq of 13 fresh full thickness CD resections containing non-involved, inflamed non-strictured, and strictured segments as well as 7 normal non-CD bowel segments.

Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation.

Macrophages are central orchestrators of the tissue response to injury, with distinct macrophage activation states playing key roles in fibrosis progression and resolution. Identifying key macrophage populations found in human fibrotic tissues could lead to new treatments for fibrosis. Here, we used human liver and lung single-cell RNA sequencing datasets to identify a subset of macrophages that express , , , and .

Single cell sequencing identifies clonally expanded synovial CD4 T cells expressing GPR56 in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease affecting synovial joints where different CD4 T cell subsets may contribute to pathology. Here, we perform single cell sequencing on synovial CD4 T cells from anti-citrullinated protein antibodies (ACPA)+ and ACPA- RA patients and identify two peripheral helper T cell (T) states and a cytotoxic CD4 T cell subset. We show that the adhesion G-protein coupled receptor 56 (GPR56) delineates synovial CXCL13 T CD4 T cells expressing LAG-3 and the tissue-resident memory receptors CXCR6 and CD69.

Humoral immunity in leishmaniasis - Prevention or promotion of parasite growth?

Leishmaniasis can present as a "spectrum" of clinical outcomes. There is evidence that these divergent clinical outcomes are attributable to genetic differences in the human host [1] as well the species of infecting parasite [2]. The spectrum of disease has largely been described by defining the polar opposites of T cell immune responses.

Immune Complex-Driven Generation of Human Macrophages with Anti-Inflammatory and Growth-Promoting Activity.

To maintain homeostasis, macrophages must be capable of assuming either an inflammatory or an anti-inflammatory phenotype. To better understand the latter, we stimulated human macrophages in vitro with TLR ligands in the presence of high-density immune complexes (IC). This combination of stimuli resulted in a broad suppression of inflammatory mediators and an upregulation of molecules involved in tissue remodeling and angiogenesis.

Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8 T cell stemness and antitumor immunity.

Interleukin (IL)-2 and IL-21 dichotomously shape CD8 T cell differentiation. IL-2 drives terminal differentiation, generating cells that are poorly effective against tumors, whereas IL-21 promotes stem cell memory T cells (T) and antitumor responses. Here we investigated the role of metabolic programming in the developmental differences induced by these cytokines.

Host and parasite responses in human diffuse cutaneous leishmaniasis caused by L. amazonensis.

Diffuse cutaneous leishmaniasis (DCL) is a rare form of leishmaniasis where parasites grow uncontrolled in diffuse lesions across the skin. Meta-transcriptomic analysis of biopsies from DCL patients infected with Leishmania amazonensis demonstrated an infiltration of atypical B cells producing a surprising preponderance of the IgG4 isotype. DCL lesions contained minimal CD8+ T cell transcripts and no evidence of persistent TH2 responses.

Correction: Meta-transcriptome Profiling of the Human-Leishmania braziliensis Cutaneous Lesion.

[This corrects the article DOI: 10.1371/journal.pntd.

Macrophages and the Recovery from Acute and Chronic Inflammation.

In recent years, researchers have devoted much attention to the diverse roles of macrophages and their contributions to tissue development, wound healing, and angiogenesis. What should not be lost in the discussions regarding the diverse biology of these cells is that when perturbed, macrophages are the primary contributors to potentially pathological inflammatory processes. Macrophages stand poised to rapidly produce large amounts of inflammatory cytokines in response to danger signals.

Meta-transcriptome Profiling of the Human-Leishmania braziliensis Cutaneous Lesion.

Host and parasite gene expression in skin biopsies from Leishmania braziliensis-infected patients were simultaneously analyzed using high throughput RNA-sequencing. Biopsies were taken from 8 patients with early cutaneous leishmaniasis and 17 patients with late cutaneous leishmaniasis. Although parasite DNA was found in all patient lesions at the time of biopsy, the patients could be stratified into two groups: one lacking detectable parasite transcripts (PTNeg) in lesions, and another in which parasite transcripts were readily detected (PTPos).

Image-guided Coring for Large-scale Studies in Molecular Pathology.

Sampling of formalin-fixed paraffin-embedded (FFPE) tissue blocks is a critical initial step in molecular pathology. Image-guided coring (IGC) is a new method for using digital pathology images to guide tissue block coring for molecular analyses. The goal of our study is to evaluate the use of IGC for both tissue-based and nucleic acid-based projects in molecular pathology.

Extensive rewiring of epithelial-stromal co-expression networks in breast cancer.

Background: Epithelial-stromal crosstalk plays a critical role in invasive breast cancer pathogenesis; however, little is known on a systems level about how epithelial-stromal interactions evolve during carcinogenesis.

Results: We develop a framework for building genome-wide epithelial-stromal co-expression networks composed of pairwise co-expression relationships between mRNA levels of genes expressed in the epithelium and stroma across a population of patients. We apply this method to laser capture micro-dissection expression profiling datasets in the setting of breast carcinogenesis.

Peptide-directed preparation and X-ray structural study of Au nanoparticles on titanium surfaces.

We report the peptide-directed preparation and X-ray structural study of biofunctionalized Au nanoparticles (NPs) deposited on Ti surfaces. Au NPs were prepared by reduction of Au(3+) compound onto HCl-refreshed Ti in the presence of thiol-functionalized small peptides. A modified extended X-ray absorption fine-structure (EXAFS) technique, equipped with a rotating-stage and glancing-angle setup, was able to more sensitively detect the structure and bonding of Au NPs on Ti with low surface coverage.

Biomolecule-coated metal nanoparticles on titanium.

Immobilizations of nanoparticles and biomolecules on biocompatible substrates such as titanium are two promising approaches to bringing new functionalities to Ti-based biomaterials. Herein, we used a variety of X-ray spectroscopic techniques to study and better understand metal-thiolate interactions in biofunctionalized metal nanoparticle systems supported on Ti substrates. Using a facile one-step procedure, a series of Au nanoparticle samples with varied biomolecule coatings ((2-mercatopropionyl)glycine (MPG) and bovine serum albumin (BSA)) and biomolecule concentrations are prepared.

Standardization of epidermal growth factor receptor (EGFR) measurement by quantitative immunofluorescence and impact on antibody-based mutation detection in non-small cell lung cancer.

Challenges in measurement of epidermal growth factor receptor (EGFR) protein expression have led to conflicting data on its prognostic value and discontinuation of its use for prediction of response. Herein is described a quantitative standardized assay for EGFR and its use in a series of retrospective cohorts of patients with non-small cell lung cancer (NSCLC). The AQUA technology of quantitative immunofluorescence was used in conjunction with Western blot analysis to calculate the absolute concentration of EGFR in two independent NSCLC cohorts (170 from Yale New Haven Hospital and 335 from Sotiria and Patras Hospitals in Greece).