Many of the ligands for Toll-like receptors (TLRs) are unique to microorganisms, such that receptor activation unequivocally indicates the presence of something foreign. However, a subset of TLRs recognizes nucleic acids, which are present in both the host and foreign microorganisms. This specificity enables broad recognition by virtue of the ubiquity of nucleic acids but also introduces the possibility of self-recognition and autoinflammatory or autoimmune disease. Defining the regulatory mechanisms required to ensure proper discrimination between foreign and self-nucleic acids by TLRs is an area of intense research. Progress over the past decade has revealed a complex array of regulatory mechanisms that ensure maintenance of this delicate balance. These regulatory mechanisms can be divided into a conceptual framework with four categories: compartmentalization, ligand availability, receptor expression and signal transduction. In this Review, we discuss our current understanding of each of these layers of regulation.

The robustness of radiomic texture analysis across different manufacturers of mammography imaging systems is investigated. We quantified feature robustness across mammography manufacturers using a dataset of 111 women who underwent consecutive screening mammography on both general electric and Hologic systems. In each mammogram, a square region of interest (ROI) directly behind the nipple was manually selected. Radiomic features describing parenchymal patterns were automatically extracted on each ROI. Feature comparisons were conducted between manufacturers (and breast densities) using newly developed robustness metrics descriptive of correlation, equivalence, and variability. By examining the distribution of these metric values, we propose the following selection criteria to guide feature evaluation in this dataset: (1) [Formula: see text] of feature ratios [Formula: see text], (2) standard deviation of feature ratios [Formula: see text], (3) correlation of features [Formula: see text], and (4) [Formula: see text]. Statistically significant correlation coefficients ranged from 0.13 to 0.68 in comparisons between the two mammographic systems tested. Features describing spatial patterns tended to exhibit high correlation coefficients, while intensity- and directionality-based features had comparatively poor correlation. Our proposed robustness metrics may be used to evaluate other datasets, for which different ranges of metric values may be appropriate.

Regular exercise reduces risk of various chronic diseases and can prevent the development and recurrence of cancer, making it a promising nonpharmacological modulator of disease. Yet the effect of regular exercise on solid organ transplant outcome remains uncertain. Using a model of voluntary wheel‐running exercise and skin transplantation in mice, we hypothesized that exercise strengthens the alloimmune response, leading to an increased rate of rejection. Instead, we found that regular exercise in mice resulted in prolonged graft survival, with mean allograft survival time increasing by almost 50%. We observed this graft survival extension in exercised mice despite evidence of a slightly enhanced alloimmune response, comprised of increased proliferation of alloreactive CD4+ T cells, as well as increased interferon‐γ production by these cells. Exercise was not associated with significant changes in numbers of conventional CD4+ or CD8+ T cells, NK cells, or Foxp3+ regulatory T cells. In conclusion, our study suggests that exercise increases skin graft resistance to a similar or slightly higher level of alloimmunity and supports regular exercise as an important beneficial pursuit for transplant recipients.

The multipass transmembrane protein UNC93B1 is critical for the proper trafficking and function of many members of the Toll-like receptor (TLR) family of innate immune receptors. A new study reports two structures of UNC93B1 in complex with full-length TLR3 or TLR7 and sheds light on how this single chaperone may differentially interact with and regulate the function of individual TLRs.