Mechanisms of airway epithelial injury and abnormal repair in asthma and COPD

The airway epithelium comprises of different cell types and acts as a physical barrier preventing pathogens, including inhaled particles and microbes, from entering the lungs. Goblet cells and submucosal glands produce mucus that traps pathogens, which are expelled from the respiratory tract by ciliated cells. Basal cells act as progenitor cells, differentiating into different epithelial cell types, to maintain homeostasis following injury. Adherens and tight junctions between cells maintain the epithelial barrier function and regulate the movement of molecules across it. In this review we discuss how abnormal epithelial structure and function, caused by chronic injury and abnormal repair, drives airway disease and specifically asthma and chronic obstructive pulmonary disease (COPD). In both diseases, inhaled allergens, pollutants and microbes disrupt junctional complexes and promote cell death, impairing the barrier function and leading to increased penetration of pathogens and a constant airway immune response. In asthma, the inflammatory response precipitates the epithelial injury and drives abnormal basal cell differentiation. This leads to reduced ciliated cells, goblet cell hyperplasia and increased epithelial mesenchymal transition, which contribute to impaired mucociliary clearance and airway remodelling. In COPD, chronic oxidative stress and inflammation trigger premature epithelial cell senescence, which contributes to loss of epithelial integrity and airway inflammation and remodelling. Increased numbers of basal cells showing deregulated differentiation, contributes to ciliary dysfunction and mucous hyperproduction in COPD airways. Defective antioxidant, antiviral and damage repair mechanisms, possibly due to genetic or epigenetic factors, may confer susceptibility to airway epithelial dysfunction in these diseases. The current evidence suggests that a constant cycle of injury and abnormal repair of the epithelium drives chronic airway inflammation and remodelling in asthma and COPD. Mechanistic understanding of injury susceptibility and damage response may lead to improved therapies for these diseases

Serum levels of mature microRNAs in DICER1-mutated pleuropulmonary blastoma.

DICER1 is a critical gene in the biogenesis of mature microRNAs, short non-coding RNAs that derive from either -3p or -5p precursor microRNA strands. Germline mutations of DICER1 are associated with a range of human malignancies, including pleuropulmonary blastoma (PPB). Additional somatic 'hotspot' mutations in the microRNA processing ribonuclease IIIb (RNase IIIb) domain of DICER1 are reported in cancer, and which affect microRNA biogenesis, resulting in a -3p mature microRNA strand bias. Here, in a germline (exon11 c.1806_1810insATTGA) DICER1-mutated PPB, we first confirmed the presence of an additional somatic RNase IIIb hotspot mutation (exon25 c.5425G>A [p.G1809R]) by conventional sequencing. Second, we investigated serum levels of mature microRNAs at the time of PPB diagnosis, and compared the findings with serum results from a comprehensive range of pediatric cancer patients and controls (n=52). We identified a panel of 45 microRNAs that were present at elevated levels in the serum at the time of PPB diagnosis, with a significant majority noted be derived from the -3p strand (P=0.013). In addition, we identified a subset of 10 serum microRNAs (namely miR-125a-3p, miR-125b-2-3p, miR-380-5p, miR-125b-1-3p, let-7f-2-3p, let-7a-3p, let-7b-3p, miR-708-3p, miR-138-1-3p and miR-532-3p) that were most abundant in the PPB case. Serum levels of two representative microRNAs, miR-125a-3p and miR-125b-2-3p, were not elevated in DICER1 germline-mutated relatives. In the PPB case, serum levels of miR-125a-3p and miR-125b-2-3p increased before chemotherapy, and then showed an early reduction following treatment. These microRNAs may offer future utility as serum biomarkers for screening patients with known germline DICER1 mutations for early detection of PPB, and for potential disease-monitoring in cases with confirmed PPB.We would like to thank the following for providing financial support: SPARKS (NC, MJM), Medical Research Council Fellowship (MJM), TD Bank/LDI scholarship (LdK), Alex’s Lemonade Stand Foundation (WDF), Cancer Research UK (NC) and European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement No. 310018 (MT).This is the final published version. It first appeared at http://www.nature.com/oncsis/journal/v3/n2/full/oncsis20141a.html

The latent structure of the adult attachment interview: Large sample evidence from the collaboration on attachment transmission synthesis

The Adult Attachment Interview (AAI) is a widely used measure in developmental science that assesses adults’ current states of mind regarding early attachment-related experiences with their primary caregivers. The standard system for coding the AAI recommends classifying individuals categorically as having an autonomous, dismissing, preoccupied, or unresolved attachment state of mind. However, previous factor and taxometric analyses suggest that: (a) adults’ attachment states of mind are captured by two weakly correlated factors reflecting adults’ dismissing and preoccupied states of mind and (b) individual differences on these factors are continuously rather than categorically distributed. The current study revisited these suggestions about the latent structure of AAI scales by leveraging individual participant data from 40 studies (N = 3,218), with a particular focus on the controversial observation from prior factor analytic work that indicators of preoccupied states of mind and indicators of unresolved states of mind about loss and trauma loaded on a common factor. Confirmatory factor analyses indicated that: (a) a 2-factor model with weakly correlated dismissing and preoccupied factors and (b) a 3-factor model that further distinguished unresolved from preoccupied states of mind were both compatible with the data. The preoccupied and unresolved factors in the 3-factor model were highly correlated. Taxometric analyses suggested that individual differences in dismissing, preoccupied, and unresolved states of mind were more consistent with a continuous than a categorical model. The importance of additional tests of predictive validity of the various models is emphasized

Yukawa-unified natural supersymmetry

Previous work on t-b-\tau Yukawa-unified supersymmetry, as expected from SUSY GUT theories based on the gauge group SO(10), tended to have exceedingly large electroweak fine-tuning (EWFT). Here, we examine supersymmetric models where we simultaneously require low EWFT ("natural SUSY") and a high degree of Yukawa coupling unification, along with a light Higgs scalar with m_h\sim125 GeV. As Yukawa unification requires large tan\beta\sim50, while EWFT requires rather light third generation squarks and low \mu\sim100-250 GeV, B-physics constraints from BR(B\to X_s\gamma) and BR(B_s\to \mu+\mu-) can be severe. We are able to find models with EWFT \Delta\lesssim 50-100 (better than 1-2% EWFT) and with Yukawa unification as low as R_yuk\sim1.3 (30% unification) if B-physics constraints are imposed. This may be improved to R_yuk\sim1.2 if additional small flavor violating terms conspire to improve accord with B-constraints. We present several Yukawa-unified natural SUSY (YUNS) benchmark points. LHC searches will be able to access gluinos in the lower 1-2 TeV portion of their predicted mass range although much of YUNS parameter space may lie beyond LHC14 reach. If heavy Higgs bosons can be accessed at a high rate, then the rare H, A\to \mu+\mu- decay might allow a determination of tan\beta\sim50 as predicted by YUNS models. Finally, the predicted light higgsinos should be accessible to a linear e+e- collider with \sqrt{s}\sim0.5 TeV.Comment: 18 pages, 7 figures, pdflatex; 3 references adde

Conceptual comparison of constructs as first step in data harmonization: Parental sensitivity, child temperament, and social support as illustrations

This article presents a strategy for the initial step of data harmonization in Individual Participant Data syntheses, i.e., making decisions as to which measures operationalize the constructs of interest - and which do not. This step is vital in the process of data harmonization, because a study can only be as good as its measures. If the construct validity of the measures is in question, study results are questionable as well. Our proposed strategy for data harmonization consists of three steps. First, a unitary construct is defined based on the existing literature, preferably on the theoretical framework surrounding the construct. Second, the various instruments used to measure the construct are evaluated as operationalizations of this construct, and retained or excluded based on this evaluation. Third, the scores of the included measures are recoded on the same metric. We illustrate the use of this method with three example constructs focal to the Collaboration on Attachment Transmission Synthesis (CATS) study: parental sensitivity, child temperament, and social support. This process description may aid researchers in their data pooling studies, filling a gap in the literature on the first step of data harmonization. • Data harmonization in studies using combined datasets is of vital importance for the validity of the study results. • We have developed and illustrated a strategy on how to define a unitary construct and evaluate whether instruments are operationalizations of this construct as the initial step in the harmonization process. • This strategy is a transferable and reproducible method to apply to the data harmonization process