The two tandem bromodomains of the BET proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1 whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET targeted therapies.

Subjectivity in natural language refers to aspects of language used to express opinions, evaluations, and speculations. There are numerous natural language processing applications for which subjectivity analysis is relevant, including information extraction and text categorization. The goal of this work is learning subjective language from corpora. Clues of subjectivity are generated and tested, including low-frequency words, collocations, and adjectives and verbs identified using distributional similarity. The features are also examined working together in concert. The features, generated from different data sets using different procedures, exhibit consistency in performance in that they all do better and worse on the same data sets. In addition, this article shows that the density of subjectivity clues in the surrounding context strongly affects how likely it is that a word is subjective, and it provides the results of an annotation study assessing the subjectivity of sentences with high-density features. Finally, the clues are used to perform opinion piece recognition (a type of text categorization and genre detection) to demonstrate the utility of the knowledge acquired in this article.

The aim of this study was to assess the effect of grazing (G) vs. zero-grazing (ZG), level of milk production, and quality and type of housing system [free stalls (FS) and straw yards (SY)] on the prevalence of lameness and leg injuries in dairy cows. Observations were made on 37 commercial dairy farms across Great Britain. A single visit of 5 d duration was made to each farm. During this visit, lameness scores and the incidence of swellings, rubs, and injuries to hocks and knees were recorded on all the peak- or mid-lactation cows. Aspects of the quality of housing and management that were likely to affect foot and leg health were recorded. There were more lame cows on ZG farms (39 +/- 0.02%) than on grazing (G) farms (15 +/- 0.01%), and lameness scores were higher on FS farms compared with SY farms (0.25 +/- 0.01 vs. 0.05 +/- 0.01). Cows on SY farms had fewer hock and knee injuries compared with FS farms. The frequency of knee swellings was higher on ZG farms (0.31 +/- 0.02) than on G farms (0.15 +/- 0.01). Aspects of the free-stall design affected foot and leg health. The number of hock swellings increased with increasing stall gradient (0.16 +/- 0.01 with no slope vs. 0.39 +/- 0.02 at a 0 to 1.5% slope). There was an interaction between the length of the free-stall lunging space and the hip width of the cow, indicating that the incidence of lameness is generally highest on farms with small free stalls and heavy cows. High levels of milk production did not affect lameness or leg injury. The results indicate that housing cows throughout the year potentially has a detrimental effect on foot and leg health. However, good free-stall design may reduce lameness and leg lesions.

In asthma and chronic obstructive pulmonary disease, activation of G q -protein-coupled receptors causes bronchoconstriction. In each case, the management of moderate-to-severe disease uses inhaled corticosteroid (glucocorticoid)/long-acting β 2 -adrenoceptor agonist (LABA) combination therapies, which are more efficacious than either monotherapy alone. In primary human airway smooth muscle cells, glucocorticoid/LABA combinations synergistically induce the expression of regulator of G-protein signaling 2 (RGS2), a GTPaseactivating protein that attenuates G q signaling. Functionally, RGS2 reduced intracellular free calcium flux elicited by histamine, methacholine, leukotrienes, and other spasmogens. Furthermore, protection against spasmogen-increased intracellular free calcium, following treatment for 6 h with LABA plus corticosteroid, was dependent on RGS2. Finally, Rgs2-deficient mice revealed enhanced bronchoconstriction to spasmogens and an absence of LABA-induced bronchoprotection. These data identify RGS2 gene expression as a genomic mechanism of bronchoprotection that is induced by glucocorticoids plus LABAs in human airway smooth muscle and provide a rational explanation for the clinical efficacy of inhaled corticosteroid (glucocorticoid)/LABA combinations in obstructive airways diseases.adrenoreceptor | beta-2-adrenergic receptor | protein kinase A | glucocorticoid receptor | NR3C1

Asthma frequently commences in early life during airway and immune development and exposure to new environmental challenges. Endobronchial biopsies from children with asthma are abnormal, and lung function is maximally reduced by 6 years of age. As longitudinal biopsy studies are unethical in children, the relationship between development of pathology and reduced lung function is unknown. We aimed to establish a novel neonatal mouse model of allergic airways disease to investigate the developmental sequence of the pathophysiologic features of asthma. Neonatal Balb/c mice were challenged three times weekly from Day 3 of life using intranasal house dust mite (HDM) or saline for up to 12 weeks. Weekly assessments of airway inflammation and remodeling were made. Airway hyperresponsiveness (AHR) to methacholine was assessed from Week 2 onward. Total and eosinophilic inflammation was significantly increased in the lungs of HDM-exposed neonates from Week 2 onwards, and a peak was seen at 3 weeks. Goblet cells and peribronchiolar reticulin deposition were significantly increased in HDM-exposed neonates from Week 3, and peribronchiolar collagen was significantly greater from Week 4. HDM-exposed neonates had increased AHR from Week 2 onward. Although inflammation and AHR had subsided after 4 weeks without allergen challenge, the increased reticulin and collagen deposition persisted in HDM-exposed mice. Neonatal mice exposed to intranasal HDM developed eosinophilic inflammation, airway remodeling, and AHR as reported in pediatric asthma. Importantly, all abnormalities developed in parallel, not sequentially, between 2 and 3 weeks of age.