Altered Innate Immune Responses in Neutrophils from Patients with Well- and Suboptimally Controlled Asthma

© 2015 Francesca S. M. Tang et al. Background. Respiratory infections are a major cause of asthma exacerbations where neutrophilic inflammation dominates and is associated with steroid refractory asthma. Structural airway cells in asthma differ from nonasthmatics; however it is unknown if neutrophils differ. We investigated neutrophil immune responses in patients who have good (AGood) and suboptimal (ASubopt) asthma symptom control. Methods. Peripheral blood neutrophils from AGood (ACQ 0.75, n=7), and healthy controls (HC) (n=9) were stimulated with bacterial (LPS (1 g/mL), fMLF (100 nM)), and viral (imiquimod (3 g/mL), R848 (1.5 g/mL), and poly I:C (10 g/mL)) surrogates or live rhinovirus (RV) 16 (MOI1). Cell-free supernatant was collected after 1 h for neutrophil elastase (NE) and matrix metalloproteinase- (MMP-) 9 measurements or after 24 h for CXCL8 release. Results. Constitutive NE was enhanced in AGood neutrophils compared to HC. fMLF stimulated neutrophils from ASubopt but not AGood produced 50% of HC levels. fMLF induced MMP-9 was impaired in ASubopt and AGood compared to HC. fMLF stimulated CXCL8 but not MMP-9 was positively correlated with FEV1 and FEV1/FVC. ASubopt and AGood responded similarly to other stimuli. Conclusions. Circulating neutrophils are different in asthma; however, this is likely to be related to airflow limitation rather than asthma control

Dating of the oldest continental sediments from the Himalayan foreland basin

A detailed knowledge of Himalayan development is important for our wider understanding of several global processes, ranging from models of plateau uplift to changes in oceanic chemistry and climate(1-4). Continental sediments 55 Myr old found in a foreland basin in Pakistan(5) are, by more than 20 Myr, the oldest deposits thought to have been eroded from the Himalayan metamorphic mountain belt. This constraint on when erosion began has influenced models of the timing and diachrony of the India-Eurasia collision(6-8), timing and mechanisms of exhumation(9,10) and uplift(11), as well as our general understanding of foreland basin dynamics(12). But the depositional age of these basin sediments was based on biostratigraphy from four intercalated marl units(5). Here we present dates of 257 detrital grains of white mica from this succession, using the Ar-40-(39) Ar method, and find that the largest concentration of ages are at 36-40 Myr. These dates are incompatible with the biostratigraphy unless the mineral ages have been reset, a possibility that we reject on the basis of a number of lines of evidence. A more detailed mapping of this formation suggests that the marl units are structurally intercalated with the continental sediments and accordingly that biostratigraphy cannot be used to date the clastic succession. The oldest continental foreland basin sediments containing metamorphic detritus eroded from the Himalaya orogeny therefore seem to be at least 15-20 Myr younger than previously believed, and models based on the older age must be re-evaluated

Mouse nuclear myosin I knock-out shows interchangeability and redundancy of myosin isoforms in the cell nucleus.

Nuclear myosin I (NM1) is a nuclear isoform of the well-known "cytoplasmic" Myosin 1c protein (Myo1c). Located on the 11(th) chromosome in mice, NM1 results from an alternative start of transcription of the Myo1c gene adding an extra 16 amino acids at the N-terminus. Previous studies revealed its roles in RNA Polymerase I and RNA Polymerase II transcription, chromatin remodeling, and chromosomal movements. Its nuclear localization signal is localized in the middle of the molecule and therefore directs both Myosin 1c isoforms to the nucleus. In order to trace specific functions of the NM1 isoform, we generated mice lacking the NM1 start codon without affecting the cytoplasmic Myo1c protein. Mutant mice were analyzed in a comprehensive phenotypic screen in cooperation with the German Mouse Clinic. Strikingly, no obvious phenotype related to previously described functions has been observed. However, we found minor changes in bone mineral density and the number and size of red blood cells in knock-out mice, which are most probably not related to previously described functions of NM1 in the nucleus. In Myo1c/NM1 depleted U2OS cells, the level of Pol I transcription was restored by overexpression of shRNA-resistant mouse Myo1c. Moreover, we found Myo1c interacting with Pol II. The ratio between Myo1c and NM1 proteins were similar in the nucleus and deletion of NM1 did not cause any compensatory overexpression of Myo1c protein. We observed that Myo1c can replace NM1 in its nuclear functions. Amount of both proteins is nearly equal and NM1 knock-out does not cause any compensatory overexpression of Myo1c. We therefore suggest that both isoforms can substitute each other in nuclear processes

Heterogeneity of Paucigranulocytic Asthma: A Prospective Cohort Study with Hierarchical Cluster Analysis.

BACKGROUND: Asthma, a heterogeneous disease, can be divided into 4 inflammatory phenotypes using induced sputum cell counts-eosinophilic asthma (EA), neutrophilic asthma (NA), mixed granulocytic asthma, and paucigranulocytic asthma (PGA). Although research has focused on EA and NA, there is little known about PGA. OBJECTIVE: To study the heterogeneity of PGA and identify possible PGA clusters to guide clinical treatment. METHODS: Patients with PGA were grouped by hierarchical cluster analysis and enrolled into a prospective cohort study to validate the clusters, relative to future risk of asthma exacerbations in a real-world setting. Clusters were validated by tree analysis in a separate population. Finally, we explored PGA stability. RESULTS: Cluster analysis of 145 patients with PGA identified 3 clusters: cluster 1 (n = 110, 75.9%) was "mild PGA," cluster 2 (n = 20, 13.8%) was "PGA with psychological dysfunction and rhinoconjunctivitis and other allergic diseases," and cluster 3 (n = 15, 10.3%) was "smoking-associated PGA." Cluster 3 had significantly increased risk of severe exacerbation (relative risk [RR] = 6.43, P = .01), emergency visit (RR = 8.61, P = .03), and hospitalization (RR = 12.94, P < .01). Results of the cluster analysis were successfully validated in an independent PGA population classified using decision tree analysis. Although PGA can transform into or develop from other phenotypes, 70% were stable over time. CONCLUSIONS: Among 3 identified PGA clusters, cluster 3 had a higher risk of severe exacerbation. PGA heterogeneity indicates the requirement of novel targeted interventions

The Impact of Global Warming and Anoxia on Marine Benthic Community Dynamics: an Example from the Toarcian (Early Jurassic)

The Pliensbachian-Toarcian (Early Jurassic) fossil record is an archive of natural data of benthic community response to global warming and marine long-term hypoxia and anoxia. In the early Toarcian mean temperatures increased by the same order of magnitude as that predicted for the near future; laminated, organic-rich, black shales were deposited in many shallow water epicontinental basins; and a biotic crisis occurred in the marine realm, with the extinction of approximately 5% of families and 26% of genera. High-resolution quantitative abundance data of benthic invertebrates were collected from the Cleveland Basin (North Yorkshire, UK), and analysed with multivariate statistical methods to detect how the fauna responded to environmental changes during the early Toarcian. Twelve biofacies were identified. Their changes through time closely resemble the pattern of faunal degradation and recovery observed in modern habitats affected by anoxia. All four successional stages of community structure recorded in modern studies are recognised in the fossil data (i.e. Stage III: climax; II: transitional; I: pioneer; 0: highly disturbed). Two main faunal turnover events occurred: (i) at the onset of anoxia, with the extinction of most benthic species and the survival of a few adapted to thrive in low-oxygen conditions (Stages I to 0) and (ii) in the recovery, when newly evolved species colonized the re-oxygenated soft sediments and the path of recovery did not retrace of pattern of ecological degradation (Stages I to II). The ordination of samples coupled with sedimentological and palaeotemperature proxy data indicate that the onset of anoxia and the extinction horizon coincide with both a rise in temperature and sea level. Our study of how faunal associations co-vary with long and short term sea level and temperature changes has implications for predicting the long-term effects of “dead zones” in modern oceans

Von Bezold assimilation effect reverses in stereoscopic conditions

Lightness contrast and lightness assimilation are opposite phenomena: in contrast, grey targets appear darker when bordering bright surfaces (inducers) rather than dark ones; in assimilation, the opposite occurs. The question is: which visual process favours the occurrence of one phenomenon over the other? Researchers provided three answers to this question. The first asserts that both phenomena are caused by peripheral processes; the second attributes their occurrence to central processes; and the third claims that contrast involves central processes, whilst assimilation involves peripheral ones. To test these hypotheses, an experiment on an IT system equipped with goggles for stereo vision was run. Observers were asked to evaluate the lightness of a grey target, and two variables were systematically manipulated: (i) the apparent distance of the inducers; and (ii) brightness of the inducers. The retinal stimulation was kept constant throughout, so that the peripheral processes remained the same. The results show that the lightness of the target depends on both variables. As the retinal stimulation was kept constant, we conclude that central mechanisms are involved in both lightness contrast and lightness assimilation

Geochemistry, faunal composition and trophic structure in reducing sediments on the southwest South Georgia margin

Despite a number of studies in areas of focused methane seepage, the extent of transitional sediments of more diffuse methane seepage, and their influence upon biological communities is poorly understood. We investigated an area of reducing sediments with elevated levels of methane on the South Georgia margin around 250 m depth and report data from a series of geochemical and biological analyses. Here, the geochemical signatures were consistent with weak methane seepage and the role of sub-surface methane consumption was clearly very important, preventing gas emissions into bottom waters. As a result, the contribution of methane-derived carbon to the microbial and metazoan food webs was very limited, although sulfur isotopic signatures indicated a wider range of dietary contributions than was apparent from carbon isotope ratios. Macrofaunal assemblages had high dominance and were indicative of reducing sediments, with many taxa common to other similar environments and no seep-endemic fauna, indicating transitional assemblages. Also similar to other cold seep areas, there were samples of authigenic carbonate, but rather than occurring as pavements or sedimentary concretions, these carbonates were restricted to patches on the shells of Axinulus antarcticus (Bivalvia, Thyasiridae), which is suggestive of microbe–metazoan interactions

The rapid assembly of an elliptical galaxy of 400 billion solar masses at a redshift of 2.3

Stellar archeology shows that massive elliptical galaxies today formed rapidly about ten billion years ago with star formation rates above several hundreds solar masses per year (M_sun/yr). Their progenitors are likely the sub-millimeter-bright galaxies (SMGs) at redshifts (z) greater than 2. While SMGs' mean molecular gas mass of 5x10^10 M_sun can explain the formation of typical elliptical galaxies, it is inadequate to form ellipticals that already have stellar masses above 2x10^11 M_sun at z ~ 2. Here we report multi-wavelength high-resolution observations of a rare merger of two massive SMGs at z = 2.3. The system is currently forming stars at a tremendous rate of 2,000 M_sun/yr. With a star formation efficiency an order-of-magnitude greater than that of normal galaxies, it will quench the star formation by exhausting the gas reservoir in only ~200 million years. At a projected separation of 19 kiloparsecs, the two massive starbursts are about to merge and form a passive elliptical galaxy with a stellar mass of ~4x10^11 M_sun. Our observations show that gas-rich major galaxy mergers, concurrent with intense star formation, can form the most massive elliptical galaxies by z ~ 1.5.Comment: Appearing in Nature online on May 22 and in print on May 30. Submitted here is the accepted version (including the Supplementary Information), see nature.com for the final versio

Deterioration of Parkinson's disease during hospitalization: survey of 684 patients

Abstract Background A substantial fraction of Parkinson's disease patients deteriorate during hospitalisation, but the precise proportion and the reasons why have not been studied systematically and the focus has been on surgical wards and on Accident & Emergency departments. We assessed the prevalence and risk factors of deterioration of Parkinson's disease symptoms during hospitalization, including all wards. Methods We invited Parkinson's disease patients from three neurology departments in The Netherlands to answer a standardised questionnaire on general, disease and hospital related issues. Patients who had been hospitalized in the previous year were included and analysed. Possible risk factors for Parkinson's disease deterioration were identified. Proportions were analysed using the Chi-Square test and a logistic regression analysis was performed. Results Eighteen percent of 684 Parkinson's disease patients had been hospitalized at least once in the last year. Twenty-one percent experienced deterioration of motor symptoms, 33% did have one or more complications and 26% had received incorrect anti-Parkinson's medication. There were no statistically significant differences for these variables between admissions on neurologic or non-neurologic wards and between having surgery or not. Incorrect medication during hospitalization was significantly associated with higher risk (OR 5.8, CI 2.5-13.7) of deterioration, as were having infections (OR 6.7 CI 1.8-24.7). A higher levodopa equivalent dose per day was a significant risk factor for deterioration. When adjusting for different variables, wrong medication distribution was the most important risk factor for deterioration. Conclusions Incorrect medication and infections are the important risk factors for deterioration of Parkinson's disease patients both for admissions with and without surgery and both for admissions on neurologic and non-neurologic wards. Measures should be taken to improve care and incorporated in guidelines.</p

Treatable Traits in Elderly Asthmatics from the Australasian Severe Asthma Network: A Prospective Cohort Study.

BACKGROUND: Data on treatable traits (TTs) in different populations are limited. OBJECTIVE: To assess TTs in elderly patients with asthma and compare them to younger patients, to evaluate the association of TTs with future exacerbations, and to develop an exacerbation prediction model. METHODS: We consecutively recruited 521 participants at West China Hospital, Sichuan University based on the Australasian Severe Asthma Network, classified as elderly (n = 62) and nonelderly (n = 459). Participants underwent a multidimensional assessment to characterize the TTs and were then followed up for 12 months. TTs and their relationship with future exacerbations were described. Based on the TTs and asthma control levels, an exacerbation prediction model was developed, and the overall performance was externally validated in an independent cohort. RESULTS: A total of 38 TTs were assessed. Elderly patients with asthma had more chronic metabolic diseases, fixed airflow limitation, emphysema, and neutrophilic inflammation, whereas nonelderly patients with asthma exhibited more allergic characteristics and psychiatric diseases. Nine traits were associated with increased future exacerbations, of which exacerbation prone, upper respiratory infection-induced asthma attack, cardiovascular disease, diabetes, and depression were the strongest. A model including exacerbation prone, psychiatric disease, cardiovascular disease, upper respiratory infection-induced asthma attack, noneosinophilic inflammation, cachexia, food allergy, and asthma control was developed to predict exacerbation risk and showed good performance. CONCLUSIONS: TTs can be systematically assessed in elderly patients with asthma, some of which are associated with future exacerbations, proving their clinical utility of evaluating them. A model based on TTs can be used to predict exacerbation risk in people with asthma