Natural Killer Cells in Asthma

The worldwide prevalence, morbidity, and mortality of asthma have dramatically increased over the last few decades and there is a clear need to identify new effective therapeutic and prophylactic strategies. Despite high numbers of NK cells in the lung and their ability to generate a variety of immunomodulatory mediators, the potential of NK cells as therapeutic targets in allergic airway disease has been largely overlooked. The fact that IgE, acting through FcγRIII, can activate NK cells resulting in cytokine/chemokine production implies that NK cells may contribute to IgE-mediated allergic responses. Indeed, current evidence suggests that NK cells can promote allergic airway responses during sensitization and ongoing inflammation. In animal models, increased NK cells are observed in the lung following antigen challenge and depletion of the cells before immunization inhibits allergic airway inflammation. Moreover, in asthmatics, NK cell phenotype is altered and may contribute to the promotion of a pro-inflammatory Th2-type environment. Conversely, driving NK cells toward an IFN-γ-secreting phenotype can reduce features of the allergic airway response in animal models. However, we have limited knowledge of the signals that drive the development of distinct subsets and functional phenotypes of NK cells in the lung and thus the role and therapeutic potential of NK cells in the allergic airway remains unclear. Here we review the potentially diverse role of NK cells in allergic airway disease, identify gaps in current knowledge, and discuss the potential of modulating NK cell function as a treatment strategy in asthma

Intraformational Parabolic Recumbent Folds in the Coconino Sandstone (Permian) and Two Other Formations in Sedona, Arizona (USA)

We report sedimentary structures that in all ways resemble parabolic recumbent folds (PRFs) in the cross-bedded portions of the Schnebly Hill Formation, the Coconino Sandstone and the Toroweap Formation (Arizona, USA). Field evidence suggests they are penecontemporaneous and intraformational. Intraformational refers to deformation that occurs between undeformed beds. Recumbent cross-bed sets occur over a wide area (\u3e375 km2 [144 mi2]) at many different locations and horizons in the Sedona area, especially within the Coconino Sandstone. Deformation resulting from slumping dunes (dry or damp) is ruled out because of the nature of the deformation along cross-bed dip, the size and length of the deformation along horizontal bedding planes (sometimes up to 170 m [557 ft] along dip) and the lack of small faults usually concurrent with such slumping known from modern dunes. Neither do the folds resemble deformation that has been caused by post-depositional groundwater movement or seismic activity which often produces convolute bedding. We do report some seismic features in the Schnebly Hill Formation, but these features have distinct characteristics that distinguish them from PRFs. Although the exact mechanism of PRF formation is still debated, it is generally agreed that strong water currents combined with liquefaction play major roles in overturning the top of a cross-bed set during the deposition of the cross-bed. Rare planar-beds, directly associated with the PRFs in the Coconino, suggest that the needed liquefaction may have occurred from changes in flow regime. Some workers have already suggested that parts of the Schnebly Hill and Coconino were deposited by marine sand waves on a shallow continental shelf; a hypothesis that is considerably strengthened in light of these new data along with additional petrographic data that we have collected

Male-male mounting and the unreliability of body size as a character for mate choice in male Japanese beetles (Popillia japonica Newman)

Background: Same-sex pairing is common in many animal species. In many insects, same-sex pairing is often thought to be a result of poor sexual discrimination (i.e., a mistake), but few detailed studies of the mechanisms underlying the mistaken pairing have been conducted. Previous studies have found that in the field, a small proportion of Japanese beetle (Popillia japonica) mating pairs consist of two males instead of a male and a female. In the current study, we investigated the relationship between body size, the tendency to mount other males, and the duration of these mounts, in laboratory experiments on male Japanese beetles. Results: In the first experiment, we observed male-male mounting in all-male groups in which each male had been uniquely marked. Males of all sizes were likely to mount other males and extend their aedeagus (copulatory organ), but the mounts were longer, and aedeagus extension was more likely to occur, if the mounted beetle (in the ‘female’ position) was larger than the mounting beetle (in the ‘male’ position). In the second experiment, we observed male-female behavior in mixed-sex groups. Females did not immediately copulate with males that had mounted them. If copulation did occur, males tended to remain on the back of females for an extended period of time. Males that mounted other males in mixed-sex groups tended to mate subsequently with a female and then stay with her. Conclusions: We propose that the minimal physical difference between the sexes, in combination with benefits to the males of rapidly attempting to pair with any available female, explains the tendency for males to mount other males. Extended mounts may occur because larger individuals are more likely to be female and because of selection on males to persist in a copulation attempt when females do not immediately copulate with a male

Rab11 rescues synaptic dysfunction and behavioural deficits in a Drosophila model of Huntington's disease

Synapse abnormalities in Huntington's disease (HD) patients can precede clinical diagnosis and neuron loss by decades. The polyglutamine expansion in the huntingtin (htt) protein that underlies this disorder leads to perturbations in many cellular pathways, including the disruption of Rab11-dependent endosomal recycling. Impairment of the small GTPase Rab11 leads to the defective formation of vesicles in HD models and may thus contribute to the early stages of the synaptic dysfunction in this disorder. Here, we employ transgenic Drosophila melanogaster models of HD to investigate anomalies at the synapse and the role of Rab11 in this pathology. We find that the expression of mutant htt in the larval neuromuscular junction decreases the presynaptic vesicle size, reduces quantal amplitudes and evoked synaptic transmission and alters larval crawling behaviour. Furthermore, these indicators of early synaptic dysfunction are reversed by the overexpression of Rab11. This work highlights a potential novel HD therapeutic strategy for early intervention, prior to neuronal loss and clinical manifestation of disease

Mucosal exposure to cockroach extract induces allergic sensitization and allergic airway inflammation

<p>Abstract</p> <p>Background</p> <p>Allergic sensitization to aeroallergens develops in response to mucosal exposure to these allergens. Allergic sensitization may lead to the development of asthma, which is characterized by chronic airway inflammation. The objective of this study is to describe in detail a model of mucosal exposure to cockroach allergens in the absence of an exogenous adjuvant.</p> <p>Methods</p> <p>Cockroach extract (CE) was administered to mice intranasally (i.n.) daily for 5 days, and 5 days later mice were challenged with CE for 4 consecutive days. A second group received CE i.n. for 3 weeks. Airway hyperresponsiveness (AHR) was assessed 24 h after the last allergen exposure. Allergic airway inflammation was assessed by BAL and lung histology 48 h after the last allergen exposure. Antigen-specific antibodies were assessed in serum. Lungs were excised from mice from measurement of cytokines and chemokines in whole lung lysate.</p> <p>Results</p> <p>Mucosal exposure of Balb/c mice to cockroach extract induced airway eosinophilic inflammation, AHR and cockroach-specific IgG1; however, AHR to methacholine was absent in the long term group. Lung histology showed patchy, multicentric damage with inflammatory infiltrates at the airways in both groups. Lungs from mice from the short term group showed increased IL-4, CCL11, CXCL1 and CCL2 protein levels. IL4 and CXCL1 were also increased in the BAL of cockroach-sensitized mice in the short-term protocol.</p> <p>Conclusions</p> <p>Mucosal exposure to cockroach extract in the absence of adjuvant induces allergic airway sensitization characterized by AHR, the presence of Th2 cytokines in the lung and eosinophils in the airways.</p

Inequity in access to transplantation in the UK

Background and objectives Despite the presence of a universal health care system, it is unclear if there is intercenter variation in access to kidney transplantation in the United Kingdom. This study aims to assess whether equity exists in access to kidney transplantation in the United Kingdom after adjustment for patient-specific factors and center practice patterns. Design, setting, participants, & measurements In this prospective, observational cohort study including all 71 United Kingdom kidney centers, incident RRT patients recruited between November 2011 and March 2013 as part of the Access to Transplantation and Transplant Outcome Measures study were analyzed to assess preemptive listing (n=2676) and listing within 2 years of starting dialysis (n=1970) by center. Results Seven hundred and six participants (26%) were listed preemptively, whereas 585 (30%) were listed within 2 years of commencing dialysis. The interquartile range across centers was 6%–33% for preemptive listing and 25%–40% for listing after starting dialysis. Patient factors, including increasing age, most comorbidities, body mass index >35 kg/m2, and lower socioeconomic status, were associated with a lower likelihood of being listed and accounted for 89% and 97% of measured intercenter variation for preemptive listing and listing within 2 years of starting dialysis, respectively. Asian (odds ratio, 0.49; 95% confidence interval, 0.33 to 0.72) and Black (odds ratio, 0.43; 95% confidence interval, 0.26 to 0.71) participants were both associated with reduced access to preemptive listing; however Asian participants were associated with a higher likelihood of being listed after starting dialysis (odds ratio, 1.42; 95% confidence interval, 1.12 to 1.79). As for center factors, being registered at a transplanting center (odds ratio, 3.1; 95% confidence interval, 2.36 to 4.07) and a universal approach to discussing transplantation (odds ratio, 1.4; 95% confidence interval, 1.08 to 1.78) were associated with higher preemptive listing, whereas using a written protocol was associated negatively with listing within 2 years of starting dialysis (odds ratio, 0.7; 95% confidence interval, 0.58 to 0.9). Conclusions Patient case mix accounts for most of the intercenter variation seen in access to transplantation in the United Kingdom, with practice patterns also contributing some variation. Socioeconomic inequity exists despite having a universal health care system