Differential gene expression patterns in cyclooxygenase-1 and cyclooxygenase-2 deficient mouse brain

BACKGROUND: Cyclooxygenase (COX)-1 and COX-2 produce prostanoids from arachidonic acid and are thought to have important yet distinct roles in normal brain function. Deletion of COX-1 or COX-2 results in profound differences both in brain levels of prostaglandin E(2 )and in activation of the transcription factor nuclear factor-κB, suggesting that COX-1 and COX-2 play distinct roles in brain arachidonic acid metabolism and regulation of gene expression. To further elucidate the role of COX isoforms in the regulation of the brain transcriptome, microarray analysis of gene expression in the cerebral cortex and hippocampus of mice deficient in COX-1 (COX-1(-/-)) or COX-2 (COX-2(-/-)) was performed. RESULTS: A majority (>93%) of the differentially expressed genes in both the cortex and hippocampus were altered in one COX isoform knockout mouse but not the other. The major gene function affected in all genotype comparisons was 'transcriptional regulation'. Distinct biologic and metabolic pathways that were altered in COX(-/- )mice included β oxidation, methionine metabolism, janus kinase signaling, and GABAergic neurotransmission. CONCLUSION: Our findings suggest that COX-1 and COX-2 differentially modulate brain gene expression. Because certain anti-inflammatory and analgesic treatments are based on inhibition of COX activity, the specific alterations observed in this study further our understanding of the relationship of COX-1 and COX-2 with signaling pathways in brain and of the therapeutic and toxicologic consequences of COX inhibition

Year-round stratospheric aerosol backscatter ratios calculated from lidar measurements above northern Norway

We present a new method for calculating backscatter ratios of the stratospheric sulfate aerosol (SSA) layer from daytime and nighttime lidar measurements. Using this new method we show a first year-round dataset of stratospheric aerosol backscatter ratios at high latitudes. The SSA layer is located at altitudes between the tropopause and about 30 km. It is of fundamental importance for the radiative balance of the atmosphere. We use a state-of-the-art Rayleigh-Mie-Raman lidar at the Arctic Lidar Observatory for Middle Atmosphere Research (ALOMAR) station located in northern Norway (69N, 16E; 380ma.s.l.). For nighttime measurements the aerosol backscatter ratios are derived using elastic and inelastic backscatter of the emitted laser wavelengths 355, 532 and 1064nm. The setup of the lidar allows measurements with a resolution of about 5 min in time and 150 m in altitude to be performed in high quality, which enables the identification of multiple sub-layers in the stratospheric aerosol layer of less than 1 km vertical thickness. We introduce a method to extend the dataset throughout the summer when measurements need to be performed under permanent daytime conditions. For that purpose we approximate the backscatter ratios from color ratios of elastic scattering and apply a correction function. We calculate the correction function using the average backscatter ratio profile at 355nm from about 1700 h of nighttime measurements from the years 2000 to 2018. Using the new method we finally present a year-round dataset based on about 4100 h of measurements during the years 2014 to 2017. © Author(s) 2019

IL-17A and serum amyloid A are elevated in a cigarette smoke cessation model associated with the persistence of pigmented macrophages, neutrophils and activated NK cells

While global success in cessation advocacy has seen smoking rates fall in many developed countries, persistent lung inflammation in ex-smokers is an increasingly important clinical problem whose mechanistic basis remains poorly understood. In this study, candidate effector mechanisms were assessed in mice exposed to cigarette smoke (CS) for 4 months following cessation from long term CS exposure. BALF neutrophils, CD4+ and CD8+ T cells and lung innate NK cells remained significantly elevated following smoking cessation. Analysis of neutrophil mobilization markers showed a transition from acute mediators (MIP-2α, KC and G-CSF) to sustained drivers of neutrophil and macrophage recruitment and activation (IL-17A and Serum Amyoid A (SAA)). Follicle-like lymphoid aggregates formed with CS exposure and persisted with cessation, where they were in close anatomical proximity to pigmented macrophages, whose number actually increased 3-fold following CS cessation. This was associated with the elastolytic protease, MMP-12 (macrophage metallo-elastase) which remained significantly elevated post-cessation. Both GM-CSF and CSF-1 were significantly increased in the CS cessation group relative to the control group. In conclusion, we show that smoking cessation mediates a transition to accumulation of pigmented macrophages, which may contribute to the expanded macrophage population observed in COPD. These macrophages together with IL-17A, SAA and innate NK cells are identified here as candidate persistence determinants and, we suggest, may represent specific targets for therapies directed towards the amelioration of chronic airway inflammation

Neonatal pneumococcal colonisation caused by Influenza A infection alters lung function in adult mice

There is emerging epidemiological data to suggest that upper respiratory tract bacterial colonisation in infancy may increase the risk of developing respiratory dysfunction later in life, and respiratory viruses are known to precipitate persistent colonisation. This study utilized a neonatal mouse model of Streptococcus pneumonia (SP) and influenza A virus (IAV) co-infection, where bronchoalveolar leukocyte infiltration had resolved by adulthood. Only co-infection resulted in persistent nasopharyngeal colonisation over 40 days and a significant increase in airway resistance in response to in vivo methacholine challenge. A significant increase in hysteresivity was also observed in IAV and co-infected mice, consistent with ventilatory heterogeneity and structural changes in the adult lung. Airway hyper-responsiveness was not associated with a detectable increase in goblet cell transdifferentiation, peribronchial smooth muscle bulk or collagen deposition in regions surrounding the airways. Increased reactivity was not observed in precision cut lung slices challenged with methacholine in vitro. Histologically, the airway epithelium appeared normal and expression of epithelial integrity markers (ZO-1, occludin-1 and E-cadherin) were not altered. In summary, neonatal co-infection led to persistent nasopharyngeal colonisation and increased airway responsiveness that was not associated with detectable smooth muscle or mucosal epithelial abnormalities, however increased hysteresivity may reflect ventilation heterogeneity

Seismic behaviour of traditional timber frame walls: experimental results on unreinforced walls

Timber frame buildings are well known as an efficient seismic resistant structure and they are used worldwide. Moreover, they have been specifically adopted in codes and regulations during the XVIII and XIX centuries in the Mediterranean area. These structures generally consist of exterior masonry walls with timber elements embedded which tie the walls together and internal walls which have a timber frame with masonry infill and act as shearwalls. In order to preserve these structureswhich characterizemany cities in theworld it is important to better understand their behaviour under seismic actions. Furthermore, historic technologies could be used even in modern constructions to build seismic resistant buildings using more natural materials with lesser costs. Generally, different types of infill could be applied to timber frame walls depending on the country, among which brick masonry, rubble masonry, hay and mud. The focus of this paper is to study the seismic behaviour of the walls considering different types of infill, specifically: masonry infill, lath and plaster and timber frame with no infill. Static cyclic tests have been performed on unreinforced timber frame walls in order to study their seismic capacity in terms of strength, stiffness, ductility and energy dissipation. The tests showed how in the unreinforced condition, the infill is able to guarantee a greater stiffness, ductility and ultimate capacity of the wall.The authors would like to acknowledge Eng. Filipe Ferreira and A.O.F. (Augusto Oliveira Ferreira & C Lda.) for their expertise and collaboration in the construction of the wall specimens. The first author would also like to acknowledge the Portuguese Science and Technology Foundation (FCT) for its financial support through grant SFRH / BD / 61908 / 2009

Sociodemographic factors and delays in the diagnosis of six cancers: analysis of data from the ‘National Survey of NHS Patients: Cancer'

This paper aims to explore the relationship between sociodemographic factors and the components of diagnostic delay (total, patient and primary care, referral, secondary care) for these six cancers (breast, colorectal, lung, ovarian, prostate, or non-Hodgkin's lymphoma). Secondary analysis of patient-reported data from the ‘National Survey of NHS patients: Cancer' was undertaken (65 192 patients). Data were analysed using univariate analysis and Generalised Linear Modelling. With regard to total delay, the findings from the GLM showed that for colorectal cancer, the significant factors were marital status and age, for lung and ovarian cancer none of the factors were significant, for prostate cancer the only significant factor was social class, for non-Hodgkin's lymphoma the only significant factor was age, and for breast cancer the significant factors were marital status and ethnic group. Where associations between any of the component delays were found, the direction of the association was always in the same direction (female subjects had longer delays than male subjects, younger people had longer delays than older people, single and separated/divorced people had longer delays than married people, lower social class groups had longer delays than higher social class groups, and Black and south Asian people had longer delays than white people). These findings should influence the design of interventions aimed at reducing diagnostic delays with the aim of improving morbidity, mortality, and psychological outcomes through earlier stage diagnosis

Impaired mucosal defense to acute colonic injury in mice lacking cyclooxygenase-1 or cyclooxygenase-2

To investigate roles in intestinal inflammation for the 2 cyclooxygenase (COX) isoforms, we determined susceptibility to spontaneous and induced acute colitis in mice lacking either the COX-1 or COX-2 isoform. We treated wild-type, COX-1–/–, COX-2–/–, and heterozygous mice with dextran sodium sulfate (DSS) to provoke acute colonic inflammation, and we quantified tissue damage, prostaglandin (PG) E2, and interleukin-1β. No spontaneous gastrointestinal inflammation was detected in mice homozygous for either mutation, despite almost undetectable basal intestinal PGE2 production in COX-1–/– mice. Both COX-1–/– and COX-2–/– mice showed increased susceptibility to a low-dose of DSS that caused mild colonic epithelial injury in wild-type mice. COX-2–/– mice were more susceptible than COX-1–/– mice, and selective pharmacologic blockade of COX-2 potentiated injury in COX-1–/– mice. At a high dose, DSS treatment was fatal to 50% of the animals in each mutant group, but all wild-type mice survived. DSS treatment increased PGE2 intestinal secretion in all groups except COX-2–/– mice. These results demonstrate that COX-1 and COX-2 share a crucial role in the defense of the intestinal mucosa (with inducible COX-2 being perhaps more active during inflammation) and that neither isoform is essential in maintaining mucosal homeostasis in the absence of injurious stimuli

PetaFLOP Molecular Dynamics for Engineering Applications

Molecular dynamics (MD) simulations enable the investigation of multicomponent and multiphase processes relevant to engineering applications, such as droplet coalescence or bubble formation. These scenarios require the simulation of ensembles containing a large number of molecules. We present recent advances within the MD framework ls1 mardyn which is being developed with particular regard to this class of problems. We discuss several OpenMP schemes that deliver optimal performance at node-level. We have further introduced nonblocking communication and communication hiding for global collective operations. Together with revised data structures and vectorization, these improvements unleash PetaFLOP performance and enable multi-trillion atom simulations on the HLRS supercomputer Hazel Hen. We further present preliminary results achieved for droplet coalescence scenarios at a smaller scale.BMBF, 01IH16008, Verbundprojekt: TaLPas - Task-basierte Lastverteilung und Auto-Tuning in der Partikelsimulatio

Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration

AbstractCyclooxygenases 1 and 2 (COX-1 and COX-2) are key enzymes in prostaglandin biosynthesis and the target enzymes for the widely used nonsteroidal anti-inflammatory drugs. To study the physiological roles of the individual isoforms, we have disrupted the mouse Ptgs1 gene encoding COX-1. Homozygous Ptgs1 mutant mice survive well, have no gastric pathology, and show less indomethacin-induced gastric ulceration than wild-type mice, even though their gastric prostaglandin E2 levels are about 1% of wild type. The homozygous mutant mice have reduced platelet aggregation and a decreased inflammatory response to arachidonic acid, but not to tetradecanoyl phorbol acetate. Ptgs1 homozygous mutant females mated to homozygous mutant males produce few live offspring. COX-1-deficient mice provide a useful model to distinguish the physiological roles of COX-1 and COX-2