Effect of hypoxia on lung gene expression and proteomic profile: insights into the pulmonary surfactant response

Exposure of lung to hypoxia has been previously reported to be associated with significant alterations in the protein content of bronchoalveolar lavage (BAL) and lung tissue. In the present work we have used a proteomic approach to describe the changes in protein complement induced by moderate long-term hypoxia (rats exposed to 10% O2 for 72h) in BAL and lung tissue, with a special focus on the proteins associated with pulmonary surfactant, which could indicate adaptation of this system to limited oxygen availability. The analysis of the general proteomic profile indicates a hypoxia-induced increase in proteins associated with inflammation both in lavage and lung tissue. Analysis at mRNA and protein levels revealed no significant changes induced by hypoxia on the content in surfactant proteins or their apparent oligomeric state. In contrast, we detected a hypoxia-induced significant increase in the expression and accumulation of hemoglobin in lung tissue, at both mRNA and protein levels, as well as an accumulation of hemoglobin both in BAL and associated with surface-active membranes of the pulmonary surfactant complex. Evaluation of pulmonary surfactant surface activity from hypoxic rats showed no alterations in its spreading ability, ruling out inhibition by increased levels of serum or inflammatory proteins.Ministerio de Ciencia BIO2012-30733Ministerio de Ciencia CSD2007-00010Gobierno de la Comunidad de Madrid S2009MAT-1507National Institutes of Health NIH HL3478

Enhancing e-Infrastructures with Advanced Technical Computing: Parallel MATLAB® on the Grid

MATLAB® is widely used within the engineering and scientific fields as the language and environment for technical computing, while collaborative Grid computing on e-Infrastructures is used by scientific communities to deliver a faster time to solution. MATLAB allows users to express parallelism in their applications, and then execute code on multiprocessor environments such as large-scale e-Infrastructures. This paper demonstrates the integration of MATLAB and Grid technology with a representative implementation that uses gLite middleware to run parallel programs. Experimental results highlight the increases in productivity and performance that users obtain with MATLAB parallel computing on Grids

Of, By, and For the People? How Demographic Pressure Affects Participation in Inter- and Intra-State Conflicts

Under what circumstances do demographic factors motivate states to engage in inter-state conflict, and when do these factors lead to civil conflict? IR and comparative politics scholars have investigated the links between population and conflict, but two common limitations are common in such studies. First, scholars have failed to differentiate between the demographic causes of inter-state (between countries) and civil conflict, as these conflict processes are not often addressed in the same study. Second, scholars have failed to define and explain adequately the difference between demographic change and demographic pressure.This project addresses these two limitations in the current research. First, I propose a second-image explanation of conflict which rests on the contractual relationship between the state and society. As the state collects rents from society to provide services, so society expects services for rents paid. When this relationship is disrupted by demographic pressure, states must respond to forestall regime change or state breakdown. If the state cannot extract rents internally, they may pursue external options to acquire additional resources. Failure to attain resources may result in internal conflict as domestic groups simultaneously evaluate the effectiveness of the government in meeting societal demands.The second limitation this project addresses is the conceptual imprecision of 'demographic pressure'. I distinguish between demographic change and demographic pressure by accounting for state capacity. All states experience demographic change, but many states have the capacity to adapt to these changes. States experiencing economic hardship, however, face 'pressure' when demographic changes cannot be accommodated easily with existing economic stagnation.I utilize two large cross-national datasets, covering the post-World War II period to test my theoretical link between demographic pressure and inter-state and civil conflict while controlling for state, dyadic and systemic factors. The empirical analysis supports my primary hypotheses that demographic pressure is associated with an increased likelihood of both inter- and intra-state conflict. Additional hypotheses to determine more specific conditions under which this increased likelihood holds generated mixed results; however, the robustness of the demographic pressure measure confirms that demographic pressure is an important predictor of both civil and inter-state conflict

The (co-)occurrence of problematic video gaming, substance use, and psychosocial problems in adolescents

Aims. The current study explored the nature of problematic (addictive) video gaming and the association with game type, psychosocial health, and substance use. Methods. Data were collected using a paper and pencil survey in the classroom setting. Three samples were aggregated to achieve a total sample of 8478 unique adolescents. Scales included measures of game use, game type, the Video game Addiction Test (VAT), depressive mood, negative self-esteem, loneliness, social anxiety, education performance, and use of cannabis, alcohol and nicotine (smoking). Results. Findings confirmed problematic gaming is most common amongst adolescent gamers who play multiplayer online games. Boys (60%) were more likely to play online games than girls (14%) and problematic gamers were more likely to be boys (5%) than girls (1%). High problematic gamers showed higher scores on depressive mood, loneliness, social anxiety, negative self-esteem, and self-reported lower school performance. Nicotine, alcohol, and cannabis using boys were almost twice more likely to report high PVG than non-users. Conclusions. It appears that online gaming in general is not necessarily associated with problems. However, problematic gamers do seem to play online games more often, and a small subgroup of gamers – specifically boys – showed lower psychosocial functioning and lower grades. Moreover, associations with alcohol, nicotine, and cannabis use are found. It would appear that problematic gaming is an undesirable problem for a small subgroup of gamers. The findings encourage further exploration of the role of psychoactive substance use in problematic gaming

Clinical biological and genetic heterogeneity of the inborn errors of pulmonary surfactant metabolism

Pulmonary surfactant is a multimolecular complex located at the air-water interface within the alveolus to which a range of physical (surface-active properties) and immune functions has been assigned. This complex consists of a surface-active lipid layer (consisting mainly of phospholipids), and of an aqueous subphase. From discrete surfactant sub-fractions one can isolate strongly hydrophobic surf acta nt proteins B (SP-B) and C (SP-C) as well as collectins SP-A and SP-D, which were shown to have specific structural, metabolic, or immune properties. Inborn or acquired abnormalities of the surfactant, qualitative or quantitative in nature, account for a number of human diseases. Beside hyaline membrane disease of the preterm neonate, a cluster of hereditary or acquired lung diseases has been characterized by periodic acid-Schiff-positive material filling the alveoli. From this heterogeneous nosologic group, at least two discrete entities presently emerge. The first is the SP-B deficiency, in which an essentially proteinaceous material is stored within the alveoli, and which represents an autosomal recessive Mendelian entity linked to the SFTPB gene (MIM 1786640). The disease usually generally entails neonatal respiratory distress with rapid fatal outcome, although partial or transient deficiencies have also been observed. The second is alveolar proteinosis, characterized by the storage of a mixed protein and lipid material, which constitutes a relatively heterogeneous clinical and biological syndrome, especially with regard to age at onset (from the neonate through to adulthood) as well as the severity of associated signs. Murine models, with a targeted mutation of the gene encoding granulocyte macrophage colony-stimulating factor (GM-CSF) (Csfgm) or the beta subunit of its receptor (II3rb1) support the hypothesis of an abnormality of surfactant turnover in which the alveolar macrophage is a key player. Apart from SP-B deficiency, in which a near-consensus diagnostic chart can be designed, the ascertainment of other abnormalities of surfactant metabolism is not straightforward. The disentanglement of this disease cluster is however essential to propose specific therapeutic procedures: repeated broncho-alveolar ravages, GM-CSF replacement, bone marrow grafting or lung transplantation

The androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate cancer.

This is the final version of the article. Available from Impact Journals via the DOI in this record.Patterns of glycosylation are important in cancer, but the molecular mechanisms that drive changes are often poorly understood. The androgen receptor drives prostate cancer (PCa) development and progression to lethal metastatic castration-resistant disease. Here we used RNA-Seq coupled with bioinformatic analyses of androgen-receptor (AR) binding sites and clinical PCa expression array data to identify ST6GalNAc1 as a direct and rapidly activated target gene of the AR in PCa cells. ST6GalNAc1 encodes a sialytransferase that catalyses formation of the cancer-associated sialyl-Tn antigen (sTn), which we find is also induced by androgen exposure. Androgens induce expression of a novel splice variant of the ST6GalNAc1 protein in PCa cells. This splice variant encodes a shorter protein isoform that is still fully functional as a sialyltransferase and able to induce expression of the sTn-antigen. Surprisingly, given its high expression in tumours, stable expression of ST6GalNAc1 in PCa cells reduced formation of stable tumours in mice, reduced cell adhesion and induced a switch towards a more mesenchymal-like cell phenotype in vitro. ST6GalNAc1 has a dynamic expression pattern in clinical datasets, beingsignificantly up-regulated in primary prostate carcinoma but relatively down-regulated in established metastatic tissue. ST6GalNAc1 is frequently upregulated concurrently with another important glycosylation enzyme GCNT1 previously associated with prostate cancer progression and implicated in Sialyl Lewis X antigen synthesis. Together our data establishes an androgen-dependent mechanism for sTn antigen expression in PCa, and are consistent with a general role for the androgen receptor in driving important coordinate changes to the glycoproteome during PCa progression.The authors would like to thank Mr Robert Jackson and Mr Ben Lee for technical assistance, Dr Stuart Williamson for kindly providing us with the prostate tissue lysates used in this study and Exeter NIHR Clinical Research Facility for providing patient RNA. This work was funded by Prostate Cancer UK (PG12-34), The J. G. W Patterson Foundation, The Wellcome Trust (grant numbers WT080368MA and WT089225/Z/09/Z) and BBSRC (grant BB/1006923/1 and BB/J007293/1). I.G.M. is supported in Oslo by funding the Norwegian Research Council, Helse Sor-Ost and the University of Oslo through the Centre for Molecular Medicine (Norway), which is the part of the Nordic EMBL (European Molecular Biology Laboratory) partnership and also supported by Oslo University Hospitals. I.G.M. is also supported by the Norwegian Cancer Society. I.G.M. holds a visiting scientist position with Cancer Research UK through the Cambridge Research Institute and a Senior Visiting Research Fellowship with Cambridge University through the Department of Oncology. I.G.M is supported in Belfast by the Belfast-Manchester Movember Centre of Excellence (CE013_2-004), funded in partnership with Prostate Cancer UK

Study of human SP-A, SP-B and SP-D loci: allele frequencies, linkage disequilibrium and heterozygosity in different races and ethnic groups

BACKGROUND: SP-A, SP-B, and SP-D are pulmonary surfactant proteins. Several linkage and association studies have been done using these genes as markers to locate pulmonary disease susceptibility genes, but few have studied the markers systematically in different ethnic groups. Here we studied eight markers in SP-A, SP-B, and SP-D genes in seven ethnic groups from three races (Caucasian, Black and Hispanic). We measured the similarity of the marker distribution among the ethnic groups in order to see whether people in different ethnic groups or races could be mixed together for linkage and association studies. To evaluate the usefulness of these markers, we estimated the informativeness of each marker loci in the seven ethnic groups by assessing their heterozygosity and PIC values. We also conducted linkage disequilibrium (LD) analysis to identify associated marker loci and to estimate the haplotype frequencies in each of the seven ethnic groups in an attempt to find valuable haplotypes so that the level of polymorphism of the "markers" could be increased. RESULTS: Our findings indicate that allele and genotype frequencies may be different between different ethnic groups, especially between ethnic groups from different races. The markers are in general polymorphic in a variety of study groups, especially for the two SP-A1 and SP-A2 markers. Two-locus LD analysis reveals that three pairs of loci are strongly associated together: B-18(A/C) with B1013(A/C), DA11(C/T) with DA160(A/G), SP-A1 with SP-A2. Three-locus LD analysis suggests that B-18(A/C), B1013(A/C) and B1580(C/T) are strongly associated with each other. CONCLUSIONS: Allele and genotype frequency differences imply that different ethnic groups should be mixed with extreme caution before performing linkage and association studies. The associated markers could be used together to increase the level of polymorphism and the informativeness of the "markers"

The impact of surfactant protein-A on ozone-induced changes in the mouse bronchoalveolar lavage proteome

<p>Abstract</p> <p>Background</p> <p>Ozone is a major component of air pollution. Exposure to this powerful oxidizing agent can cause or exacerbate many lung conditions, especially those involving innate immunity. Surfactant protein-A (SP-A) plays many roles in innate immunity by participating directly in host defense as it exerts opsonin function, or indirectly via its ability to regulate alveolar macrophages and other innate immune cells. The mechanism(s) responsible for ozone-induced pathophysiology, while likely related to oxidative stress, are not well understood.</p> <p>Methods</p> <p>We employed 2-dimensional difference gel electrophoresis (2D-DIGE), a discovery proteomics approach, coupled with MALDI-ToF/ToF to compare the bronchoalveolar lavage (BAL) proteomes in wild type (WT) and SP-A knockout (KO) mice and to assess the impact of ozone or filtered air on the expression of BAL proteins. Using the PANTHER database and the published literature most identified proteins were placed into three functional groups.</p> <p>Results</p> <p>We identified 66 proteins and focused our analysis on these proteins. Many of them fell into three categories: defense and immunity; redox regulation; and protein metabolism, modification and chaperones. In response to the oxidative stress of acute ozone exposure (2 ppm; 3 hours) there were many significant changes in levels of expression of proteins in these groups. Most of the proteins in the redox group were decreased, the proteins involved in protein metabolism increased, and roughly equal numbers of increases and decreases were seen in the defense and immunity group. Responses between WT and KO mice were similar in many respects. However, the percent change was consistently greater in the KO mice and there were more changes that achieved statistical significance in the KO mice, with levels of expression in filtered air-exposed KO mice being closer to ozone-exposed WT mice than to filtered air-exposed WT mice.</p> <p>Conclusion</p> <p>We postulate that SP-A plays a role in reactive oxidant scavenging in WT mice and that its absence in the KO mice in the presence or absence of ozone exposure results in more pronounced, and presumably chronic, oxidative stress.</p

Maintaining Disorder: Some Technical and Aesthetic Issues Involved in the Performance of Ligeti’s E´ tudes for Piano

This article examines some of the particular questions and associated strategies concerning matters of rhythm, perceived metre, notation, accentuation, line, physical approach to the keyboard, pedalling, and more in the performance of Ligeti’s Études for piano. I relate these issues to those encountered in earlier repertoire, including works of Schumann, Liszt, Stravinsky, Prokofiev, Bartók and Blacher, and argue that particular approaches and attitudes to both technical and musical matters in the context of these Études can fundamentally affect the concept of the music. A particular focus is upon issues of continuity and discontinuity, and the ‘situation’ of these works within particular pianistic and other traditions by virtue of the approach taken to performance