Microparticle alpha-2-macroglobulin enhances pro-resolving responses and promotes survival in sepsis

These studies were supported by The Wellcome Trust (program 086867/Z/08) and the William Harvey Research Foundation to MP, the United Kingdom Intensive Care Society to CJH and the National Institutes of Health GM Grant P01GM095967 (awarded to Charles N. Serhan). LVN is supported by an Arthritis Research UK Career Development Fellowship (19909). EPSRC Seed Funding Cross disciplinary Grant (QMUL) awarded to GBS and MP. This work forms part of the research themes contributing to the translational research portfolio of Barts and The London NIHR Cardiovascular BRU

The Forward-Discount Puzzle in Central and Eastern Europe

This paper adds to evidence that the forward-discount puzzle is at least partly explained as a compensation for taking crash-risk. A number of Central and Eastern European exchange rates are compared. A Hidden Markov Model is used to identify two regimes for most of the exchange rates. These two regimes can be characterised as being either periods of stability or periods of instability. The level of international risk aversion and changes in US interest rates affect the probability of switching from one regime to the other. This model is then used to assess the way that these two factors affect the probability of a currency crisis. While the Czech Republic, Hungary and Bulgaria are very sensitive to international financial conditions, Poland and Romania are relatively immune. JEL classifications: C24, F31, F32; Key words: Exchange rates, uncovered interest parity, foreign exchange risk discount, hidden-Markov model, carry-trad

Understanding the Role of PknJ in Mycobacterium tuberculosis: Biochemical Characterization and Identification of Novel Substrate Pyruvate Kinase A

Reversible protein phosphorylation is a prevalent signaling mechanism which modulates cellular metabolism in response to changing environmental conditions. In this study, we focus on previously uncharacterized Mycobacterium tuberculosis Ser/Thr protein kinase (STPK) PknJ, a putative transmembrane protein. PknJ is shown to possess autophosphorylation activity and is also found to be capable of carrying out phosphorylation on the artificial substrate myelin basic protein (MyBP). Previous studies have shown that the autophosphorylation activity of M. tuberculosis STPKs is dependent on the conserved residues in the activation loop. However, our results show that apart from the conventional conserved residues, additional residues in the activation loop may also play a crucial role in kinase activation. Further characterization of PknJ reveals that the kinase utilizes unusual ions (Ni2+, Co2+) as cofactors, thus hinting at a novel mechanism for PknJ activation. Additionally, as shown for other STPKs, we observe that PknJ possesses the capability to dimerize. In order to elucidate the signal transduction cascade emanating from PknJ, the M. tuberculosis membrane-associated protein fraction is treated with the active kinase and glycolytic enzyme Pyruvate kinase A (mtPykA) is identified as one of the potential substrates of PknJ. The phospholabel is found to be localized on serine and threonine residue(s), with Ser37 identified as one of the sites of phosphorylation. Since Pyk is known to catalyze the last step of glycolysis, our study shows that the fundamental pathways such as glycolysis can also be governed by STPK-mediated signaling

Has the Euro changed business cycle synchronization? Evidence from the core and the periphery

Using a Bayesian dynamic factor model, I examine the comovement of output, investmentand consumption growth among Euro area countries before and after the introduction of theEuro. For that purpose, I compare a pre-Euro period (19911998) to a Euro period(20002010) and identify a common Euro factor for each period separately. I find thatthe comovement of main macroeconomic variables and the common factor increases forcore Eurozone countries from the first to the second period, while it decreases for mostperipheral economies. This can be interpreted as a rise in business cycle synchronizationfor the core and a respective decline for the periphery.Different to the implications made by the endogeneity argument of currency areas(Frankel and Rose, 1998), my evidence suggest that the introduction of the Euro hasfostered imbalances between core and peripheral Eurozone countries

Proteins with Complex Architecture as Potential Targets for Drug Design: A Case Study of Mycobacterium tuberculosis

Lengthy co-evolution of Homo sapiens and Mycobacterium tuberculosis, the main causative agent of tuberculosis, resulted in a dramatically successful pathogen species that presents considerable challenge for modern medicine. The continuous and ever increasing appearance of multi-drug resistant mycobacteria necessitates the identification of novel drug targets and drugs with new mechanisms of action. However, further insights are needed to establish automated protocols for target selection based on the available complete genome sequences. In the present study, we perform complete proteome level comparisons between M. tuberculosis, mycobacteria, other prokaryotes and available eukaryotes based on protein domains, local sequence similarities and protein disorder. We show that the enrichment of certain domains in the genome can indicate an important function specific to M. tuberculosis. We identified two families, termed pkn and PE/PPE that stand out in this respect. The common property of these two protein families is a complex domain organization that combines species-specific regions, commonly occurring domains and disordered segments. Besides highlighting promising novel drug target candidates in M. tuberculosis, the presented analysis can also be viewed as a general protocol to identify proteins involved in species-specific functions in a given organism. We conclude that target selection protocols should be extended to include proteins with complex domain architectures instead of focusing on sequentially unique and essential proteins only

Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer

We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 x 10(-8)), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 x 10(-9)). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 x 10(-6)) than in HPV-negative (OR = 0.75, P = 0.16) cancers

Genomic analysis of Acinetobacter baumannii prophages reveals remarkable diversity and suggests significant impact on bacterial virulence and fitness

[Abstract] Bacterial genomics has revealed substantial amounts of prophage DNA in bacterial genomes. This integrated viral DNA has been shown to play important roles in the evolution of bacterial pathogenicity. Acinetobacter baumannii has shown a fast progression as a nosocomial multi-resistant pathogen in recent years, and is now considered one of the most dangerous microorganisms in hospital environments. The role of prophages in the evolution of A. baumannii pathogenicity has not yet been explored. In this context, we aimed at evaluating the impact of prophages on A. baumannii genomic diversity and pathogenicity. [...]info:eu-repo/semantics/publishedVersio

Mining the human phenome using allelic scores that index biological intermediates

J. Kaprio ja M-L. Lokki työryhmien jäseniä.It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.Peer reviewe

Does Integration and Economic Policy Coordination Promote Business Cycle Synchronization in the EU?

Previous studies have discounted important factors and indirect channels that might contribute to business cycle synchronization (BSC) in the EU. We estimate the effects of market integration and economic policy coordination on bilateral business cycle correlations over the period 1995-2012 using a simultaneous equations model that takes into accounts both the endogenous relationships and unveils direct and indirect effects. The results suggest that (i) trade and FDI have a pronounced positive effect on BCS, particularly between incumbent and new EU members. (ii) Rising specialization does not decouple business cycles. (iii) The decline of income disparities in EU27 contributes to BCS, as converging countries develop stronger trade and FDI linkages. (iv) There is strong evidence that poor fiscal discipline of EU members is a major impediment of business cycle synchronization. (v) The same argument holds true for exchange rate fluctuations that hinder BCS, particularly in EU15. Since BCS is a fundamental prerequisite and objective in an effective monetary union, the EU has to promote market integration and strengthen the common setting of economic policies

Tropospheric emissions: Monitoring of pollution (TEMPO)

TEMPO was selected in 2012 by NASA as the first Earth Venture Instrument, for launch between 2018 and 2021. It will measure atmospheric pollution for greater North America from space using ultraviolet and visible spectroscopy. TEMPO observes from Mexico City, Cuba, and the Bahamas to the Canadian oil sands, and from the Atlantic to the Pacific, hourly and at high spatial resolution (~2.1kmN/S x 4.4 kmE/W at 36.5°N, 100°W). TEMPO provides a tropospheric measurement suite that includes the key elements of tropospheric air pollution chemistry, as well as contributing to carbon cycle knowledge. Measurements are made hourly from geostationary (GEO) orbit, to capture the high variability present in the diurnal cycle of emissions and chemistry that are unobservable from current low-Earth orbit (LEO) satellites that measure once per day. The small product spatial foot print resolves pollution sources at sub-urban scale. Together, this temporal and spatial resolution improves emission inventories, monitors population exposure, and enables effective emission-control strategies. TEMPO takes advantage of a commercial GEO host space craft to provide a modest cost mission that measures the spectra required to retrieve ozone(O3), nitrogen dioxide(NO2), sulfur dioxide(SO2), formaldehyde(H2CO), glyoxal (C2H2O2), bromine monoxide(BrO), IO (iodine monoxide), water vapor, aerosols, cloud parameters, ultraviolet radiation,and foliage properties. TEMPO thus measures the major elements,directly or by proxy, in the tropospheric O3 chemistry cycle. Multi-spectral observations provide sensitivity to O3 in the lower most troposphere, substantially reducing uncertainty in air quality predictions. TEMPO quantifies and tracks the evolution of aerosol loading. It provides these near-real- time air quality products that will be made publicly available. TEMPO will launch at a prime time to be the North American component of the global geostationary constellation of pollution monitoring together with the European Sentinel-4 (S4) and Korean Geostationary Environment Monitoring Spectrometer (GEMS) instruments