Conformation study of 2-arylbenzimidazoles as inhibitors of Chlamydia pneumoniae growth

Chlamydia pneumoniae is a worldwide cause of various respiratory track diseases ranging from asymptomatic pharyngeal infection to severe, sometimes fatal pneumonia. We have previously identified 2-arylbenzimidazoles as highly active antichlamydial compounds. In this work the importance of conformational effects on the structure-activity relationship of these compounds was studied. To simplify calculations, properly substituted N-phenylbenzamides, or the corresponding heterocyclic compounds, and 2-arylbenzimidazoles were used as model compounds. They were energy minimized and the energy differences between certain conformations were calculated. The main finding was that the compounds which can more easily adopt a non-planar conformation show higher bioactivity. This finding can be utilized in designing new derivatives or in constructing a pharmacophore model.     

CD200 positive human mesenchymal stem cells suppress TNF-alpha secretion from CD200 receptor positive macrophage-like cells

Human mesenchymal stem cells (hMSCs) display immunosuppressive properties in vitro and the potential has also been transferred successfully to clinical trials for treatment of autoimmune diseases. OX-2 (CD200), a member of the immunoglobulin superfamily, is widely expressed in several tissues and has recently been found from hMSCs. The CD200 receptor (CD200R) occurs only in myeloid-lineage cells. The CD200-CD200R is involved in down-regulation of several immune cells, especially macrophages. The present study on 20 hMSC lines shows that the CD200 expression pattern varied from high (CD200Hi) to medium (CD200Me) and low (CD200Lo) in bone marrow-derived mesenchymal stem cell (BMMSC) lines, whereas umbilical cord blood derived mesenchymal stem cells (UCBMSCs) were constantly negative for CD200. The role of the CD200-CD200R axis in BMMSCs mediated immunosuppression was studied using THP-1 human macrophages. Interestingly, hMSCs showed greater inhibition of TNF-α secretion in co-cultures with IFN-γ primed THP-1 macrophages when compared to LPS activated cells. The ability of CD200Hi BMMSCs to suppress TNF-α secretion from IFN-γ stimulated THP-1 macrophages was significantly greater when compared to CD200Lo whereas UCBMSCs did not significantly reduce TNF-α secretion. The interference of CD200 binding to the CD200R by anti-CD200 antibody weakened the capability of BMMSCs to inhibit TNF-α secretion from IFN-γ activated THP-1 macrophages. This study clearly demonstrated that the efficiency of BMMSCs to suppress TNF-α secretion of THP-1 macrophages was dependent on the type of stimulus. Moreover, the CD200-CD200r axis could have a previously unidentified role in the BMMSC mediated immunosuppression.     

Net atmospheric impacts of forest bioenergy production and utilization in Finnish boreal conditions

The net CO₂ exchange of forests was investigated to study net atmospheric impact of forest bioenergy production (BP) and utilization in Finnish boreal conditions. Net CO₂ exchange was simulated with a life cycle assessment tool over a 90‐year period and over the whole Finland based on National Forest Inventory data. The difference in the net exchanges between the traditional timber production (TP) and BP regime was considered the net atmospheric impact of forest bioenergy utilization. According to the results, forests became net sources of CO₂ after about 20 years of simulation, and the net exchange was higher in the BP regime than in the TP regime until the middle of the simulation period. From 2040 onwards, the net exchange started to decrease in both regimes and became higher in the TP regime, excluding the last decade of the simulation. The shift of forests to becoming a CO₂ source reflected the decrease in CO₂ sequestration due to the increasing share of recently harvested and seedling stands that are acting as sources of CO₂, and an increase of emissions from degradation of wood products. When expressed in terms of radiative forcing, the net atmospheric impact was on average 19% less for bioenergy compared with that for coal energy over the whole simulation period. The results show the importance of time dependence when considering dynamic forest ecosystems in BP and climate change mitigation. Furthermore, the results emphasize the dualistic role and possibilities of forest management in controlling the build and release of carbon into and from the stocks and in controlling the rate of the build speed, i.e. growth. This information is needed in identifying the capability and possibilities of ecosystems to produce biomass for energy, alongside other products and ecosystem services (e.g. pulp wood and timber), and simultaneously to mitigate climate change.     

New insights into Staphylococcus aureus stress tolerance and virulence regulation from an analysis of the role of the ClpP protease in the strains Newman, COL, and SA564

In Staphylococcus aureus, ClpP proteases were previously shown to be essential for virulence and stress tolerance in strains derived from NCTC8325. Because these strains exhibit a severely reduced activity of the alternative sigma factor, SigB, we here reassessed the role of ClpP in SigB-proficient clinical strains. To this end, clpP was deleted in strains COL, Newman, and SA564, and the strains were characterized phenotypically. The proteomic changes accomplished by the clpP deletion in the different strains were analyzed using the 2-D DIGE technique. The proteomic analyses revealed mostly conserved changes in the protein profiles of the ClpP-deficient strains. Among the strain-specific changes were the up-regulation of prophage proteins that coincided with an increased spontaneous release of prophages and the relatively poorer growth of the clpP mutants in some strain backgrounds. Interestingly, the effect of ClpP on the expression of selected virulence genes was strain-dependent despite the fact that the expression of the global virulence regulators RNAIII, mgrA, sarZ, sarR, and arlRS was similarly changed in all clpP mutants. ClpP affected the expression of sarS in a strain-dependent manner, and we propose that the differential expression of sarS is central to the strain-dependent effect of ClpP on the expression of virulence genes.     

Web search queries can predict stock market volumes

We live in a computerized and networked society where many of our actions leave a digital trace and affect other people's actions. This has lead to the emergence of a new data-driven research field: mathematical methods of computer science, statistical physics and sociometry provide insights on a wide range of disciplines ranging from social science to human mobility. A recent important discovery is that search engine traffic (i.e., the number of requests submitted by users to search engines on the www) can be used to track and, in some cases, to anticipate the dynamics of social phenomena. Successful examples include unemployment levels, car and home sales, and epidemics spreading. Few recent works applied this approach to stock prices and market sentiment. However, it remains unclear if trends in financial markets can be anticipated by the collective wisdom of on-line users on the web. Here we show that daily trading volumes of stocks traded in NASDAQ-100 are correlated with daily volumes of queries related to the same stocks. In particular, query volumes anticipate in many cases peaks of trading by one day or more. Our analysis is carried out on a unique dataset of queries, submitted to an important web search engine, which enable us to investigate also the user behavior. We show that the query volume dynamics emerges from the collective but seemingly uncoordinated activity of many users. These findings contribute to the debate on the identification of early warnings of financial systemic risk, based on the activity of users of the www.     

Genetics of microenvironmental sensitivity of body weight in rainbow trout (Oncorhynchus mykiss) selected for improved growth

Microenvironmental sensitivity of a genotype refers to the ability to buffer against non-specific environmental factors, and it can be quantified by the amount of residual variation in a trait expressed by the genotype's offspring within a (macro)environment. Due to the high degree of polymorphism in behavioral, growth and life-history traits, both farmed and wild salmonids are highly susceptible to microenvironmental variation, yet the heritable basis of this characteristic remains unknown. We estimated the genetic (co)variance of body weight and its residual variation in 2-year-old rainbow trout (Oncorhynchus mykiss) using a multigenerational data of 45,900 individuals from the Finnish national breeding programme. We also tested whether or not microenvironmental sensitivity has been changed as a correlated genetic response when genetic improvement for growth has been practiced over five generations. The animal model analysis revealed the presence of genetic heterogeneity both in body weight and its residual variation. Heritability of residual variation was remarkably lower (0.02) than that for body weight (0.35). However, genetic coefficient of variation was notable in both body weight (14%) and its residual variation (37%), suggesting a substantial potential for selection responses in both traits. Furthermore, a significant negative genetic correlation (-0.16) was found between body weight and its residual variation, i.e., rapidly growing genotypes are also more tolerant to perturbations in microenvironment. The genetic trends showed that fish growth was successfully increased by selective breeding (an average of 6% per generation), whereas no genetic change occurred in residual variation during the same period. The results imply that genetic improvement for body weight does not cause a concomitant increase in microenvironmental sensitivity. For commercial production, however, there may be high potential to simultaneously improve weight gain and increase its uniformity if both criteria are included in a selection index.     

Pair-wise multicomparison and OPLS analyses of cold-acclimation phases in Siberian spruce

Analysis of metabolomics data often goes beyond the task of discovering biomarkers and can be aimed at recovering other important characteristics of observed metabolomic changes. In this paper we explore different methods to detect the presence of distinctive phases in seasonal-responsive changes of metabolomic patterns of Siberian spruce (Picea obovata) during cold acclimation occurred in the period from mid-August to January. Multivariate analysis, specifically orthogonal projection to latent structures discriminant analysis (OPLS-DA), identified time points where the metabolomic patterns underwent substantial modifications as a whole, revealing four distinctive phases during acclimation. This conclusion was re-examined by a univariate analysis consisting of multiple pair-wise comparisons to identify homogeneity intervals for each metabolite. These tests complemented OPLS-DA, clarifying biological interpretation of the classification: about 60% of metabolites found responsive to the cold stress indeed changed at one or more of the time points predicted by OPLS-DA. However, the univariate approach did not support the proposed division of the acclimation period into four phases: less than 10% of metabolites altered during the acclimation had homogeneous levels predicted by OPLS-DA. This demonstrates that coupling the classification found by OPLS-DA and the analysis of dynamics of individual metabolites obtained by pair-wise multicomparisons reveals a more correct characterization of biochemical processes in freezing tolerant trees and leads to interpretations that cannot be deduced by either method alone. The combined analysis can be used in other ‘omics’-studies, where response factors have a causal dependence (like the time in the present work) and pair-wise multicomparisons are not conservative.     

Mycobacterium marinum Causes a Latent Infection that Can Be Reactivated by Gamma Irradiation in Adult Zebrafish

The mechanisms leading to latency and reactivation of human tuberculosis are still unclear, mainly due to the lack of standardized animal models for latent mycobacterial infection. In this longitudinal study of the progression of a mycobacterial disease in adult zebrafish, we show that an experimental intraperitoneal infection with a low dose (∼35 bacteria) of Mycobacterium marinum, results in the development of a latent disease in most individuals. The infection is characterized by limited mortality (25%), stable bacterial loads 4 weeks following infection and constant numbers of highly organized granulomas in few target organs. The majority of bacteria are dormant during a latent mycobacterial infection in zebrafish, and can be activated by resuscitation promoting factor ex vivo. In 5–10% of tuberculosis cases in humans, the disease is reactivated usually as a consequence of immune suppression. In our model, we are able to show that reactivation can be efficiently induced in infected zebrafish by γ-irradiation that transiently depletes granulo/monocyte and lymphocyte pools, as determined by flow cytometry. This immunosuppression causes reactivation of the dormant mycobacterial population and a rapid outgrowth of bacteria, leading to 88% mortality in four weeks. In this study, the adult zebrafish presents itself as a unique non-mammalian vertebrate model for studying the development of latency, regulation of mycobacterial dormancy, as well as reactivation of latent or subclinical tuberculosis. The possibilities for screening for host and pathogen factors affecting the disease progression, and identifying novel therapeutic agents and vaccine targets make this established model especially attractive.     

Intracranial aneurysm risk locus 5q23.2 is associated with elevated systolic blood pressure

Although genome-wide association studies (GWAS) have identified hundreds of complex trait loci, the pathomechanisms of most remain elusive. Studying the genetics of risk factors predisposing to disease is an attractive approach to identify targets for functional studies. Intracranial aneurysms (IA) are rupture-prone pouches at cerebral artery branching sites. IA is a complex disease for which GWAS have identified five loci with strong association and a further 14 loci with suggestive association. To decipher potential underlying disease mechanisms, we tested whether there are IA loci that convey their effect through elevating blood pressure (BP), a strong risk factor of IA. We performed a meta-analysis of four population-based Finnish cohorts (n(FIN) = 11 266) not selected for IA, to assess the association of previously identified IA candidate loci (n = 19) with BP. We defined systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure as quantitative outcome variables. The most significant result was further tested for association in the ICBP-GWAS cohort of 200 000 individuals. We found that the suggestive IA locus at 5q23.2 in PRDM6 was significantly associated with SBP in individuals of European descent (p(FIN) = 3.01E-05, p(ICBP-GWAS) = 0.0007, p(ALL) = 8.13E-07). The risk allele of IA was associated with higher SBP. PRDM6 encodes a protein predominantly expressed in vascular smooth muscle cells. Our study connects a complex disease (IA) locus with a common risk factor for the disease (SBP). We hypothesize that common variants in PRDM6 can contribute to altered vascular wall structure, hence increasing SBP and predisposing to IA. True positive associations often fail to reach genome-wide significance in GWAS. Our findings show that analysis of traditional risk factors as intermediate phenotypes is an effective tool for deciphering hidden heritability. Further, we demonstrate that common disease loci identified in a population isolate may bear wider significance.