Nasal gene expression differentiates COPD from controls and overlaps bronchial gene expression

Background

Nasal gene expression profiling is a promising method to characterize COPD non-invasively. We aimed to identify a nasal gene expression profile to distinguish COPD patients from healthy controls. We investigated whether this COPD-associated gene expression profile in nasal epithelium is comparable with the profile observed in bronchial epithelium.

Methods

Genome wide gene expression analysis was performed on nasal epithelial brushes of 31 severe COPD patients and 22 controls, all current smokers, using Affymetrix Human Gene 1.0 ST Arrays. We repeated the gene expression analysis on bronchial epithelial brushes in 2 independent cohorts of mild-to-moderate COPD patients and controls.

Results

In nasal epithelium, 135 genes were significantly differentially expressed between severe COPD patients and controls, 21 being up- and 114 downregulated in COPD (false discovery rate?<?0.01). Gene Set Enrichment Analysis (GSEA) showed significant concordant enrichment of COPD-associated nasal and bronchial gene expression in both independent cohorts (FDR_GSEA <?0.001).

Conclusion

We identified a nasal gene expression profile that differentiates severe COPD patients from controls. Of interest, part of the nasal gene expression changes in COPD mimics differentially expressed genes in the bronchus. These findings indicate that nasal gene expression profiling is potentially useful as a non-invasive biomarker in COPD.

Trial registration

ClinicalTrials.gov registration number NCT01351792 (registration date May 10, 2011), ClinicalTrials.gov registration number NCT00848406 (registration date February 19, 2009), ClinicalTrials.gov registration number NCT00807469 (registration date December 11, 2008).

     

Polymorphisms in vitamin D receptor,toll-like receptor 2 and Toll-Like receptor 4 genes links with Dengue susceptibility

Host genetic factors are known to determine disease susceptibility in dengue virus infection. Therefore, in this study association of gene polymorphisms of Vitamin D Receptor [rs731236 (Taq) and rs7975232 (Apa1)], Toll-like receptor 2 [rs5743708 (Arg735Gln) and rs5743704 (Pro631His)] and Toll-like receptor 4 [rs4986790A/G(Asp299Gly13843) and rs4986791 C/T(Thr399Ile)] were studied in cases with dengue as compared to controls. Total 98 cases of confirmed dengue virus infection and 98 age, sex and geographically matched healthy controls were enrolled and their genetic polymorphisms for the above mentioned regions were studied by Sanger sequencing. Mutant genotypes CC of VDR rs731236 (Taq1) [(OR 3.808, p value =0.02, CI 1.160-12.498)], GG of VDR rs7975232 (Apa1) [(OR 3.485, p value =0.02, CI 1.162-10.45)] and heterozygous genotypes of TLR4 rs4986790 A/G Asp299Gly [OR 2.40, p value= 0.02, CI 1.12-5.14], TLR4 rs4986791 C/T Thr399Ile [OR 2.09, p value=0.02, CI 1.12-5.14] were found to be significantly more in cases with dengue virus infection as compared to the controls. Also, at these positions mutant alleles were observed in significantly higher number of cases than controls. The values for C allele at VDR rs731236 (Taq1) were OR 1.86, p value 0.009, CI 1.162-3.001; for allele G at rs7975232( Apa1) were OR 2.71, p value 0.006, CI 1.196-2.98 for allele G at TLR4s rs4986790 A/G Asp299Gly were OR 2.35, p value 0.009, CI 1.23-4.50 and for allele T at rs4986791 C/T Thr399Ile were OR 2.36, p value=0.006, CI 1.28-4.38. VDR and TLR4 but not TLR2 gene polymorphisms were found to be associated with dengue susceptibility in Indian population.     

Removal of acidic residues of the prodomain of PCSK9 increases its activity towards the LDL receptor

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low density lipoprotein receptor (LDLR) at the cell surface and mediates intracellular degradation of the LDLR. The amino-terminus of mature PCSK9, residues 31–53 of the prodomain, has an inhibitory effect on this function of PCSK9, but the underlying mechanism is not fully understood. In this study, we have identified two highly conserved negatively charged segments (residues 32–40 and 48–50, respectively) within this part of the prodomain and performed deletions and substitutions to study their importance for degradation of the LDLRs.Deletion of the acidic residues of the longest negatively charged segment increased PCSK9’s ability to degrade the LDLR by 31%, whereas a modest 8% increase was observed when these residues were mutated to uncharged amino acids. Thus, both the length and the charge of this part of the prodomain were important for its inhibitory effect. Deletion of the residues of the shorter second negatively charged segment only increased PCSK9’s activity by 8%. Substitution of the amino acids of both charged segments to uncharged residues increased PCSK9’s activity by 36%. These findings indicate that the inhibitory effect of residues 31–53 of the prodomain is due to the negative charge of this segment. The underlying mechanism could involve the binding of this peptide segment to positively charged structures which are important for PCSK9’s activity. One possible candidate could be the histidine-rich C-terminal domain of PCSK9.     

Fledging success of little auks in the high Arctic: do provisioning rates and the quality of foraging grounds matter?

Long-lived birds often face a dilemma between self-maintenance and reproduction. In order to maximize fitness, some seabird parents alternate short trips to collect food for offspring with long trips for self-feeding (bimodal foraging strategy). In this study, we examined whether temporal and spatial variation in the quality of foraging grounds affect provisioning and fledging success of a long-lived, bimodal forager, the little auk (Alle alle), the most abundant seabird species in the Arctic ecosystem. We predicted that an increase in sea surface temperature (SST), with an associated decrease in the preferred Arctic zooplankton prey, would increase foraging trip durations, decrease chick provisioning rates and decrease chick fledging success. Chick provisioning and survival were observed during three consecutive years (2008–2010) at two colonies with variable foraging conditions in Spitsbergen: Isfjorden and Magdalenefjorden. We found that a change in SST (range 1.6–5.4 °C) did not influence trip durations or provisioning rates. SST was, however, negatively correlated with the number of prey items delivered to a chick. Furthermore, provisioning rates did not influence chick’s probability to fledge; instead, SST was also negatively correlated with fledging probability. This was likely related to the prey availability and quality in the little auk’s foraging grounds. Our findings suggest that predicted warmer climate in the Arctic will negatively influence the ability of parents to provide their chicks, and consequently, the fledging prospects of little auk chicks.     

Alterations in osteoclast morphology following osteoprotegerin administration in the magnesium-deficient mouse

In the present study, we used osteoprotegerin (OPG), which blocks osteoclastogenesis, to correct and thus explain the hypercalcemia that is seen during dietary Mg deficiency in the mouse. Control and Mg-deficient mice received injections for 12 days of either OPG or vehicle only. Serum Ca was similar in Mg-deficient mice treated with OPG and in control mice receiving OPG (9.2±0.3 mg/dl vs. 9.2±0.5). Both groups had significantly higher serum Ca than controls or Mg-deficient animals receiving vehicle alone. Surprisingly, Mg-depleted mice that received OPG in doses that inhibit osteoclastic bone resorption remained hypercalcemic. Because mature osteoclasts still present in the marrow might be hyperactive, we examined osteoclast morphology at the light microscopic and ultrastructural level. Light microscopic examination of trabecular bone showed few osteoclasts in OPG-treated mice. Ultrastructural examination revealed that osteoclasts in OPG-treated mice have decreased contact with the endosteal bone surface and absence of a ruffled border. Because the morphology of the existing pool of mature osteoclasts did not enhance resorption, another mechanism, such as increased intestinal absorption of Ca in Mg-deficient mice, likely contributes to the hypercalcemia observed during Mg deficiency.     

A simple mathematical model for Ebola in Africa

We deal with the following question: Can the consumption of contaminated bush meat, the funeral practices and the environmental contamination explain the recurrence and persistence of Ebola virus disease outbreaks in Africa? We develop an SIR-type model which, incorporates both the direct and indirect transmissions in such a manner that there is a provision of Ebola viruses. We prove that the full model has one (endemic) equilibrium which is locally asymptotically stable whereas, it is globally asymptotically stable in the absence of the Ebola virus shedding in the environment. For the sub-model without the provision of Ebola viruses, the disease dies out or stabilizes globally at an endemic equilibrium. At the endemic level, the number of infectious is larger for the full model than for the sub-model without provision of Ebola viruses. We design a nonstandard finite difference scheme, which preserves the dynamics of the model. Numerical simulations are provided.     

Monosized, magnetic polymer particles: their use in separation of cells and subcellular components, and in the study of lymphocyte function in vitro

By employing the principles of "activated swelling", monosized, superparamagnetic polymer particles have been prepared ranging in size from 1-100 microns. Both during and after the swelling process, the particles can be modified to meet a series of specific demands making them potentially very interesting for many separation and assay purposes. Using monoclonal antibodies to direct the magnetic beads to their targets, immunomagnetic separation has turned out to be one of the most specific, reliable and, above all, the fastest technique available today to isolate particulate material for further studies. So far, most efforts have been concentrated on methodology for fractionation of cells in suspension, such as removal of tumour cells from bone marrow or isolation of lymphoid cells from peripheral blood. These studies have both established the parameters necessary for optimal performance and at the same time laid the groundwork for future developments making immunomagnetic separation an exciting new tool in many research areas. High speed and specificity are the most conspicuous features of immunomagnetic cell separation. These properties have been exploited in the successful development of a new technique for tissue typing of cells directly from peripheral blood specimens. Both higher sensitivity and specificity have been obtained. The same principles can be used for fast and safe quantification of cell populations and subpopulations in blood and cell suspensions. The functions of, and interactions between, peripheral blood cell populations or subpopulations in the immune response have also been studied with high precision. The significance of direct cell contact on the one hand, and soluble factors on the other, can now be established in detail. Immunomagnetic beads have also been used to study the interaction between various T lymphocyte membrane molecules in the early phases of the activation process. Finally, the usefulness of specially developed particles for the fractionation of subcellular components is described.     

Spatial Variation of Soil CO<Subscript>2</Subscript>, CH<Subscript>4</Subscript> and N<Subscript>2</Subscript>O Fluxes Across Topographical Positions in Tropical Forests of the Guiana Shield

The spatial variation of soil greenhouse gas fluxes (GHG; carbon dioxide—CO₂, methane—CH₄ and nitrous oxide—N₂O) remains poorly understood in highly complex ecosystems such as tropical forests. We used 240 individual flux measurements of these three GHGs from different soil types, at three topographical positions and in two extreme hydric conditions in the tropical forests of the Guiana Shield (French Guiana, South America) to (1) test the effect of topographical positions on GHG fluxes and (2) identify the soil characteristics driving flux variation in these nutrient-poor tropical soils. Surprisingly, none of the three GHG flux rates differed with topographical position. CO₂ effluxes covaried with soil pH, soil water content (SWC), available nitrogen and total phosphorus. The CH₄ fluxes were best explained by variation in SWC, with soils acting as a sink under drier conditions and as a source under wetter conditions. Unexpectedly, our study areas were generally sinks for N₂O and N₂O fluxes were partly explained by total phosphorus and available nitrogen concentrations. This first study describing the spatial variation of soil fluxes of the three main GHGs measured simultaneously in forests of the Guiana Shield lays the foundation for specific studies of the processes underlying the observed patterns.