Immune modulatory properties of nanoparticles on human dendritic cells

Dendritic cells (DCs) are professional antigen presenting cells that play a potent role as a key link between innate and adaptive immunity. Given the quintessential role of DCs in orchestrating immune responses, better understanding of conditions that control DC function could provide opportunities for developing new treatment strategies for infectious and autoimmune diseases. Recently, there is a growing interest to utilize nanoparticles (NPs) with diverse chemistry, size and other physicochemical attributes in vaccination, drug delivery systems, and diagnostics. There is emerging evidence for the effect of NPs size, shape, and other physiochemical properties on cellular responses; however, the impact of NPs on the immune system, and particularly the function and phenotype of DCs, is yet to be fully understood. The overall aim of this study was investigating the influence of different properties of NPs on DC phenotype, cytokine profile, function (e.g. endocytic ability) and metabolic profile. This was done by exposing DCs to a defined concentration of NPs, particularly, PLGA NPs, Silica (SNPs) and polystyrene (PS NPs), which were successfully fabricated or commercially sourced, respectively. The findings clearly demonstrated that particle size and the choice of material can affect different aspects of DC phenotype. While spherical Silica and PLGA NPs of 100 nm and 160 nm size range respectively do not change DC phenotype and function (endocytic ability), PS NPs of similar size and PLGA NPs of 500 nm size induce significant changes in DC phenotype and function. PS NPs of 150 nm and 200 nm size significantly suppress the expression of mannose receptor (MR or CD206) on DCs by around 90%-80% without affecting their viability, maturation status or cytokine profile. In addition, PLGA NPs of 500 nm size induced DC maturation as evidenced by high levels of CD83 expression. Accordingly, the impact of NP properties on one DC key function, namely endocytic ability, was investigated. Interestingly, the data showed that PS NPs (150 nm/200 nm) and PLGA NPs (500 nm) significantly influenced this function. While PLGA NPs (160 nm) and SNPs (100 nm/500 nm) did not induce changes in DC endocytic ability. Furthermore, with regard to NP cellular uptake by antigen presenting cells, our data demonstrated that specific NP size and material (PLGA NPs 120 nm) reflect a preferential uptake by DCs compared to 500 nm PLGA NPs. By contrast, macrophages (Mϕs) showed similar trend of uptake for both PLGA NP sizes. Our data also showed the role of NP surface modification on cellular uptake. Modified SNPs to positive charge showed high percentage of uptake by DCs. Examining the impact of NP material type (PLGA NPs and PS NPs) on DC metabolic profile could provide valuable information about the impact of NPs on overall DC function in an unbiased manner. The metabolomics profile data showed a significant increase in glycolysis pathway upon stimulation by PLGA NPs and PS NPs, as indicated by lactate production. Also, significant changes were observed in DC purine and amino acid metabolism upon PLGA NPs and PS NPs treatment, respectively. In conclusion, this study gives new insights into understanding how DCs react to different properties of NPs, which can pave the way for the rational design of NPs with tuneable immune-modulatory properties for immunotherapy applications

Clinical Significance of Bronchodilator Responsiveness Evaluated by Forced Vital Capacity in COPD: SPIROMICS Cohort Analysis.

ObjectiveBronchodilator responsiveness (BDR) is prevalent in COPD, but its clinical implications remain unclear. We explored the significance of BDR, defined by post-bronchodilator change in FEV1 (BDRFEV1) as a measure reflecting the change in flow and in FVC (BDRFVC) reflecting the change in volume.MethodsWe analyzed 2974 participants from a multicenter observational study designed to identify varying COPD phenotypes (SPIROMICS). We evaluated the association of BDR with baseline clinical characteristics, rate of prospective exacerbations and mortality using negative binomial regression and Cox proportional hazards models.ResultsA majority of COPD participants exhibited BDR (52.7%). BDRFEV1 occurred more often in earlier stages of COPD, while BDRFVC occurred more frequently in more advanced disease. When defined by increases in either FEV1 or FVC, BDR was associated with a self-reported history of asthma, but not with blood eosinophil counts. BDRFVC was more prevalent in subjects with greater emphysema and small airway disease on CT. In a univariate analysis, BDRFVC was associated with increased exacerbations and mortality, although no significance was found in a model adjusted for post-bronchodilator FEV1.ConclusionWith advanced airflow obstruction in COPD, BDRFVC is more prevalent in comparison to BDRFEV1 and correlates with the extent of emphysema and degree of small airway disease. Since these associations appear to be related to the impairment of FEV1, BDRFVC itself does not define a distinct phenotype nor can it be more predictive of outcomes, but it can offer additional insights into the pathophysiologic mechanism in advanced COPD.Clinical trials registrationClinicalTrials.gov: NCT01969344T4

The \u3cem\u3eChlamydomonas\u3c/em\u3e Genome Reveals the Evolution of Key Animal and Plant Functions

Chlamydomonas reinhardtii is a unicellular green alga whose lineage diverged from land plants over 1 billion years ago. It is a model system for studying chloroplast-based photosynthesis, as well as the structure, assembly, and function of eukaryotic flagella (cilia), which were inherited from the common ancestor of plants and animals, but lost in land plants. We sequenced the ∼120-megabase nuclear genome of Chlamydomonas and performed comparative phylogenomic analyses, identifying genes encoding uncharacterized proteins that are likely associated with the function and biogenesis of chloroplasts or eukaryotic flagella. Analyses of the Chlamydomonas genome advance our understanding of the ancestral eukaryotic cell, reveal previously unknown genes associated with photosynthetic and flagellar functions, and establish links between ciliopathy and the composition and function of flagella

The Metagenomics and Metadesign of the Subways and Urban Biomes (MetaSUB) International Consortium inaugural meeting report

The Metagenomics and Metadesign of the Subways and Urban Biomes (MetaSUB) International Consortium is a novel, interdisciplinary initiative comprised of experts across many fields, including genomics, data analysis, engineering, public health, and architecture. The ultimate goal of the MetaSUB Consortium is to improve city utilization and planning through the detection, measurement, and design of metagenomics within urban environments. Although continual measures occur for temperature, air pressure, weather, and human activity, including longitudinal, cross-kingdom ecosystem dynamics can alter and improve the design of cities. The MetaSUB Consortium is aiding these efforts by developing and testing metagenomic methods and standards, including optimized methods for sample collection, DNA/RNA isolation, taxa characterization, and data visualization. The data produced by the consortium can aid city planners, public health officials, and architectural designers. In addition, the study will continue to lead to the discovery of new species, global maps of antimicrobial resistance (AMR) markers, and novel biosynthetic gene clusters (BGCs). Finally, we note that engineered metagenomic ecosystems can help enable more responsive, safer, and quantified cities

Family physicians\u27 professional identity formation: a study protocol to explore impression management processes in institutional academic contexts.

BACKGROUND: Despite significant differences in terms of medical training and health care context, the phenomenon of medical students\u27 declining interest in family medicine has been well documented in North America and in many other developed countries as well. As part of a research program on family physicians\u27 professional identity formation initiated in 2007, the purpose of the present investigation is to examine in-depth how family physicians construct their professional image in academic contexts; in other words, this study will allow us to identify and understand the processes whereby family physicians with an academic appointment seek to control the ideas others form about them as a professional group, i.e. impression management. METHODS/DESIGN: The methodology consists of a multiple case study embedded in the perspective of institutional theory. Four international cases from Canada, France, Ireland and Spain will be conducted; the \u22case\u22 is the medical school. Four levels of analysis will be considered: individual family physicians, interpersonal relationships, family physician professional group, and organization (medical school). Individual interviews and focus groups with academic family physicians will constitute the main technique for data generation, which will be complemented with a variety of documentary sources. Discourse techniques, more particularly rhetorical analysis, will be used to analyze the data gathered. Within- and cross-case analysis will then be performed. DISCUSSION: This empirical study is strongly grounded in theory and will contribute to the scant body of literature on family physicians\u27 professional identity formation processes in medical schools. Findings will potentially have important implications for the practice of family medicine, medical education and health and educational policies

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Synthesis of bone-targeted oestrogenic compounds for the inhibition of bone resorption

Syntheses have been realised for several members of a new class of potential bone resorption inhibitors consisting of steroidal oestrogenic compounds linked at the 17 position to a geminal bia(phosphonic acid) moiety through an ester linkage. The approach used has the potential to allow other biologically active compounds to be coupled to the geminal bisphosphonate unit. (C) 2001 Elsevier Science Ltd. All rights reserved

Effects of extracellular nucleotides on single cells and populations of human osteoblasts: contribution of cell heterogeneity to relative potencies

1. Human osteoblasts responded to the application of extracellular nucleotides, acting at P(2)-receptors, with increases in cytosolic free calcium concentration ([Ca(2+)](i)). 2. In populations of human osteoblasts, adenosine 5′-diphosphate (ADP) evoked a rise in [Ca(2+)](i) with less than 40% of the amplitude of that induced by adenosine 5′-triphosphate (ATP). 3. ATP and uridine 5′-triphosphate (UTP) were applied to single human osteoblasts and induced [Ca(2+)](i) rises of comparable amplitude in every cell tested. 4. However, from the results of single cell studies with ADP (and 2-methylthioATP (2-meSATP)) two groups of cells were delineated: one group responded to ADP (or 2-meSATP) with a rise in [Ca(2+)](i) indistinguishable from that evoked by ATP; whereas the second group failed completely to respond to ADP (or 2-meSATP). 5. Therefore heterogeneity of receptor expression exists within this population of human osteoblasts. The limited distribution of the ADP-responsive receptor underlies the small response to ADP, compared with ATP, recorded in populations of human osteoblasts. This heterogeneity may reflect differences in the differentiation status of individual cells

Significance of FEV3/FEV6 in Recognition of Early Airway Disease in Smokers at Risk of Development of COPD Analysis of the SPIROMICS Cohort

BackgroundSmall airways are known to be affected early in the course of COPD; however, traditional spirometric indices may not accurately identify small airways disease.Research questionCan forced expiratory volume in 3 s/forced expiratory volume in 6 s (FEV3/FEV6) identify early airflow abnormalities and predict future clinically important respiratory-related outcomes, including development of COPD?Study design and methodsThe study included 832 current and former smokers with post-bronchodilator FEV1/FVC ≥ 0.7 from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Participants were classified as having a reduced pre-bronchodilator FEV3/FEV6 based on lower limit of normal (LLN) values. Repeatability analysis was performed for FEV3 and FEV6. Regression modeling was used to evaluate the relationship between baseline FEV3/FEV6 and outcome measures, including functional small airways disease, on thoracic imaging and respiratory exacerbations. Interval-censored analysis was used to assess progression to COPD.ResultsFEV3/FEV6 less than the LLN at baseline, defined as reduced compared with FEV3/FEV6 at or above the LLN, was associated with lower FEV1, poorer health status (St. George's Respiratory Questionnaire score), more emphysema, and more functional small airways disease on quantitative imaging. FEV3 and FEV6 showed excellent agreement between repeat measurements. A reduced FEV3/FEV6 was associated with increased odds of a severe respiratory exacerbation within the first year of follow-up and decreased time to first exacerbation. A low FEV3/FEV6 was also associated with development of COPD according to spirometry results (post-bronchodilator FEV1/FVC < 0.7) during study follow-up.InterpretationFEV3/FEV6 is a routinely available and repeatable spirometric index that can be useful in the evaluation of early airflow obstruction in current and former smokers without COPD. A reduced FEV3/FEV6 can identify those at risk for future development of COPD and respiratory exacerbations.Clinical trial registrationClinicalTrials.gov; No.: NCT01969344; URL: www.Clinicaltrialsgov: ClinicalTrials.gov