193 research outputs found
Hierarchical Assembly of Nucleic Acid/Coiled-Coil Peptide Nanostructures
DNA and peptides are two of the most commonly used biomolecules for building self-assembling materials, but few examples exist of hybrid nanostructures that contain both components. Here we report the modification of two peptides that comprise a coiled-coil heterodimer pair with unique DNA handles in order to link DNA origami nanostructures bearing complementary strands into micrometer-long one-dimensional arrays. We probed the effect of number of coils on self-assembly and demonstrated the formation of structures through multiple routes: one-pot assembly, formation of dimers and trimers and an alternating copolymer of two different origami structures, and stepwise assembly of purified structures with coiled-coil conjugates. Our results demonstrate the successful merging of two distinct self-assembly modes to create hybrid bionanomaterials expected to have a range of potential applications in the future
Correlation between centrality metrics and their application to the opinion model
In recent decades, a number of centrality metrics describing network
properties of nodes have been proposed to rank the importance of nodes. In
order to understand the correlations between centrality metrics and to
approximate a high-complexity centrality metric by a strongly correlated
low-complexity metric, we first study the correlation between centrality
metrics in terms of their Pearson correlation coefficient and their similarity
in ranking of nodes. In addition to considering the widely used centrality
metrics, we introduce a new centrality measure, the degree mass. The m order
degree mass of a node is the sum of the weighted degree of the node and its
neighbors no further than m hops away. We find that the B_{n}, the closeness,
and the components of x_{1} are strongly correlated with the degree, the
1st-order degree mass and the 2nd-order degree mass, respectively, in both
network models and real-world networks. We then theoretically prove that the
Pearson correlation coefficient between x_{1} and the 2nd-order degree mass is
larger than that between x_{1} and a lower order degree mass. Finally, we
investigate the effect of the inflexible antagonists selected based on
different centrality metrics in helping one opinion to compete with another in
the inflexible antagonists opinion model. Interestingly, we find that selecting
the inflexible antagonists based on the leverage, the B_{n}, or the degree is
more effective in opinion-competition than using other centrality metrics in
all types of networks. This observation is supported by our previous
observations, i.e., that there is a strong linear correlation between the
degree and the B_{n}, as well as a high centrality similarity between the
leverage and the degree.Comment: 20 page
Hall Effect and Resistivity in High-Tc Superconductors: The Conserving Approximation
The Hall coefficient (R_H) of high-Tc cuprates in the normal state shows the
striking non-Fermi liquid behavior: R_H follows a Curie-Weiss type temperature
dependence, and |R_H|>>1/|ne| at low temperatures in the under-doped compounds.
Moreover, R_H is positive for hole-doped compounds and is negative for
electron-doped ones, although each of them has a similar hole-like Fermi
surface. In this paper, we give the explanation of this long-standing problem
from the standpoint of the nearly antiferromagnetic (AF) Fermi liquid. We
consider seriously the vertex corrections for the current which are
indispensable to satisfy the conservation laws, which are violated within the
conventional Boltzmann transport approximation. The obtained total current J_k
takes an enhanced value and is no more perpendicular to the Fermi surface due
to the strong AF fluctuations. By virtue of this mechanism, the anomalous
behavior of R_H in high-Tc cuprates is neutrally explained. We find that both
the temperature and the (electron, or hole) doping dependences of R_H in
high-T_c cuprates are reproduced well by numerical calculations based on the
fluctuation-exchange (FLEX) approximation, applied to the single-band Hubbard
model. We also discuss the temperature dependence of R_H in other nearly AF
metals, e.g., V_2O_3, kappa-BEDT-TTF organic superconductors, and heavy fermion
systems close to the AF phase boundary.Comment: 19 pages, to appear in Phys. Rev. B, No.59, Vol.22, 199
Epidemic centrality - is there an underestimated epidemic impact of network peripheral nodes?
In the study of disease spreading on empirical complex networks in SIR model,
initially infected nodes can be ranked according to some measure of their
epidemic impact. The highest ranked nodes, also referred to as
"superspreaders", are associated to dominant epidemic risks and therefore
deserve special attention. In simulations on studied empirical complex
networks, it is shown that the ranking depends on the dynamical regime of the
disease spreading. A possible mechanism leading to this dependence is
illustrated in an analytically tractable example. In systems where the
allocation of resources to counter disease spreading to individual nodes is
based on their ranking, the dynamical regime of disease spreading is frequently
not known before the outbreak of the disease. Therefore, we introduce a
quantity called epidemic centrality as an average over all relevant regimes of
disease spreading as a basis of the ranking. A recently introduced concept of
phase diagram of epidemic spreading is used as a framework in which several
types of averaging are studied. The epidemic centrality is compared to
structural properties of nodes such as node degree, k-cores and betweenness.
There is a growing trend of epidemic centrality with degree and k-cores values,
but the variation of epidemic centrality is much smaller than the variation of
degree or k-cores value. It is found that the epidemic centrality of the
structurally peripheral nodes is of the same order of magnitude as the epidemic
centrality of the structurally central nodes. The implications of these
findings for the distributions of resources to counter disease spreading are
discussed
Alveolar eosinophilia in current smokers with chronic obstructive pulmonary disease in the SPIROMICS cohort
To the Editor: Novel therapies for chronic obstructive pulmonary disease (COPD) are urgently needed. Eosinophilic inflammation is an appealing target, because blood or sputum eosinophils in stable COPD may predict responses to systemic or inhaled corticosteroid therapy. Titrating steroid therapy in the stable state on the basis of sputum eosinophils reduced severe exacerbations and has been recommended for clinical practice. However, the prevalence of eosinophilic inflammation in COPD and its uniformity between systemic and lung compartments remain incompletely defined. Controversy exists on whether sputum analysis (reflecting large airway events) is required, or whether blood eosinophilia can suffice, on the basis of strong correlation between the 2 found by 1 group. Thus, better understanding of eosinophils in COPD is needed
Sulforaphane induces neurovascular protection against a systemic inflammatory challenge via both Nrf2-dependent and independent pathways
NIH/NHLBI; German Research Foundation
Association of sputum and blood eosinophil concentrations with clinical measures of COPD severity: an analysis of the SPIROMICS cohort
Background Increased concentrations of eosinophils in blood and sputum in chronic obstructive pulmonary disease (COPD) have been associated with increased frequency of exacerbations, reduced lung function, and corticosteroid responsiveness. We aimed to assess whether high eosinophil concentrations in either sputum or blood are associated with a severe COPD phenotype, including greater exacerbation frequency, and whether blood eosinophils are predictive of sputum eosinophils. Methods We did a multicentre observational study analysing comprehensive baseline data from SPIROMICS in patients with COPD aged 40–80 years who had a smoking history of at least 20 pack-years, recruited from six clinical sites and additional subsites in the USA between Nov 12, 2010, and April 21, 2015. Inclusion criteria for this analysis were SPIROMICS baseline visit data with complete blood cell counts and, in a subset, acceptable sputum counts. We stratified patients on the basis of blood and sputum eosinophil concentrations and compared their demographic characteristics, as well as results from questionnaires, clinical assessments, and quantitative CT (QCT). We also analysed whether blood eosinophil concentrations reliably predicted sputum eosinophil concentrations. This study is registered with ClinicalTrials.gov (NCT01969344). Findings Of the 2737 patients recruited to SPIROMICS, 2499 patients were smokers and had available blood counts, and so were stratified by mean blood eosinophil count: 1262 patients with low (<200 cells per μL) and 1237 with high (≥200 cells per μL) blood eosinophil counts. 827 patients were eligible for stratification by mean sputum eosinophil percentage: 656 with low (<1·25%) and 171 with high (≥1·25%) sputum eosinophil percentages. The high sputum eosinophil group had significantly lower median FEV1 percentage predicted than the low sputum eosinophil group both before (65·7% [IQR 51·8–81·3] vs 75·7% [59·3–90·2], p<0·0001) and after (77·3% [63·1–88·5] vs 82·9% [67·8–95·9], p=0·001) bronchodilation. QCT density measures for emphysema and air trapping were significantly higher in the high sputum eosinophil group than the low sputum eosinophil group. Exacerbations requiring corticosteroids treatment were more common in the high versus low sputum eosinophil group (p=0·002). FEV1 percentage predicted was significantly different between low and high blood eosinophil groups, but differences were less than those observed between the sputum groups. The high blood eosinophil group had slightly increased airway wall thickness (0·02 mm difference, p=0·032), higher St George Respiratory Questionnaire symptom scores (p=0·037), and increased wheezing (p=0·018), but no evidence of an association with COPD exacerbations (p=0·35) or the other indices of COPD severity, such as emphysema measured by CT density, COPD assessment test scores, Body-mass index, airflow Obstruction, Dyspnea, and Exercise index, or Global Initiative for Chronic Obstructive Lung Disease stage. Blood eosinophil counts showed a weak but significant association with sputum eosinophil counts (receiver operating characteristic area under the curve of 0·64, p<0·0001), but with a high false-discovery rate of 72%. Interpretation In a large, well characterised cohort of former and current smoking patients with a broad range of COPD severity, high concentrations of sputum eosinophils were a better biomarker than high concentrations of blood eosinophils to identify a patient subgroup with more severe disease, more frequent exacerbations, and increased emphysema by QCT. Blood eosinophils alone were not a reliable biomarker for COPD severity or exacerbations, or for sputum eosinophils. Clinical trials targeting eosinophilic inflammation in COPD should consider assessing sputum eosinophils. Funding National Institutes of Health, and National Heart, Lung, and Blood Institute
Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants
Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe
Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort
Background Present treatment strategies to stratify exacerbation risk in patients with chronic obstructive pulmonary disease (COPD) rely on a history of two or more events in the previous year. We aimed to understand year to year variability in exacerbations and factors associated with consistent exacerbations over time. Methods In this longitudinal, prospective analysis of exacerbations in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort, we analysed patients aged 40–80 years with COPD for whom 3 years of prospective data were available, identified through various means including care at academic and non-academic medical centres, word of mouth, and existing patient registries. Participants were enrolled in the study between Nov 12, 2010, and July 31, 2015. We classified patients according to yearly exacerbation frequency: no exacerbations in any year; one exacerbation in every year during 3 years of follow-up; and those with inconsistent exacerbations (individuals who had both years with exacerbations and years without during the 3 years of follow-up). Participants were characterised by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric category (1–4) on the basis of post-bronchodilator FEV1. Stepwise logistic regression was used to compare factors associated with one or more acute exacerbations of COPD every year for 3 years versus no exacerbations in the same timeframe. Additionally, a stepwise zero-inflated negative binomial model was used to assess predictors of exacerbation count during follow-up in all patients with available data. Baseline symptom burden was assessed with the COPD assessment test. This trial is registered with ClinicalTrials.gov, number NCT01969344. Findings 2981 patients were enrolled during the study. 1843 patients had COPD, of which 1105 patients had 3 years of complete, prospective follow-up data. 538 (49%) of 1105 patients had at least one acute exacerbation during the 3 years of follow-up, whereas 567 (51%) had none. 82 (7%) of 1105 patients had at least one acute exacerbation each year, whereas only 23 (2%) had two or more acute exacerbations in each year. An inconsistent pattern (both years with and without acute exacerbations) was common (456 [41%] of the group), particularly among GOLD stages 3 and 4 patients (256 [56%] of 456). In logistic regression, consistent acute exacerbations (≥1 event per year for 3 years) were associated with higher baseline symptom burden, previous exacerbations, greater evidence of small airway abnormality on CT, lower interleukin-15 concentrations, and higher interleukin-8 concentrations, than were no acute exacerbations. Interpretation Although acute exacerbations are common, the exacerbation status of most individuals varies markedly from year to year. Among patients who had any acute exacerbation over 3 years, very few repeatedly had two or more events per year. In addition to symptoms and history of exacerbations in the year before study enrolment, we identified several novel biomarkers associated with consistent exacerbations, including CT-defined small airway abnormality, and interleukin-15 and interleukin-8 concentrations. Funding National Institutes of Health, and National Heart, Lung, and Blood Institute
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