C-reactive protein, sodium azide, and endothelial connexin43 gap junctions

We investigated the effect of C-reactive protein (CRP) and sodium azide (NaN(3)) on endothelial Cx43 gap junctions. Human aortic endothelial cells (HAEC) were treated with (a) detoxified CRP, (b) detoxified dialyzed CRP, (c) detoxified dialyzed CRP plus NaN(3), (d) NaN(3), or (e) dialyzed NaN(3). The concentration of CRP in all preparations was fixed to 25 mu g/ml and that of NaN(3) in the preparations of (c) to (e) was equivalent to that contained in the 25 mu g/ml CRP purchased commercially. The results showed that both the expression of Cx43 protein and gap junctional communication function post-48-h incubation were reduced and inhibited by the detoxified CRP, NaN(3), or detoxified dialyzed CRP plus NaN(3), but not by the detoxified dialyzed CRP or dialyzed NaN(3). Reverse transcription-polymerase chain reaction analysis of cells treated for 72 h also showed a pattern of transcriptional regulation essentially the same as that for the proteins. We concluded that CRP does not have a significant effect on Cx43 gap junctions of HAEC, but NaN(3) inhibited the viability of cells and downregulate their junctions

Replica Symmetry Breaking Instability in the 2D XY model in a random field

We study the 2D vortex-free XY model in a random field, a model for randomly pinned flux lines in a plane. We construct controlled RG recursion relations which allow for replica symmetry breaking (RSB). The fixed point previously found by Cardy and Ostlund in the glass phase $T<T_c$ is {\it unstable} to RSB. The susceptibility $\chi$ associated to infinitesimal RSB perturbation in the high-temperature phase is found to diverge as $\chi \propto (T-T_c)^{-\gamma}$ when $T \rightarrow T_c^{+}$. This provides analytical evidence that RSB occurs in finite dimensional models. The physical consequences for the glass phase are discussed.Comment: 8 pages, REVTeX, LPTENS-94/2

Clinical outcomes in patients with severe asthma who had or had not initiated biologic therapy : results from the CLEAR study

Peer reviewedPostprin

Clinical outcomes and emergency healthcare utilization in patients with severe asthma who continued, switched or stopped biologic therapy : results from the CLEAR study

Funding This study was funded by AstraZeneca. The International Severe Asthma Registry is jointly funded by Optimum Patient Care Global and AstraZeneca. Acknowledgments Medical writing support was provided by Madeleine Wynn, MRes, of PharmaGenesis London, London, UK, with funding from AstraZeneca.Peer reviewe

Exact multilocal renormalization on the effective action : application to the random sine Gordon model statics and non-equilibrium dynamics

We extend the exact multilocal renormalization group (RG) method to study the flow of the effective action functional. This important physical quantity satisfies an exact RG equation which is then expanded in multilocal components. Integrating the nonlocal parts yields a closed exact RG equation for the local part, to a given order in the local part. The method is illustrated on the O(N) model by straightforwardly recovering the $\eta$ exponent and scaling functions. Then it is applied to study the glass phase of the Cardy-Ostlund, random phase sine Gordon model near the glass transition temperature. The static correlations and equilibrium dynamical exponent $z$ are recovered and several new results are obtained. The equilibrium two-point scaling functions are obtained. The nonequilibrium, finite momentum, two-time $t,t'$ response and correlations are computed. They are shown to exhibit scaling forms, characterized by novel exponents $\lambda_R \neq \lambda_C$, as well as universal scaling functions that we compute. The fluctuation dissipation ratio is found to be non trivial and of the form $X(q^z (t-t'), t/t')$. Analogies and differences with pure critical models are discussed.Comment: 33 pages, RevTe

Exploring definitions and predictors of severe asthma clinical remission post-biologic in adults

Peer reviewe

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

The ELFIN mission

The Electron Loss and Fields Investigation with a Spatio-Temporal Ambiguity-Resolving option (ELFIN-STAR, or heretoforth simply: ELFIN) mission comprises two identical 3-Unit (3U) CubeSats on a polar (∼93∘ inclination), nearly circular, low-Earth (∼450 km altitude) orbit. Launched on September 15, 2018, ELFIN is expected to have a >2.5 year lifetime. Its primary science objective is to resolve the mechanism of storm-time relativistic electron precipitation, for which electromagnetic ion cyclotron (EMIC) waves are a prime candidate. From its ionospheric vantage point, ELFIN uses its unique pitch-angle-resolving capability to determine whether measured relativistic electron pitch-angle and energy spectra within the loss cone bear the characteristic signatures of scattering by EMIC waves or whether such scattering may be due to other processes. Pairing identical ELFIN satellites with slowly-variable along-track separation allows disambiguation of spatial and temporal evolution of the precipitation over minutes-to-tens-of-minutes timescales, faster than the orbit period of a single low-altitude satellite (Torbit ∼ 90 min). Each satellite carries an energetic particle detector for electrons (EPDE) that measures 50 keV to 5 MeV electrons with Δ E/E 1 MeV. This broad energy range of precipitation indicates that multiple waves are providing scattering concurrently. Many observed events show significant backscattered fluxes, which in the past were hard to resolve by equatorial spacecraft or non-pitch-angle-resolving ionospheric missions. These observations suggest that the ionosphere plays a significant role in modifying magnetospheric electron fluxes and wave-particle interactions. Routine data captures starting in February 2020 and lasting for at least another year, approximately the remainder of the mission lifetime, are expected to provide a very rich dataset to address questions even beyond the primary mission science objective.Published versio

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications