Regulatory T cell DNA methyltransferase inhibition accelerates resolution of lung inflammation

Acute respiratory distress syndrome (ARDS) is a common and often fatal inflammatory lung condition without effective targeted therapies. Regulatory T cells (Tregs) resolve lung inflammation, but mechanisms that enhance Tregs to promote resolution of established damage remain unknown. DNA demethylation at the forkhead box protein 3 (Foxp3) locus and other key Treg loci typify the Treg lineage. To test how dynamic DNA demethylation affects lung injury resolution, we administered the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (DAC) to wild-type (WT) mice beginning 24 hours after intratracheal LPS-induced lung injury. Mice that received DAC exhibited accelerated resolution of their injury. Lung CD4+CD25hi Foxp3+ Tregs from D AC-treated WT mice increased in number and displayed enhanced Foxp3 expression, activation state, suppressive phenotype, and proliferative capacity. Lymphocyte-deficient recombinase activating gene-1-null mice and Treg-depleted (diphtheria toxin-treated Foxp3DTR) mice did not resolve their injury in response to DAC. Adoptive transfer of 2 ×105 DAC-treated, but not vehicle-treated, exogenous Tregs rescued Treg-deficient mice from ongoing lung inflammation. In addition, in WT mice with influenza-induced lung inflammation, DAC rescue treatment facilitated recovery of their injury and promoted an increase in lung Treg number. Thus, DNA methyltransferase inhibition, at least in part, augments Treg number and function to accelerate repair of experimental lung injury. Epigenetic pathways represent novel manipulable targets for the treatment of ARDS

Symmetry-breaking Effects for Polariton Condensates in Double-Well Potentials

We study the existence, stability, and dynamics of symmetric and anti-symmetric states of quasi-one-dimensional polariton condensates in double-well potentials, in the presence of nonresonant pumping and nonlinear damping. Some prototypical features of the system, such as the bifurcation of asymmetric solutions, are similar to the Hamiltonian analog of the double-well system considered in the realm of atomic condensates. Nevertheless, there are also some nontrivial differences including, e.g., the unstable nature of both the parent and the daughter branch emerging in the relevant pitchfork bifurcation for slightly larger values of atom numbers. Another interesting feature that does not appear in the atomic condensate case is that the bifurcation for attractive interactions is slightly sub-critical instead of supercritical. These conclusions of the bifurcation analysis are corroborated by direct numerical simulations examining the dynamics of the system in the unstable regime.MICINN (Spain) project FIS2008- 0484

Comparative Pharmacokinetics of Tixagevimab/Cilgavimab (AZD7442) Administered Intravenously Versus Intramuscularly in Symptomatic SARS-CoV-2 Infection

AZD7442 (Evusheld) is a combination of two human anti-severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) monoclonal antibodies (mAbs), tixagevimab (AZD8895) and cilgavimab (AZD1061). Route of administration is an important consideration to improve treatment access. We assessed pharmacokinetics (PKs) of AZD7442 absorption following 600 mg administered intramuscularly (i.m.) in the thigh compared with 300 mg intravenously (i.v.) in ambulatory adults with symptomatic COVID-19. PK analysis included 84 of 110 participants randomized to receive i.m. AZD7442 and 16 of 61 randomized to receive i.v. AZD7442. Serum was collected prior to AZD7442 administration and at 24 hours and 3, 7, and 14 days later. PK parameters were calculated using noncompartmental methods. Following 600 mg i.m., the geometric mean maximum concentration (Cmax) was 38.19 μg/mL (range: 17.30–60.80) and 37.33 μg/mL (range: 14.90–58.90) for tixagevimab and cilgavimab, respectively. Median observed time to maximum concentration (Tmax) was 7.1 and 7.0 days for tixagevimab and cilgavimab, respectively. Serum concentrations after i.m. dosing were similar to the i.v. dose (27–29 μg/mL each component) at 3 days. The area under the concentration-time curve (AUC)0–7d geometric mean ratio was 0.9 for i.m. vs. i.v. Participants with higher weight or body mass index were more likely to have lower concentrations with either route. Women appeared to have higher interparticipant variability in concentrations compared with men. The concentrations of tixagevimab and cilgavimab after administration i.m. to the thigh were similar to those achieved with i.v. after 3 days from dosing. Exposure in the i.m. group was 90% of i.v. over 7 days. Administration to the thigh can be considered to provide consistent mAb exposure and improve access

The Drosophila melanogaster Genetic Reference Panel

A major challenge of biology is understanding the relationship between molecular genetic variation and variation in quantitative traits, including fitness. This relationship determines our ability to predict phenotypes from genotypes and to understand how evolutionary forces shape variation within and between species. Previous efforts to dissect the genotype-phenotype map were based on incomplete genotypic information. Here, we describe the Drosophila melanogaster Genetic Reference Panel (DGRP), a community resource for analysis of population genomics and quantitative traits. The DGRP consists of fully sequenced inbred lines derived from a natural population. Population genomic analyses reveal reduced polymorphism in centromeric autosomal regions and the X chromosome, evidence for positive and negative selection, and rapid evolution of the X chromosome. Many variants in novel genes, most at low frequency, are associated with quantitative traits and explain a large fraction of the phenotypic variance. The DGRP facilitates genotype-phenotype mapping using the power of Drosophila genetics

Nondestructive assay methods for solids containing plutonium

Specific nondestructive assay (NDA) methods, e.g. calorimetry, coincidence neutron counting, singles neutron counting, and gamma ray spectrometry, were studied to provide the Savannah River Plant with an NDA method to measure the plutonium content of solid scrap (slag and crucible) generated in the JB-Line plutonium metal production process. Results indicate that calorimetry can be used to measure the plutonium content to within about 3% in 4 to 6 hours by using computerized equilibrium sample power predictive models. Calorimetry results confirm that a bias exists in the present indirect measurement method used to estimate the plutonium content of slag and crucible. Singles neutron counting of slag and crucible can measure plutonium to only +-30%, but coincidence neutron counting methods improve measurement precision to better than +-10% in less than ten minutes. Only four portions of a single slag and crucible sample were assayed, and further study is recommended

Structure and development of the southeast Newfoundland continental passive margin: Derived from SCREECH Transect 3

New seismic reflection data from the Grand Banks of Newfoundland and the Newfoundland Basin add to the growing knowledge of the composition, structure and history of this nonvolcanic margin. Geophysical imaging is now approaching the extent of that done previously on the conjugate margin along Iberia, providing a valuable database for the development of rifting models. Two parallel profiles over the shelf platform image deep crustal fabric representing Precambrian or possibly Appalachian deformation as well asMesozoic extension. Progressively more intense extension of continental crust is imaged oceanwards without the highly reflective detachments frequently seen on profiles off Galicia. A landward-dipping event ‘L’ is imaged sporadically and appears to be analogous to a similar event on the Iberian IAM9 profile. The transition zone is probably exposed serpentinized mantle as interpreted off the Iberian margin although there appears to be a difference in the character of ridge development and reflectivity. The distinctive ‘U’ reflection identified previously at the base of the Newfoundland Basin deep water sedimentary section and recently identified as one or more thin basalt sills is imaged on newly presented profiles that connect previously published profiles SCR3 and SCR2 showing that ‘U’ is highly regular and continuous except where interrupted by basement highs. ‘U’ is also seen to have a major impact on the ability to image underlying basement. A full transect beginning over completely unextended continental crust through to oceanic crust has provided a data set from which estimates of extension and the pre-rifting location of the present continental edge can be made. Two estimates were obtained; 85 km based on faulting and 120 km based on crustal thickness

Portfolios and PDPs

The ePortfolio—love it or loathe it—is an integral part of the workplace-based assessment, it is now a fact of life for general practice trainees. It is also preparation for the appraisal system for qualified GPs, which is heavily reliant upon portfolios of evidence and the creation of personal development plans (or PDPs). Such reliance is only likely to increase with the proposed new revalidation system, which is currently expected to be introduced in 2010–11. Given this context, it is wise for GP trainees to learn how to use these tools to best effect, not only to provide robust evidence of good practice but also to aid personal development. This article aims to describe the way in which PDPs and portfolios can be best employed during your years as a trainee, equipping you with useful skills for a career in general practice. Although the use of tools such as significant event analysis, audit and the consultation observation tool (COT) and case-based discussion, assessments are all important reflective components of the ePortfolio, they will not be discussed in depth in this article