Disease progression in patients with the restrictive and mixed phenotype of Chronic Lung Allograft dysfunction—A retrospective analysis in five European centers to assess the feasibility of a therapeutic trial

Pulmonary function; Graft survival; Respiratory failureFunción pulmonar; Supervivencia del injerto; Insuficiencia respiratoriaFunció pulmonar; Supervivència de l'empelt; Insuficiència respiratòriaBackground: Chronic Lung Allograft Dysfunction (CLAD) is a major obstacle for long term survival after lung transplantation (LTx). Besides Bronchiolitis Obliterans Syndrome, two other phenotypes of CLAD, restrictive allograft syndrome (RAS) and mixed phenotype, have been described. Trials to test in these conditions are desperately needed and analyzing natural outcome to plan such trials is essential. Methods: We performed a retrospective analysis of functional outcome in bilateral LTx recipients with RAS and mixed phenotype, transplanted between 2009 and 2018 in five large European centers with follow- up spirometry up to 12 months after diagnosis. Based on these data, sample size and power calculations for randomized therapeutic trial was estimated using two imputation methods for missing values. Results: Seventy patients were included (39 RAS and 31 mixed phenotype), median 3.1 years after LTx when CLAD was diagnosed. Eight, 13 and 25 patients died within 6, 9 and 12 months after diagnosis and a two patients underwent re-transplantation within 12 months leading to a graft survival of 89, 79 and 61% six, nine and 12 months after diagnosis, respectively. Observed FEV1 decline was 451 ml at 6 months and stabilized at 9 and 12 months, while FVC showed continuous decline. Using two methods of imputation, a progressive further decline after 6 months for FEV1 was noted. Conclusion: The poor outcome of these two specific CLAD phenotypes suggests the urgent need for future therapeutic randomized trials. The number of missing values in a potential trial seems to be high and most frequently attributed to death. Survival may be used as an endpoint in clinical trials in these distinct phenotypes and imputation techniques are relevant if graft function is used as a surrogate of disease progression in future trials

Cdc42, dynein, and dynactin regulate MTOC reorientation independent of Rho-regulated microtubule stabilization

AbstractIn migrating adherent cells such as fibroblasts and endothelial cells, the microtubule-organizing center (MTOC) reorients toward the leading edge [1–3]. MTOC reorientation repositions the Golgi toward the front of the cell [1] and contributes to directional migration [4]. The mechanism of MTOC reorientation and its relation to the formation of stabilized microtubules (MTs) in the leading edge, which occurs concomitantly with MTOC reorientation [3], is unknown. We show that serum and the serum lipid, lysophosphatidic acid (LPA), increased Cdc42 GTP levels and triggered MTOC reorientation in serum-starved wounded monolayers of 3T3 fibroblasts. Cdc42, but not Rho or Rac, was both sufficient and necessary for LPA-stimulated MTOC reorientation. MTOC reorientation was independent of Cdc42-induced changes in actin and was not blocked by cytochalasin D. Inhibition of dynein or dynactin blocked LPA- and Cdc42-stimulated MTOC reorientation. LPA also stimulates a Rho/mDia pathway that selectively stabilizes MTs in the leading edge [5, 6]; however, activators and inhibitors of MTOC reorientation and MT stabilization showed that each response was regulated independently. These results establish an LPA/Cdc42 signaling pathway that regulates MTOC reorientation in a dynein-dependent manner. MTOC reorientation and MT stabilization both act to polarize the MT array in migrating cells, yet these processes act independently and are regulated by separate Rho family GTPase-signaling pathways

Isotropization of Ultra-High Energy Cosmic Ray Arrival Directions by Radio Ghosts

The isotropy in the ultra high energy cosmic ray (UHECR) flux observed by Yakutsk and AGASA experiments, is a very strong constraint to production and propagation models alike. Most of the scenarios proposed in the literature should produce a sizable anisotropy as either extragalactic luminous or dark matter is normally associated with the invoked particle sources. We explore the possibility that the magnetic fields in fossil cocoons of former radio galaxies -- so called {\it radio ghosts} -- are able to scatter UHECR in the intergalactic medium giving rise to the observed isotropy. We show, through numerical simulations, under which conditions this process can be operative and the magnitude of the effect. We further demonstrate, that if radio ghosts mix with the ambient medium, they might be able to produce the observed magnetic fields in clusters of galaxies. In the case of mixing, the UHECR isotropization would be even stronger than in our conservative estimates.Comment: Astroparticle Physics (accepted)--30 pages, 13 figures--please, contact GMT for higher quality figure

Simulations of small-scale turbulent dynamo

We report an extensive numerical study of the small-scale turbulent dynamo at large magnetic Prandtl numbers Pm. A Pm scan is given for the model case of low-Reynolds-number turbulence. We concentrate on three topics: magnetic-energy spectra and saturation levels, the structure of the field lines, and the field-strength distribution. The main results are (1) the folded structure (direction reversals at the resistive scale, field lines curved at the scale of the flow) persists from the kinematic to the nonlinear regime; (2) the field distribution is self-similar and appears to be lognormal during the kinematic regime and exponential in the saturated state; and (3) the bulk of the magnetic energy is at the resistive scale in the kinematic regime and remains there after saturation, although the spectrum becomes much shallower. We propose an analytical model of saturation based on the idea of partial two-dimensionalization of the velocity gradients with respect to the local direction of the magnetic folds. The model-predicted spectra are in excellent agreement with numerical results. Comparisons with large-Re, moderate-Pm runs are carried out to confirm the relevance of these results. New features at large Re are elongation of the folds in the nonlinear regime from the viscous scale to the box scale and the presence of an intermediate nonlinear stage of slower-than-exponential magnetic-energy growth accompanied by an increase of the resistive scale and partial suppression of the kinetic-energy spectrum in the inertial range. Numerical results for the saturated state do not support scale-by-scale equipartition between magnetic and kinetic energies, with a definite excess of magnetic energy at small scales. A physical picture of the saturated state is proposed.Comment: aastex using emulateapj; 32 pages, final published version; a pdf file (4Mb) of the paper containing better-quality versions of figs. 5, 8, 12, 15, 17 is available from http://www.damtp.cam.ac.uk/user/as629 or by email upon request

Long-term evolution of the coupled boundary layers (STRATUS) mooring recovery and deployment cruise report NOAA Research Vessel R H Brown • cruise RB-01-08 9 October - 25 October 2001

This report documents the work done on cruise RB-01-08 of the NOAA R/V Ron Brown. This was Leg 2 of R/V Ron Brown’s participation in Eastern Pacific Investigation of Climate (EPIC) 2001, a study of air-sea interaction, the atmosphere, and the upper ocean in the eastern tropical Pacific. The science party included groups from the Woods Hole Oceanographic Institution (WHOI), NOAA Environmental Technology Laboratory (ETL), the University of Washington (UW), the University of California, Santa Barbara (UCSB), and the University Nacional Autonoma de Mexico (UNAM). The work done by these groups is summarized in this report. In addition, the routine underway data collected while aboard R/V Ron Brown is also summarized here.Funding was provided by the National Oceanic and Atmospheric Administration under Grant Numbers NA96GPO429 and NA17RJ1223

Live bird markets characterization and trading network analysis in Mali: Implications for the surveillance and control of avian influenza and Newcastle disease

Live bird markets (LBMs) play an important role in the transmission of avian influenza (AI) and Newcastle disease (ND) viruses in poultry. Our study had two objectives: (1) characterizing LBMs in Mali with a focus on practices influencing the risk of transmission of AI and ND, and (2) identifying which LBMs should be targeted for surveillance and control based on properties of the live poultry trade network. Two surveys were conducted in 2009–2010: a descriptive study in all 96 LBMs of an area encompassing approximately 98% of the Malian poultry population and a network analysis study in Sikasso county, the main poultry supplying county for the capital city Bamako. Regarding LBMs' characteristics, risk factors for the presence of AI and ND viruses (being open every day, more than 2 days before a bird is sold, absence of zoning to segregate poultry-related work flow areas, waste removal or cleaning and disinfecting less frequently than on a daily basis, trash disposal of dead birds and absence of manure processing) were present in 80–100% of the LBMs. Furthermore, LBMs tended to have wide catchment areas because of consumers' preference for village poultry meat, thereby involving a large number of villages in their supply chain. In the poultry trade network from/to Sikasso county, 182 traders were involved and 685 links were recorded among 159 locations. The network had a heterogeneous degree distribution and four hubs were identified based on measures of in-degrees, out-degrees and betweenness: the markets of Medine and Wayerma and the fairs of Farakala and Niena. These results can be used to design biosecurity-improvement interventions and to optimize the prevention, surveillance and control of transmissible poultry diseases in Malian LBMs. Further studies should investigate potential drivers (seasonality, prices) of the poultry trade network and the acceptability of biosecurity and behavior-change recommendations in the Malian socio-cultural context. (Résumé d'auteur

A chicken bioreactor for efficient production of functional cytokines

The global market for protein drugs has the highest compound annual growth rate of any pharmaceutical class but their availability, especially outside of the US market, is compromised by the high cost of manufacture and validation compared to traditional chemical drugs. Improvements in transgenic technologies allow valuable proteins to be produced by genetically-modified animals; several therapeutic proteins from such animal bioreactors are already on the market after successful clinical trials and regulatory approval. Chickens have lagged behind mammals in bioreactor development, despite a number of potential advantages, due to the historic difficulty in producing transgenic birds, but the production of therapeutic proteins in egg white of transgenic chickens would substantially lower costs across the entire production cycle compared to traditional cell culture-based production systems. This could lead to more affordable treatments and wider markets, including in developing countries and for animal health applications. Here we report the efficient generation of new transgenic chicken lines to optimize protein production in eggs. As proof-of-concept, we describe the expression, purification and functional characterization of three pharmaceutical proteins, the human cytokine interferon α2a and two species-specific Fc fusions of the cytokine CSF1. Our work optimizes and validates a transgenic chicken system for the cost-effective production of pure, high quality, biologically active protein for therapeutics and other applications

The CD34-Related Molecule Podocalyxin Is a Potent Inducer of Microvillus Formation

BACKGROUND: Podocalyxin is a CD34-related transmembrane protein involved in hematopoietic cell homing, kidney morphogenesis, breast cancer progression, and epithelial cell polarization. Although this sialomucin has been shown to block cell adhesion, the mechanisms involved remain enigmatic. It has, however, been postulated that the adaptor proteins NHERF-1 and 2 could regulate apical targeting of Podocalyxin by linking it to the actin cytoskeleton. PRINCIPAL FINDINGS: Here, in contrast, we find that full-length Podocalyxin acts to recruit NHERF-1 to the apical domain. Moreover, we show that ectopic expression of Podocalyxin in epithelial cells leads to microvillus formation along an expanded apical domain that extends laterally to the junctional complexes. Removal of the C-terminal PDZ-binding domain of Podocalyxin abolishes NHERF-1 recruitment but, surprisingly, has no effect on the formation of microvilli. Instead, we find that the extracellular domain and transmembrane region of Podocalyxin are sufficient to direct recruitment of filamentous actin and ezrin to the plasma membrane and induce microvillus formation. CONCLUSIONS/SIGNIFICANCE: Our data suggest that this single molecule can modulate NHERF localization and, independently, act as a key orchestrator of apical cell morphology, thereby lending mechanistic insights into its multiple roles as a polarity regulator, tumor progression marker, and anti-adhesin

Myocardial extravascular extracellular volume fraction measurement by gadolinium cardiovascular magnetic resonance in humans: slow infusion versus bolus

<p>Abstract</p> <p>Background</p> <p>Myocardial extravascular extracellular volume fraction (Ve) measures quantify diffuse fibrosis not readily detectable by conventional late gadolinium (Gd) enhancement (LGE). Ve measurement requires steady state equilibrium between plasma and interstitial Gd contrast. While a constant infusion produces steady state, it is unclear whether a simple bolus can do the same. Given the relatively slow clearance of Gd, we hypothesized that a bolus technique accurately measures Ve, thus facilitating integration of myocardial fibrosis quantification into cardiovascular magnetic resonance (CMR) workflow routines. Assuming equivalence between techniques, we further hypothesized that Ve measures would be reproducible across scans.</p> <p>Methods</p> <p>In 10 volunteers (ages 20-81, median 33 yr, 3 females), we compared serial Ve measures from a single short axis slice from two scans: first, during a constant infusion, and second, 12-50 min after a bolus (0.2 mmol/kg gadoteridol) on another day. Steady state during infusion was defined when serial blood and myocardial T1 data varied <5%. We measured T1 on a 1.5 T Siemens scanner using a single-shot modified Look Locker inversion recovery sequence (MOLLI) with balanced SSFP. To shorten breath hold times, T1 values were measured with a shorter sampling scheme that was validated with spin echo relaxometry (TR = 15 sec) in CuSO4-Agar phantoms. Serial infusion vs. bolus Ve measures (n = 205) from the 10 subjects were compared with generalized estimating equations (GEE) with exchangeable correlation matrices. LGE images were also acquired 12-30 minutes after the bolus.</p> <p>Results</p> <p>No subject exhibited LGE near the short axis slices where Ve was measured. The Ve range was 19.3-29.2% and 18.4-29.1% by constant infusion and bolus, respectively. In GEE models, serial Ve measures by constant infusion and bolus did not differ significantly (difference = 0.1%, p = 0.38). For both techniques, Ve was strongly related to age (p < 0.01 for both) in GEE models, even after adjusting for heart rate. Both techniques identically sorted older individuals with higher mean Ve values.</p> <p>Conclusion</p> <p>Myocardial Ve can be measured reliably and accurately 12-50 minutes after a simple bolus. Ve measures are also reproducible across CMR scans. Ve estimation can be integrated into CMR workflow easily, which may simplify research applications involving the quantification of myocardial fibrosis.</p