Eddy formation near the west coast of Greenland

Author Posting. © American Meteorological Society, 2008. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 38 (2008): 1992-2002, doi:10.1175/2008JPO3669.1.This paper extends A. Bracco and J. Pedlosky’s investigation of the eddy-formation mechanism in the eastern Labrador Sea by including a more realistic depiction of the boundary current. The quasigeostrophic model consists of a meridional, coastally trapped current with three vertical layers. The current configuration and topographic domain are chosen to match, as closely as possible, the observations of the boundary current and the varying topographic slope along the West Greenland coast. The role played by the bottom-intensified component of the boundary current on the formation of the Labrador Sea Irminger Rings is explored. Consistent with the earlier study, a short, localized bottom-trapped wave is responsible for most of the perturbation energy growth. However, for the instability to occur in the three-layer model, the deepest component of the boundary current must be sufficiently strong, highlighting the importance of the near-bottom flow. The model is able to reproduce important features of the observed vortices in the eastern Labrador Sea, including the polarity, radius, rate of formation, and vertical structure. At the time of formation, the eddies have a surface signature as well as a strong circulation at depth, possibly allowing for the transport of both surface and near-bottom water from the boundary current into the interior basin. This work also supports the idea that changes in the current structure could be responsible for the observed interannual variability in the number of Irminger Rings formed.AB is supported by WHOI unrestricted funds, JP by the National Science Foundation OCE 85108600, and RP by 0450658

Reprogramming human T cell function and specificity with non-viral genome targeting.

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells

Efficacy of an insecticide paint against malaria vectors and nuisance in West Africa - Part 2: Field evaluation

<p>Abstract</p> <p>Background</p> <p>Widespread resistance of the main malaria vector <it>Anopheles gambiae </it>to pyrethroids reported in many African countries and operational drawbacks to current IRS methods suggest the convenience of exploring new products and approaches for vector control. Insecticide paint Inesfly 5A IGR™, containing two organophosphates (OPs), chlorpyrifos and diazinon, and one insect growth regulator (IGR), pyriproxyfen, was tested in Benin, West Africa, for 12 months.</p> <p>Methods</p> <p>Field trials were conducted in six experimental huts that were randomly allocated to one or two layers of insecticide at 1 Kg/6 m²or control. Evaluations included: (i) early mosquito collection, (ii) mosquito release experiments, (iii) residual efficacy tests and (iv) distance tests. Early mosquito collections were performed on local populations of pyrethroid-resistant <it>An. gambiae </it>and <it>Culex quinquefasciatus</it>. As per WHOPES phase II procedures, four entomological criteria were evaluated: deterrence, excito-repellence, blood-feeding inhibition and mortality. Mosquito release experiments were done using local malaria-free <it>An. gambiae </it>females reared at the CREC insectarium. Residual efficacy tests and distance tests were performed using reference susceptible strains of <it>An. gambiae </it>and <it>Cx. quinquefasciatus</it>.</p> <p>Results</p> <p>Six months after treatment, mortality rates were still 90-100% against pyrethroid-resistant mosquito populations in experimental huts. At nine months, mortality rates in huts treated with two layers was still about 90-93% against <it>An. gambiae </it>and 55% against <it>Cx. quinquefasciatus</it>. Malaria-free local mosquito release experiments yielded a 90% blood-feeding inhibition in the absence of a physical barrier. A long-term residual efficacy of 12 months was observed by WHO-bioassays in huts treated with two layers (60-80%). Mortality after an overnight exposition at distances of 1 meter was 96-100% for up to 12 months.</p> <p>Conclusion</p> <p>The encouraging results obtained on the insecticide paint Inesfly 5A IGR™ in terms of mortality, be it in direct contact or at a distance, and its new operational approach could constitute an additional option in malaria control efforts in areas of pyrethroid resistance. Phase III studies will be performed to assess the product's epidemiological impact and sociological acceptance.</p

Field efficacy of a new mosaic long-lasting mosquito net (PermaNet® 3.0) against pyrethroid-resistant malaria vectors: a multi centre study in Western and Central Africa

<p>Abstract</p> <p>Background</p> <p>Due to the spread of pyrethroid-resistance in malaria vectors in Africa, new strategies and tools are urgently needed to better control malaria transmission. The aim of this study was to evaluate the performances of a new mosaic long-lasting insecticidal net (LLIN), i.e. PermaNet^®3.0, against wild pyrethroid-resistant <it>Anopheles gambiae s.l</it>. in West and Central Africa.</p> <p>Methods</p> <p>A multi centre experimental hut trial was conducted in Malanville (Benin), Vallée du Kou (Burkina Faso) and Pitoa (Cameroon) to investigate the exophily, blood feeding inhibition and mortality induced by PermaNet^®3.0 (i.e. a mosaic net containing piperonyl butoxide and deltamethrin on the roof) comparatively to the WHO recommended PermaNet^®2.0 (unwashed and washed 20-times) and a conventionally deltamethrin-treated net (CTN).</p> <p>Results</p> <p>The personal protection and insecticidal activity of PermaNet 3.0 and PermaNet^®2.0 were excellent (>80%) in the "pyrethroid-tolerant" area of Malanville. In the pyrethroid-resistance areas of Pitoa (metabolic resistance) and Vallée du Kou (presence of the L1014F <it>kdr </it>mutation), PermaNet^®3.0 showed equal or better performances than PermaNet^®2.0. It should be noted however that the deltamethrin content on PermaNet^®3.0 was up to twice higher than that of PermaNet^®2.0. Significant reduction of efficacy of both LLIN was noted after 20 washes although PermaNet^®3.0 still fulfilled the WHO requirement for LLIN.</p> <p>Conclusion</p> <p>The use of combination nets for malaria control offers promising prospects. However, further investigations are needed to demonstrate the benefits of using PermaNet^®3.0 for the control of pyrethroid resistant mosquito populations in Africa.</p

Molecular basis of microhomology-mediated end-joining by purified full-length Polθ

DNA polymerase θ (Polθ) is a unique polymerase-helicase fusion protein that promotes microhomology-mediated end-joining (MMEJ) of DNA double-strand breaks (DSBs). How full-length human Polθ performs MMEJ at the molecular level remains unknown. Using a biochemical approach, we find that the helicase is essential for Polθ MMEJ of long ssDNA overhangs which model resected DSBs. Remarkably, Polθ MMEJ of ssDNA overhangs requires polymerase-helicase attachment, but not the disordered central domain, and occurs independently of helicase ATPase activity. Using single-particle microscopy and biophysical methods, we find that polymerase-helicase attachment promotes multimeric gel-like Polθ complexes that facilitate DNA accumulation, DNA synapsis, and MMEJ. We further find that the central domain regulates Polθ multimerization and governs its DNA substrate requirements for MMEJ. These studies identify unexpected functions for the helicase and central domain and demonstrate the importance of polymerase-helicase tethering in MMEJ and the structural organization of Polθ

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P &lt; 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P &lt; 0.001), sNox2-dp (r(s), -0.57; P &lt; 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P &lt; 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation