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Focusing laser light onto a very small target can produce the conditions for laboratory-scale nuclear fusion of hydrogen isotopes. The lack of accurate predictive models, which are essential for the design of high-performance laser-fusion experiments, is a major obstacle to achieving thermonuclear ignition. Here we report a statistical approach that was used to design and quantitatively predict the results of implosions of solid deuterium–tritium targets carried out with the 30-kilojoule OMEGA laser system, leading to tripling of the fusion yield to its highest value so far for direct-drive laser fusion. When scaled to the laser energies of the National Ignition Facility (1.9 megajoules), these targets are predicted to produce a fusion energy output of about 500 kilojoules—several times larger than the fusion yields currently achieved at that facility. This approach could guide the exploration of the vast parameter space of thermonuclear ignition conditions and enhance our understanding of laser-fusion physics. A statistical approach to designing and predicting the fusion yield of cryogenic deuterium–tritium implosions leads to tripled yield in direct-drive laser fusion of deuterium–tritium layered targets.

Irradiating a small capsule containing deuterium and tritium fuel directly with intense laser light causes it to implode, which creates a plasma hot enough to initiate fusion reactions between the fuel nuclei. Here we report on such laser direct-drive experiments and observe that the fusion reactions produce more energy than the amount of energy in the central so-called hot-spot plasma. This condition is identified as having a hot-spot fuel gain greater than unity. A hot-spot fuel gain of around four was previously accomplished at the National Ignition Facility in indirect-drive inertial confinement fusion experiments where the capsule is irradiated by X-rays. In that case, up to 1.9 MJ of laser energy was used, but in contrast, our experiments on the OMEGA laser system require as little as 28 kJ. As the hot-spot fuel gain is predicted to grow with laser energy and target size, our work establishes the direct-drive approach to inertial fusion as a promising path towards burning and ignited plasmas in the laboratory. Additionally, we report a record (direct-drive) fusion yield of 0.9 kJ on OMEGA, which we achieved with thin-ice deuterium–tritium liner targets. Inertial confinement fusion experiments in a direct-drive configuration report more energy produced in deuterium–tritium fusion reactions than the amount of energy in the central part of the plasma created by laser irradiation of the fuel capsule.

Focussing laser light onto the surface of a small target filled with deuterium and tritium implodes it and leads to the creation of a hot and dense plasma, in which thermonuclear fusion reactions occur. In order for the plasma to become self-sustaining, the heating of the plasma must be dominated by the energy provided by the fusion reactions—a condition known as a burning plasma. A metric for this is the generalized Lawson parameter, where values above around 0.8 imply a burning plasma. Here, we report on hydro-equivalent scaling of experimental results on the OMEGA laser system and show that these have achieved core conditions that reach a burning plasma when the central part of the plasma, the hotspot, is scaled in size by at least a factor of 3.9 ± 0.10, which would require a driver laser energy of at least 1.7 ± 0.13 MJ. In addition, we hydro-equivalently scale the results to the 2.15 MJ of laser energy available at the National Ignition Facility and find that these implosions reach 86% of the Lawson parameter required for ignition. Our results support direct-drive inertial confinement fusion as a credible approach for achieving thermonuclear ignition and net energy in laser fusion. Hydro-equivalent scaling of recent direct-drive inertial confinement fusion implosions shows that a burning plasma can be achieved with a higher laser energy.

Background Clostridium difficile is an important cause of intestinal infections in some animal species and animals might be a reservoir for community associated human infections. Here we describe a collection of animal associated C. difficile strains from 12 countries based on inclusion criteria of one strain (PCR ribotype) per animal species per laboratory. Results Altogether 112 isolates were collected and distributed into 38 PCR ribotypes with agarose based approach and 50 PCR ribotypes with sequencer based approach. Four PCR ribotypes were most prevalent in terms of number of isolates as well as in terms of number of different host species: 078 (14.3% of isolates; 4 hosts), 014/020 (11.6%; 8 hosts); 002 (5.4%; 4 hosts) and 012 (5.4%; 5 hosts). Two animal hosts were best represented; cattle with 31 isolates (20 PCR ribotypes; 7 countries) and pigs with 31 isolates (16 PCR ribotypes; 10 countries). Conclusions This results show that although PCR ribotype 078 is often reported as the major animal C. difficile type, especially in pigs, the variability of strains in pigs and other animal hosts is substantial. Most common human PCR ribotypes (014/020 and 002) are also among most prevalent animal associated C. difficile strains worldwide. The widespread dissemination of toxigenic C. difficile and the considerable overlap in strain distribution between species furthers concerns about interspecies, including zoonotic, transmission of this critically important pathogen.

Many G protein-coupled receptors (GPCRs) are organized as dynamic macromolecular complexes in human cells. Unraveling the structural determinants of unique GPCR complexes may identify unique protein:protein interfaces to be exploited for drug development. We previously reported α 1D -adrenergic receptors (α 1D -ARs) – key regulators of cardiovascular and central nervous system function – form homodimeric, modular PDZ protein complexes with cell-type specificity. Towards mapping α 1D -AR complex architecture, biolayer interferometry (BLI) revealed the α 1D -AR C-terminal PDZ ligand selectively binds the PDZ protein scribble (SCRIB) with >8x higher affinity than known interactors syntrophin, CASK and DLG1. Complementary in situ and in vitro assays revealed SCRIB PDZ domains 1 and 4 to be high affinity α 1D -AR PDZ ligand interaction sites. SNAP-GST pull-down assays demonstrate SCRIB binds multiple α 1D -AR PDZ ligands via a co-operative mechanism. Structure-function analyses pinpoint R1110 PDZ4 as a unique, critical residue dictating SCRIB:α 1D -AR binding specificity. The crystal structure of SCRIB PDZ4 R1110G predicts spatial shifts in the SCRIB PDZ4 carboxylate binding loop dictate α 1D -AR binding specificity. Thus, the findings herein identify SCRIB PDZ domains 1 and 4 as high affinity α 1D -AR interaction sites, and potential drug targets to treat diseases associated with aberrant α 1D -AR signaling.

The global organization of protein binding sites is analyzed by constructing a weighted network of binding sites based on their structural similarities and detecting communities of structurally similar binding sites based on the minimum description length principle. The analysis reveals that there are two central binding site communities that play the roles of the network hubs of smaller peripheral communities. The sizes of communities follow a power-law distribution, which indicates that the binding sites included in larger communities may be older and have been evolutionary structural scaffolds of more recent ones. Structurally similar binding sites in the same community bind to diverse ligands promiscuously and they are also embedded in diverse domain structures. Understanding the general principles of binding site interplay will pave the way for improved drug design and protein design.

Molecular and structural consequences of early renal allograft injury. Chronic allograft nephropathy is an important cause of graft failure. Many donor and recipient factors contribute to its development. Prospective analysis of these factors has been hindered by the lack of sensitive and specific indicators of renal injury. As a consequence protocol biopsies have been increasingly used in the assessment of renal allograft injury. We performed protocol renal allograft biopsies to prospectively examine the role of important determinants and mediators of chronic allograft nephropathy. A total of 51 consecutive cadaveric renal transplant recipients entered a randomized prospective study of tacrolimus (Tac) versus cyclosporine (CsA) microemulsion based immunosuppression. Study patients underwent protocol renal allograft biopsies at the time of engraftment and at 3, 6 and 12 months post-transplantation. Biopsies were analyzed by quantitative polymerase chain reaction (PCR) for mRNA for transforming growth factor-β (TGF-β), thrombospondin, and fibronectin. Measurements of renal structural injury were estimated by quantitative assessment of interstitial fibrosis and glomerulosclerosis. Changes in profibrotic growth factors and renal structural injury were related to donor and recipient determinants by stepwise regression analysis. Longitudinal assessment of renal injury demonstrated an early and progressive increase in mRNA for TGF-β, thrombospondin (TSP) and fibronectin (FBN): TGF-β baseline, 1.9 ± 0.2 log copies; TGF-β 6 months, 2.5 ± 0.2 log copies, P < 0.05 6 months vs. baseline; TSP baseline, 1.9 ± 0.2 log copies; TSP 6 months, 2.4 ± 0.2 log copies, P < 0.05 6 months vs. baseline; FBN baseline, 2.0 ± 0.2 log copies; FBN 12 months, 2.3 ± 0.2 log copies, P < 0.05 12 months vs. baseline. This increase in profibrotic growth factors within the allograft was associated with a significant increase in interstitial fibrosis (Vvi) on renal biopsies: Vvi baseline, 13 ± 1%; Vvi 3 months, 18 ± 1%; Vvi 6 months, 28 ± 2%; Vvi 12 months, 34 ± 2%; P < 0.05 3, 6, and 12 months vs. baseline. Histological analysis demonstrated chronic allograft nephropathy in 4% biopsies at 3 months, 12% at 6 months and in 49% at 12 months. These changes in renal structure were not associated with any change in creatinine clearance (CCr): CCr 3 months, 56 ± 2mL/min, CCr 24 months, 56 ± 2mL/min; P = NS. Stepwise regression analysis of key donor and recipient determinants of chronic renal injury identified calcineurin inhibitors and acute rejection episodes as important factors involved in the development of chronic renal injury. In particular, the use of cyclosporine compared to tacrolimus was associated with a tenfold increase in TGF-β mRNA (TGF-β mRNA at 6 months, CsA vs. Tac, 3 ± 0.3 vs. 2 ± 0.3 log copies, P < 0.05), interstitial fibrosis (Vvi at 6 months, CsA vs. Tac, 33 ± 4% vs. 24 ± 2%, P < 0.05). Changes in growth factors and renal structure predicted impaired renal function (CCr at 12 months, CsA vs. Tac, 53 ± 4mL/min vs. 62 ± 2mL/min, P < 0.05). Similarly, acute rejection episodes were associated with an accelerated development of interstitial fibrosis (Vvi at 6 months, acute rejection vs. no rejection, 34 ± 3% vs. 25 ± 2%; P < 0.05), but not with changes in TGF-β, thrombospondin or fibronectin expression. Our results suggest that structural injury develops early in the natural history of the renal allograft and is mediated, in part, by the early up-regulation of profibrotic growth factors. We have determined that calcineurin inhibitors, in particular cyclosporine, and acute rejection episodes are key factors in the development of renal structural injury.

Aim: To evaluate the influence of wheat bran and oat bran on the oxidative stress induced by a high proportion of fat in the diet. Methods: Forty-eight growing pigs were penned individually and after an adaptation period divided into four groups. All groups received isocaloric daily rations composed of basal diet which was then supplemented with: starch (controls; CONT), linseed oil (OIL), linseed oil and wheat bran, or linseed oil and oat bran. The experimental period lasted 14-days. The oxidative stress was evaluated by measuring the malondialdehyde (MDA) concentration in blood plasma, the 48-hour urinary MDA excretion, and the degree of leukocyte nuclear DNA damage. Results: In comparison with the CONT group, a significant increase in the MDA concentration in blood plasma and in the MDA excretion in urine was found in the OIL group. The degree of DNA damage in the OIL group was also significantly higher. In comparison with the OIL group, the wheat bran and oat bran supplementation significantly reduced the 24-hour MDA excretion in urine and reduced the degree of DNA damage in leukocytes to the level of the CONT group. Conclusion: The results of the experiments confirmed that a high wheat bran and oat bran intake effectively reduces oxidative stress induced by a high-fat diet.

Many G protein-coupled receptors (GPCRs) are organized as dynamic macromolecular complexes in human cells. Unraveling the structural determinants of unique GPCR complexes may identify unique protein:protein interfaces to be exploited for drug development. We previously reported α -adrenergic receptors (α -ARs) - key regulators of cardiovascular and central nervous system function - form homodimeric, modular PDZ protein complexes with cell-type specificity. Towards mapping α -AR complex architecture, biolayer interferometry (BLI) revealed the α -AR C-terminal PDZ ligand selectively binds the PDZ protein scribble (SCRIB) with >8x higher affinity than known interactors syntrophin, CASK and DLG1. Complementary in situ and in vitro assays revealed SCRIB PDZ domains 1 and 4 to be high affinity α -AR PDZ ligand interaction sites. SNAP-GST pull-down assays demonstrate SCRIB binds multiple α -AR PDZ ligands via a co-operative mechanism. Structure-function analyses pinpoint R1110 as a unique, critical residue dictating SCRIB:α -AR binding specificity. The crystal structure of SCRIB PDZ4 R1110G predicts spatial shifts in the SCRIB PDZ4 carboxylate binding loop dictate α -AR binding specificity. Thus, the findings herein identify SCRIB PDZ domains 1 and 4 as high affinity α -AR interaction sites, and potential drug targets to treat diseases associated with aberrant α -AR signaling.