Chirped pulse Raman amplification in warm plasma: towards controlling saturation

Stimulated Raman backscattering in plasma is potentially an efficient method of amplifying laser pulses to reach exawatt powers because plasma is fully broken down and withstands extremely high electric fields. Plasma also has unique nonlinear optical properties that allow simultaneous compression of optical pulses to ultra-short durations. However, current measured efficiencies are limited to several percent. Here we investigate Raman amplification of short duration seed pulses with different chirp rates using a chirped pump pulse in a preformed plasma waveguide. We identify electron trapping and wavebreaking as the main saturation mechanisms, which lead to spectral broadening and gain saturation when the seed reaches several millijoules for durations of 10's - 100's fs for 250 ps, 800 nm chirped pump pulses. We show that this prevents access to the nonlinear regime and limits the efficiency, and interpret the experimental results using slowly-varying-amplitude, current-averaged particle-in-cell simulations. We also propose methods for achieving higher efficiencies.close0

An ultra-high gain and efficient amplifier based on Raman amplification in plasma

Raman amplification arising from the excitation of a density echelon in plasma could lead to amplifiers that significantly exceed current power limits of conventional laser media. Here we show that 1-100 J pump pulses can amplify picojoule seed pulses to nearly joule level. The extremely high gain also leads to significant amplification of backscattered radiation from "noise", arising from stochastic plasma fluctuations that competes with externally injected seed pulses, which are amplified to similar levels at the highest pump energies. The pump energy is scattered into the seed at an oblique angle with 14 J sr(-1), and net gains of more than eight orders of magnitude. The maximum gain coefficient, of 180 cm(-1), exceeds high-power solid-state amplifying media by orders of magnitude. The observation of a minimum of 640 J sr(-1) directly backscattered from noise, corresponding to approximate to 10% of the pump energy in the observation solid angle, implies potential overall efficiencies greater than 10%

Comparing online campaigning: The evolution of interactive campaigning from Royal to Obama to Hollande

© 2016 Macmillan Publishers Ltd.Studies of election campaigning from a comparative perspective have a long history; this study approaches the topic through a most-similar regime perspective to explore the ebb and flow of innovations in digital campaigning between presidential campaigns in France and the United States. The hype surrounding the 2008 Obama campaign overshadowed innovations in France the previous year, while the 2011 contest gained little serious academic attention. Using a well-established content analysis methodology the research explains the strategic design of the digital dimension of the campaigns of the leading candidates (Sarkozy and Royal in 2007, Obama and McCain in 2008, Hollande and Sarkozy in 2011, and Obama and Romney in 2012). The research then assesses the strategic contribution of each feature using schematics for understanding the flow of communication, as well as the strategy employed by each candidate. The key findings are that the campaigns are becoming more interactive, with the citizens increasingly more able to enter into conversations with the campaign teams, however interactivity when it happens is carefully controlled. Largely, however, there is a strong similarity masked by the sophistication of US contests. Despite the advances in communication technology and the social trends they have instigated, campaign communication remains top-down and digital technologies are used to gather data and push supporters towards activism than creating an inclusive space for the co-creation that cyberoptimists argued would revitalise the structures of democracy

Differential hypoglycaemic, anorectic, autonomic and emetic effects of the glucagon-like peptide receptor agonist, exendin-4, in the conscious telemetered ferret.

Background: Rodents are incapable of emesis and consequently the emetic potential of glucagon-like peptide-1 receptor (GLP-1R) agonists in studies designed to assess a potential blood glucose lowering action of the compound was missed. Therefore, we investigated if the ferret, a carnivore with demonstrated translation capability in emesis research, would identify the emetic potential of the GLP-1R agonist, exendin-4, and any associated effects on gastric motor function, appetite and cardiovascular homeostasis. Methods: The biological activity of the GLP-1R ligands was investigated in vivo using a glucose tolerance test in pentobarbitone-anesthetised ferrets and in vitro using organ bath studies. Radiotelemetry was used to investigate the effect of exendin-4 on gastric myoelectric activity (GMA) and cardiovascular function in conscious ferrets; behaviour was also simultaneously assessed. Western blot was used to characterize GLP-1R distribution in the gastrointestinal and brain tissues. Results: In anesthetised ferrets, exendin-4 (30 nmol/kg, s.c.) reduced experimentally elevated blood glucose levels by 36.3%, whereas the GLP-1R antagonist, exendin (9–39) (300 nmol/kg, s.c.) antagonised the effect and increased AUC0–120 by 31.0% when injected alone (P < 0.05). In animals with radiotelemetry devices, exendin-4 (100 nmol/kg, s.c.) induced emesis in 1/9 ferrets, but inhibited food intake and decreased heart rate variability (HRV) in all animals (P < 0.05). In the animals not exhibiting emesis, there was no effect on GMA, mean arterial blood pressure, heart rate, or core body temperature. In the ferret exhibiting emesis, there was a shift in the GMA towards bradygastria with a decrease in power, and a concomitant decrease in HRV. Western blot revealed GLP-1R throughout the gastrointestinal tract but exendin-4 (up to 300 nM) and exendin (9–39), failed to contract or relax isolated ferret gut tissues. GLP-1R were found in all major brain regions and the levels were comparable those in the vagus nerve. Conclusions: Peripherally administered exendin-4 reduced blood glucose and inhibited feeding with a low emetic potential similar to that in humans (11% vs 12.8%). A disrupted GMA only occurred in the animal exhibiting emesis raising the possibility that disruption of the GMA may influence the probability of emesis occurring in response to treatment with GLP-1R agonists

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

TonEBP suppresses adipogenesis and insulin sensitivity by blocking epigenetic transition of PPAR gamma 2

TonEBP is a key transcription factor in cellular adaptation to hypertonic stress, and also in macrophage activation. Since TonEBP is involved in inflammatory diseases such as rheumatoid arthritis and atherosclerosis, we asked whether TonEBP played a role in adipogenesis and insulin resistance. Here we report that TonEBP suppresses adipogenesis and insulin signaling by inhibiting expression of the key transcription factor PPAR gamma 2. TonEBP binds to the PPAR gamma 2 promoter and blocks the epigenetic transition of the locus which is required for the activation of the promoter. When TonEBP expression is reduced, the epigenetic transition and PPAR gamma 2 expression are markedly increased leading to enhanced adipogenesis and insulin response while inflammation is reduced. Thus, TonEBP is an independent determinant of adipose insulin sensitivity and inflammation. TonEBP is an attractive therapeutic target for insulin resistance in lieu of PPAR gamma agonistsopen0

Voretigene Neparvovec for Treating Inherited Retinal Dystrophies Caused by RPE65 Gene Mutations: An Evidence Review Group Perspective of a NICE Highly Specialised Technology Appraisal

The UK National Institute for Health and Care Excellence (NICE) considered evidence for voretigene neparvovec (VN; Luxturna®) for the treatment of RPE65-mediated inherited retinal dystrophies (IRD) within its highly specialised technology programme. This paper summarises the evidence provided by the company; the appraisal of the evidence by the Peninsula Technology Appraisal Group, who were commissioned to act as the independent evidence review group (ERG); and the development of the NICE guidance by the appraisal committee. The evidence presented by the company highlighted the significant lifelong burden of IRD for patients and carers. Evidence to support the effectiveness of VN was lacking, but the available evidence showed a modest, sustained improvement across a variety of vision-related outcomes. While patients would remain visually impaired, the committee considered that VN would prevent further deterioration in vision. The modelling approach used by the company had a number of limitations and relied heavily upon a large volume of clinical expert input to produce cost-effectiveness estimates with large uncertainty around long-term effectiveness. The ERG’s main concerns revolved around these long-term outcomes and the plausibility of utility values. The NICE committee were convinced that the clinical benefits of VN were important and an appropriate use of national health service resources within a specialised service. The committee concluded that a high unmet need existed in patients with RPE65-mediated IRD and that VN represents a step change in the management of this condition

MTH1 deficiency selectively increases non-cytotoxic oxidative DNA damage in lung cancer cells: more bad news than good?

Representative images of “Comets” and the corresponding intensity profiles, showing (i) ~ 5% Tail DNA damage, typical of the NSCLC cells treated with no siRNA or scramble siRNA, and analysed by regular Fpg-modified alkaline comet assay (0.8 U Fpg/gel); and (ii) comets showing ~ 10% tail DNA, typical of the NSCLC cells treated with MTH1 siRNA. Superimposed on the Comet images are the image analysis software (Komet 5.5, Andor Technology) determined boundaries demarcating the ‘Comet head’ (pink circle) and ‘tail extent’ (vertical orange line) (Barber RC, Hickenbotham P, Hatch T, Kelly D, Topchiy N, Almeida GM, et al. Radiation-induced transgenerational alterations in genome stability and DNA damage. Oncogene. 2006;25(56):7336–7342). % tail DNA = 100 - % head DNA; % head DNA = (integrated optical head intensity / (integrated optical head intensity + integrated optical tail intensity)) × 100. (PDF 1431 kb

Cardiac fibrosis in aging mice

Dystrophic cardiac calcinosis (DCC), also called epicardial and myocardial fibrosis and mineralization, has been detected in mice of a number of laboratory inbred strains, most commonly C3H/HeJ and DBA/2J. In previous mouse breeding studies between these DCC susceptible and the DCC-resistant strain C57BL/6J, 4 genetic loci harboring genes involved in DCC inheritance were identified and subsequently termed Dyscalc loci 1 through 4. Here, we report susceptibility to cardiac fibrosis, a sub-phenotype of DCC, at 12 and 20 months of age and close to natural death in a survey of 28 inbred mouse strains. Eight strains showed cardiac fibrosis with highest frequency and severity in the moribund mice. Using genotype and phenotype information of the 28 investigated strains, we performed genome-wide association studies (GWAS) and identified the most significant associations on chromosome (Chr) 15 at 72 million base pairs (Mb) (P < 10(-13)) and Chr 4 at 122 Mb (P < 10(-11)) and 134 Mb (P < 10(-7)). At the Chr 15 locus, Col22a1 and Kcnk9 were identified. Both have been reported to be morphologically and functionally important in the heart muscle. The strongest Chr 4 associations were located approximately 6 Mb away from the Dyscalc 2 quantitative trait locus peak within the boundaries of the Extl1 gene and in close proximity to the Trim63 and Cap1 genes. In addition, a single-nucleotide polymorphism association was found on chromosome 11. This study provides evidence for more than the previously reported 4 genetic loci determining cardiac fibrosis and DCC. The study also highlights the power of GWAS in the mouse for dissecting complex genetic traits.The authors thank Jesse Hammer and Josiah Raddar for technical assistance. Research reported in this publication was supported by the Ellison Medical Foundation, Parker B. Francis Foundation, and the National Institutes of Health (R01AR055225 and K01AR064766). Mouse colonies were supported by the National Institutes of Health under Award Number AG025707 for the Jackson Aging Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Jackson Laboratory Shared Scientific Services were supported in part by a Basic Cancer Center Core Grant from the National Cancer Institute (CA34196).This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00335-016-9634-

The potential contribution of disruptive low-carbon innovations to 1.5 °C climate mitigation

This paper investigates the potential for consumer-facing innovations to contribute emission reductions for limiting warming to 1.5 °C. First, we show that global integrated assessment models which characterise transformation pathways consistent with 1.5 °C mitigation are limited in their ability to analyse the emergence of novelty in energy end-use. Second, we introduce concepts of disruptive innovation which can be usefully applied to the challenge of 1.5 °C mitigation. Disruptive low-carbon innovations offer novel value propositions to consumers and can transform markets for energy-related goods and services while reducing emissions. Third, we identify 99 potentially disruptive low-carbon innovations relating to mobility, food, buildings and cities, and energy supply and distribution. Examples at the fringes of current markets include car clubs, mobility-as-a-service, prefabricated high-efficiency retrofits, internet of things, and urban farming. Each of these offers an alternative to mainstream consumer practices. Fourth, we assess the potential emission reductions from subsets of these disruptive low-carbon innovations using two methods: a survey eliciting experts’ perceptions and a quantitative scaling-up of evidence from early-adopting niches to matched segments of the UK population. We conclude that disruptive low-carbon innovations which appeal to consumers can help efforts to limit warming to 1.5 °C