Migration towards Bangladesh coastlines projected to increase with sea-level rise through 2100.

To date, projections of human migration induced by sea-level change (SLC) largely suggest large-scale displacement away from vulnerable coastlines. However, results from our model of Bangladesh suggest counterintuitively that people will continue to migrate toward the vulnerable coastline irrespective of the flooding amplified by future SLC under all emissions scenarios until the end of this century. We developed an empirically calibrated agent-based model of household migration decision-making that captures the multi-faceted push, pull and mooring influences on migration at a household scale. We then exposed ~4800 000 simulated migrants to 871 scenarios of projected 21st-century coastal flooding under future emissions pathways. Our model does not predict flooding impacts great enough to drive populations away from coastlines in any of the scenarios. One reason is that while flooding does accelerate a transition from agricultural to non-agricultural income opportunities, livelihood alternatives are most abundant in coastal cities. At the same time, some coastal populations are unable to migrate, as flood losses accumulate and reduce the set of livelihood alternatives (so-called 'trapped' populations). However, even when we increased access to credit, a commonly-proposed policy lever for incentivizing migration in the face of climate risk, we found that the number of immobile agents actually rose. These findings imply that instead of a straightforward relationship between displacement and migration, projections need to consider the multiple constraints on, and preferences for, mobility. Our model demonstrates that decision-makers seeking to affect migration outcomes around SLC would do well to consider individual-level adaptive behaviors and motivations that evolve through time, as well as the potential for unintended behavioral responses.

Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device - the SERCA-LVAD TRIAL.

The SERCA-LVAD trial was a phase 2a trial assessing the safety and feasibility of delivering an adeno-associated vector 1 carrying the cardiac isoform of the sarcoplasmic reticulum calcium ATPase (AAV1/SERCA2a) to adult chronic heart failure patients implanted with a left ventricular assist device. The SERCA-LVAD trial was one of a program of AAV1/SERCA2a cardiac gene therapy trials including CUPID1, CUPID 2 and AGENT trials. Enroled subjects were randomised to receive a single intracoronary infusion of 1 × 1013 DNase-resistant AAV1/SERCA2a particles or a placebo solution in a double-blinded design, stratified by presence of neutralising antibodies to AAV. Elective endomyocardial biopsy was performed at 6 months unless the subject had undergone cardiac transplantation, with myocardial samples assessed for the presence of exogenous viral DNA from the treatment vector. Safety assessments including ELISPOT were serially performed. Although designed as a 24 subject trial, recruitment was stopped after five subjects had been randomised and received infusion due to the neutral result from the CUPID 2 trial. Here we describe the results from the 5 patients at 3 years follow up, which confirmed that viral DNA was delivered to the failing human heart in 2 patients receiving gene therapy with vector detectable at follow up endomyocardial biopsy or cardiac transplantation. Absolute levels of detectable transgene DNA were low, and no functional benefit was observed. There were no safety concerns in this small cohort. This trial identified some of the challenges of performing gene therapy trials in this LVAD patient cohort which may help guide future trial design.

Supersonic plasma turbulence in the laboratory.

The properties of supersonic, compressible plasma turbulence determine the behavior of many terrestrial and astrophysical systems. In the interstellar medium and molecular clouds, compressible turbulence plays a vital role in star formation and the evolution of our galaxy. Observations of the density and velocity power spectra in the Orion B and Perseus molecular clouds show large deviations from those predicted for incompressible turbulence. Hydrodynamic simulations attribute this to the high Mach number in the interstellar medium (ISM), although the exact details of this dependence are not well understood. Here we investigate experimentally the statistical behavior of boundary-free supersonic turbulence created by the collision of two laser-driven high-velocity turbulent plasma jets. The Mach number dependence of the slopes of the density and velocity power spectra agree with astrophysical observations, and supports the notion that the turbulence transitions from being Kolmogorov-like at low Mach number to being more Burgers-like at higher Mach numbers.

Laboratory evidence of dynamo amplification of magnetic fields in a turbulent plasma.

Magnetic fields are ubiquitous in the Universe. The energy density of these fields is typically comparable to the energy density of the fluid motions of the plasma in which they are embedded, making magnetic fields essential players in the dynamics of the luminous matter. The standard theoretical model for the origin of these strong magnetic fields is through the amplification of tiny seed fields via turbulent dynamo to the level consistent with current observations. However, experimental demonstration of the turbulent dynamo mechanism has remained elusive, since it requires plasma conditions that are extremely hard to re-create in terrestrial laboratories. Here we demonstrate, using laser-produced colliding plasma flows, that turbulence is indeed capable of rapidly amplifying seed fields to near equipartition with the turbulent fluid motions. These results support the notion that turbulent dynamo is a viable mechanism responsible for the observed present-day magnetization.

Quantum radiation reaction in laser-electron-beam collisions.

It is possible using current high-intensity laser facilities to reach the quantum radiation reaction regime for energetic electrons. An experiment using a wakefield accelerator to drive GeV electrons into a counterpropagating laser pulse would demonstrate the increase in the yield of high-energy photons caused by the stochastic nature of quantum synchrotron emission: we show that a beam of 10(9) 1 GeV electrons colliding with a 30 fs laser pulse of intensity 10(22) W cm(-2) will emit 6300 photons with energy greater than 700 MeV, 60× the number predicted by classical theory.

Dense electron-positron plasmas and ultraintense γ rays from laser-irradiated solids.

In simulations of a 10 PW laser striking a solid, we demonstrate the possibility of producing a pure electron-positron plasma by the same processes as those thought to operate in high-energy astrophysical environments. A maximum positron density of 10(26) m(-3) can be achieved, 7 orders of magnitude greater than achieved in previous experiments. Additionally, 35% of the laser energy is converted to a burst of γ rays of intensity 10(22) W cm(-2), potentially the most intense γ-ray source available in the laboratory. This absorption results in a strong feedback between both pair and γ-ray production and classical plasma physics in the new "QED-plasma" regime.

Generation of scaled protogalactic seed magnetic fields in laser-produced shock waves.

The standard model for the origin of galactic magnetic fields is through the amplification of seed fields via dynamo or turbulent processes to the level consistent with present observations. Although other mechanisms may also operate, currents from misaligned pressure and temperature gradients (the Biermann battery process) inevitably accompany the formation of galaxies in the absence of a primordial field. Driven by geometrical asymmetries in shocks associated with the collapse of protogalactic structures, the Biermann battery is believed to generate tiny seed fields to a level of about 10(-21) gauss (refs 7, 8). With the advent of high-power laser systems in the past two decades, a new area of research has opened in which, using simple scaling relations, astrophysical environments can effectively be reproduced in the laboratory. Here we report the results of an experiment that produced seed magnetic fields by the Biermann battery effect. We show that these results can be scaled to the intergalactic medium, where turbulence, acting on timescales of around 700 million years, can amplify the seed fields sufficiently to affect galaxy evolution.

Laser absorption in relativistically underdense plasmas by synchrotron radiation.

A novel absorption mechanism for linearly polarized lasers propagating in relativistically underdense solids in the ultrarelativistic (a ~ 100) regime is presented. The mechanism is based on strong synchrotron emission from electrons reinjected into the laser by the space charge field they generate at the front of the laser pulse. This laser absorption, termed reinjected electron synchrotron emission, is due to a coupling of conventional plasma physics processes to quantum electrodynamic processes in low density solids at intensities above 10(22) W/cm(2). Reinjected electron synchrotron emission is identified in 2D QED-particle-in-cell simulations and then explained in terms of 1D QED-particle-in-cell simulations and simple analytical theory. It is found that between 1% (at 10(22) W/cm(2)) and 14% (at 8 × 10(23) W/cm(2)) of the laser energy is converted into gamma ray photons, potentially providing an ultraintense future gamma ray source.

Possibility of prolific pair production with high-power lasers.

Prolific electron-positron pair production is possible at laser intensities approaching 10;{24} W cm;{-2} at a wavelength of 1 mum. An analysis of electron trajectories and interactions at the nodes (B=0) of two counterpropagating, circularly polarized laser beams shows that a cascade of gamma rays and pairs develops. The geometry is generalized qualitatively to linear polarization and laser beams incident on a solid target.

Effect of target composition on proton energy spectra in ultraintense laser-solid interactions.

We study how the proton density in a target irradiated by an ultraintense laser affects the proton spectrum, with analytical models and Vlasov simulations. A low relative proton density gives rise to peaks in the energy spectrum. Furthermore, a target with the protons confined to a thin, low density layer produces a quasimonoenergetic spectrum. This is a simple technique for producing proton beams with a narrow energy spread for proton radiography of laser-plasma interactions.

Resistive collimation of electron beams in laser-produced plasmas.

Intense relativistic electron beams, produced by high-intensity short-pulse laser irradiation of a solid target, have many potential applications including fusion by fast ignition. Using a unique Fokker-Planck code, supported by analytic calculations, we show that fast electrons can be collimated into a beam even when the fast electron source is not strongly anisotropic, and we derive a condition for collimation to occur.

mRNA and protein expression of dog liver cytochromes P450 in relation to the metabolism of human CYP2C substrates.

1. Interpretation of novel drug exposure and toxicology data from the dog is tempered by our limited molecular and functional knowledge of dog cytochromes P450 (CYPs). The aim was to study the mRNA and protein expression of hepatic dog CYPs in relation to the metabolism of substrates of human CYP, particularly those of the CYP2C subfamily. 2. The rate of 7-hydroxylation of S-warfarin (CYP2C9 in humans) by dog liver microsomes (mean +/- SD from 12 (six male and six female) dogs = 10.8 +/- 1.9 fmol mg(-1) protein min(-1)) was 1.5-2 orders of magnitude lower than that in humans. 3. The rate of 4'-hydroxylation of S-mephenytoin, catalysed in humans by CYP2C19, was also low in dog liver (4.6 +/-1.5 pmol mg(-1) protein min(-1)) compared with human liver. In contrast, the rate of 4'-hydroxylation of the R-enantiomer of mephenytoin by dog liver was much higher. The kinetics of this reaction (range of K(m) or K(0.5) 15-22 micro M, V(max) 35-59 pmol mg(-1) protein min(-1), n = 4 livers) were consistent with the involvement of a single enzyme. 4. In contrast to our findings for S-mephenytoin, dog liver microsomes 5'-hydroxylated omeprazole (also catalysed by CYP2C19 in humans) at considerably higher rates (range of K(m) 42-64 micro M, V(max) 22-46 pmol mg(-1) protein min(-1), n = 4 livers). 5. For all the substrates except omeprazole, a sex difference in their metabolism was observed in the dog (dextromethorphan N-demethylation: female range = 0.7-0.9, male = 0.4-0.8 nmol mg(-1) protein min(-1) (p < 0.02); S-warfarin 7-hydroxylation: female = 9-15.5, male = 8-12 fmol mg(-1) protein min(-1) (p < 0.02); R-mephenytoin 4'-hydroxylation: female = 16-35, male = 11.5-19 pmol mg(-1) protein min(-1) (p < 0.01); omeprazole 5'-hydroxylation: female = 15-20, male 13-22 pmol mg(-1) protein min(-1) (p < 0.2)). 6. All dog livers expressed mRNA and CYP3A12, CYP2B11, CYP2C21 proteins, with no sex differences being found. Expression of CYP2C41 mRNA was undetectable in the livers of six of 11 dogs. 7. Correlation analysis suggested that CYP2B11 catalyses the N-demethylation of dextromethorphan (mediated in humans by CYP3A) and the 4'-hydroxylation of mephenytoin (mediated in humans by CYP2C19) in the dog, and that this enzyme and CYP3A12 contribute to S-warfarin 7-hydroxylation (mediated in humans by CYP2C9). 8. In conclusion, we have identified a distinct pattern of hepatic expression of the CYP2C41 gene in the Alderley Park beagle dog. Furthermore, marked differences in the metabolism of human CYP2C substrates were observed in this dog strain compared with humans with respect to rate of reaction, stereoselectivity and CYP enzyme selectivity.

Nonlocal magnetic-field generation in plasmas without density gradients.

Conventional theories of magnetic-field generation by laser pulses in collisional plasmas require the presence of density gradients or anisotropic pressure. Using the first two-dimensional Fokker-Planck code to self-consistently include magnetic fields, we find that magnetic fields can be spontaneously generated when a collisional plasma is nonuniformly heated even though inverted delta n = 0 and the pressure is purely isotropic. These magnetic fields, which can become strong enough to significantly affect transport, are attributed to nonlocal effects that are missing in the standard, local theories.

Species differences in peroxisome proliferation; mechanisms and relevance.

Peroxisome proliferators are a class of structurally diverse chemicals, which induce liver carcinogenesis in rodents through interaction and activation of the Peroxisome Proliferator-Activated Receptor alpha (PPARalpha). PPARalpha agonists elicit a powerful pleiotropic response, which include hypolipidaemia. We have examined the response of species that are classically unresponsive to peroxisome proliferators. Whereas hamster responds to PPARalpha agonists by hepatomegaly and induction of marker genes, the guinea pig does not undergo hepatomegaly or induction of marker genes, such as CYP4A13. Both the hamster and the guinea pig have PPARalpha, and the guinea pig receptor has been characterised to be fully functional, as demonstrated in reporter gene expression assays. However, the guinea pig PPARalpha is expressed at low levels in liver, and the currently favoured hypothesis to explain species differences in hepatic peroxisome proliferation invokes the low level of PPARalpha as the principal determinant of species responsiveness. However, the demonstration that guinea pigs and humans undergo hypolipidaemia induced by PPARalpha-agonists calls into question the mode of action of PPARalpha agonists in "non-responsive" species.

Magnetic focusing and trapping of high-intensity laser-generated fast electrons at the rear of solid targets.

The transport of fast electrons generated by a 1 ps, 20 J, 10(19) W cm(-2), 1 microm wavelength laser pulse through 70-250 microm thick deuterated polyethylene (CD2) targets is modeled with a Fokker-Planck hybrid code in r-z geometry. Initially, electric field generation inhibits propagation, which then proceeds by the formation of a low resistivity channel due to Ohmic heating. The magnetic field generated at the edge of the channel leads to strong collimation. This is observed for a wide range of parameters. Reflection of electrons at the rear surface forms a magnetic field which focuses the incident electrons on to the rear surface and forces the reflected electrons outwards. This would lead to the formation of a small diameter plasma on the rear surface, as observed in experiments. The reflected electrons are confined to a cone by a self-generated magnetic field, enhancing energy deposition at the rear of the target.

Molecular basis of non-responsiveness to peroxisome proliferators: the guinea-pig PPARalpha is functional and mediates peroxisome proliferator-induced hypolipidaemia.

The guinea pig does not undergo peroxisome proliferation in response to peroxisome proliferators, in contrast with other rodents. To understand the molecular basis of this phenotype, the peroxisome proliferator activated receptor alpha (PPARalpha) from guinea-pig liver was cloned; it encodes a protein of 467 amino acid residues that is similar to rodent and human PPARalpha. The guinea-pig PPARalpha showed a high substitution rate: maximum likelihood analysis was consistent with rodent monophyly, but could not exclude rodent polyphyly (P approximately 0.06). The guinea-pig PPARalpha cDNA was expressed in 293 cells and mediated the induction of the luciferase reporter gene by the peroxisome proliferator, Wy-14,643, dependent on the presence of a peroxisome proliferator response element. Moreover the PPARalpha RNA and protein were expressed in guinea-pig liver, although at lower levels than in a species which is responsive to peroxisome proliferators, the mouse. To determine whether the guinea-pig PPARalpha mediated any physiological effects, guinea pigs were exposed to two selective PPARalpha agonists, Wy-14, 643 and methylclofenapate; both compounds induced hypolipidaemia. Thus the guinea pig is a useful model for human responses to peroxisome proliferators.

Long-term survival in allogeneic bone marrow transplant recipients following acyclovir prophylaxis for CMV infection. The European Acyclovir for CMV Prophylaxis Study Group.

Recipients of HLA-matched, related or unrelated allogeneic BMT who were CMV seropositive or those receiving unmanipulated marrow from a seropositive donor were randomised to receive one of three treatment regimens, i.v. acyclovir 500 mg/m2 three times a day from 5 days before transplant to 30 days after transplant followed by oral acyclovir 800 mg four times a day for a further 6 months, i.v. acyclovir followed by placebo, or 400 mg oral acyclovir four times a day followed by placebo (control). This paper reports the 1 year data on the same cohort of patients which was previously reported. Intravenous acyclovir (i.v./PCB) significantly reduced the risk of CMV infection when compared to the control group. The frequency of adverse events reported was comparable among the three groups. The mortality rate was significantly reduced by the sequential use of i.v. acyclovir followed by oral acyclovir, resulting in a 19% survival advantage at 1 year from transplant.

Chromosomal localisation, inducibility, tissue-specific expression and strain differences in three murine peroxisome-proliferator-activated-receptor genes.

Three murine peroxisome-proliferator-activated-receptor (PPAR) genes were localised to chromosome 15 (PPAR alpha), chromosome 17 (PPAR beta) and chromosome 6 (PPAR gamma). The expression of the three PPAR RNAs was determined using a specific RNase protection assay. In liver RNA, PPAR alpha was expressed at the highest level, with 20-fold lower levels of PPAR beta, and very low levels of PPAR gamma. The three PPAR RNAs showed no sex-specific differences in expression, and the levels of these transcripts were unaffected by treatment of mice with testosterone or the potent peroxisome proliferator, methylclofenapate. In agreement with this data, the level of PPAR alpha protein in liver was unchanged after treatment of mice with methylclofenapate. Investigation of the tissue-specific distribution revealed that the PPAR alpha RNA was expressed at highest levels in liver, to moderate levels in kidney and brown adipose tissue, and at low levels elsewhere. PPAR beta was expressed at moderate levels in liver, and lower levels in other tissues, including brown adipose tissue. In contrast, PPAR gamma RNA was expressed at low levels in liver or epididymal white adipose tissue and at very low levels elsewhere, but was expressed at high levels in brown adipose tissue. The tissue distribution of these receptors suggests an important role in lipid metabolism and toxicity for individual members of the PPAR family. The expression of PPAR alpha and PPAR beta RNAs was examined in 13 strains of mice, and the levels of expression varied within a fourfold range. Polymorphism in the size of PPAR alpha RNA from Swiss-Webster mice was detected, and shown to be due to a 2-bp mutation in the 3' non-coding region of PPAR alpha in Swiss Webster mice.