Proteostasis and ageing: insights from long-lived mutant mice

The global increase in life expectancy is creating significant medical, social and economic challenges to current and future generations. Consequently, there is a need to identify the fundamental mechanisms underlying the ageing process. This knowledge should help develop realistic interventions capable of combatting age-related disease, and thus improving late-life health and vitality. While several mechanisms have been proposed as conserved lifespan determinants, the loss of proteostasis- where proteostasis is defined here as the maintenance of the proteome- appears highly relevant to both ageing and disease. Several studies have shown that multiple proteostatic mechanisms, including the endoplasmic reticulum (ER)-induced unfolded protein response (UPR), the ubiquitin-proteasome system (UPS) and autophagy, all appear indispensable for longevity in many long-lived invertebrate mutants. Similarly, interspecific comparisons suggest that proteostasis may be an important lifespan determinant in vertebrates. Over the last 20 years a number of long-lived mouse mutants have been described, many of which carry single-gene mutations within the growth-hormone, insulin/IGF-1 or mTOR signalling pathways. However, we still do not know how these mutations act mechanistically to increase lifespan and healthspan, and accordingly whether mechanistic commonality occurs between different mutants. Recent evidence supports the premise that the successful maintenance of the proteome during ageing may be linked to the increased lifespan and healthspan of long-lived mouse mutants

Speed of reaction diffusion in embryogenesis

Reaction diffusion systems have been proposed as mechanisms for patterning during many stages of embryonic development. While much attention has been focused on the study of the steady state patterns formed and the robustness of pattern selection, much less is known about the time scales required for pattern formation. Studies of gradient formation by the diffusion of a single morphogen from a localized source have shown that patterning can occur on realistic time scales over distances of a millimeter or less. Reaction diffusion has the potential to give rise to patterns on a faster time scale, since all points in the domain can act as sources of morphogen. However, the speed at which patterning can occur has hitherto not been explored in depth. In this paper, we investigate this issue in specific reaction diffusion models and address the question of whether patterning via reaction diffusion is fast enough to be applicable to morphogenesis

Complex pattern formation in reaction diffusion systems with spatially-varying parameters

Spontaneous pattern formation in reaction–diffusion systems on a spatially homogeneous domain has been well studied. However, in embryonic development and elsewhere, pattern formation often takes place on a spatially heterogeneous background. We explore the effects of spatially varying parameters on pattern formation in one and two dimensions using the Gierer–Meinhardt reaction–diffusion model. We investigate the effect of the wavelength of a pre-pattern and demonstrate a novel form of moving pattern. We find that spatially heterogeneous parameters can both increase the range and complexity of possible patterns and enhance the robustness of pattern selection

Agnesi Weighting for the Measure Problem of Cosmology

The measure problem of cosmology is how to assign normalized probabilities to observations in a universe so large that it may have many observations occurring at many different spacetime locations. I have previously shown how the Boltzmann brain problem (that observations arising from thermal or quantum fluctuations may dominate over ordinary observations if the universe expands sufficiently and/or lasts long enough) may be ameliorated by volume averaging, but that still leaves problems if the universe lasts too long. Here a solution is proposed for that residual problem by a simple weighting factor 1/(1+t^2) to make the time integral convergent. The resulting Agnesi measure appears to avoid problems other measures may have with vacua of zero or negative cosmological constant.Comment: 26 pages, LaTeX; discussion is added of how Agnesi weighting appears better than other recent measure

Biological Assessments of Six Selected Fishes, Amphibians, and Mussels in Illinois

ID: 8758; issued November 1, 1996INHS Technical Report prepared for Illinois Department of Natural Resources, Division of Natural Heritag

Nonequilibrium plasmons with gain in graphene

Graphene supports strongly confined transverse-magnetic sheet plasmons whose spectral characteristics depend on the energetic distribution of Dirac particles. The question arises whether plasmons can become amplified when graphene is pumped into a state of inversion. In establishing a theory for the dynamic non-equilibrium polarizability, we are able to determine the exact complex-frequency plasmon dispersion of photo-inverted graphene and study the impact of doping, collision loss, and temperature on the plasmon gain. We calculate the spontaneous emission spectra and carrier recombination rates self-consistently and compare the results with approximations based on Fermi's golden rule. Our results show that amplification of plasmons is possible under realistic conditions but inevitably competes with ultrafast spontaneous emission, which for intrinsic graphene, is a factor 5 faster than previously estimated. This work casts new light on the nature of non-equilibrium plasmons and may aid the experimental realization of active plasmonic devices based on graphene.Comment: 17 pages, 7 figures, published in PR

Submm-bright QSOs at z~2: signposts of co-evolution at high z

We have assembled a sample of 5 X-ray and submm-luminous z~2 QSOs which are therefore both growing their central black holes through accretion and forming stars copiously at a critical epoch. Hence, they are good laboratories to investigate the co-evolution of star formation and AGN. We have performed a preliminary analysis of the AGN and SF contributions to their UV-to-FIR SEDs, fitting them with simple direct (disk), reprocessed (torus) and star formation components. All three are required by the data and hence we confirm that these objects are undergoing strong star formation in their host galaxies at rates 500-2000 Msun/y. Estimates of their covering factors are between about 30 and 90%. In the future, we will assess the dependence of these results on the particular models used for the components and relate their observed properties to the intrinsice of the central engine and the SF material, as well as their relevance for AGN-galaxy coevolution.Comment: 6 pages, 2 figures, contributed talk to "Nuclei of Seyfert galaxies and QSOs - Central engine & conditions of star formation" November 6-8, 2012. MPIfR, Bonn, Germany. Po

Cosmological Measures without Volume Weighting

Many cosmologists (myself included) have advocated volume weighting for the cosmological measure problem, weighting spatial hypersurfaces by their volume. However, this often leads to the Boltzmann brain problem, that almost all observations would be by momentary Boltzmann brains that arise very briefly as quantum fluctuations in the late universe when it has expanded to a huge size, so that our observations (too ordered for Boltzmann brains) would be highly atypical and unlikely. Here it is suggested that volume weighting may be a mistake. Volume averaging is advocated as an alternative. One consequence may be a loss of the argument that eternal inflation gives a nonzero probability that our universe now has infinite volume.Comment: 15 pages, LaTeX, added references for constant-H hypersurfaces and also an idea for minimal-flux hypersurface