Everolimus dosing recommendations for tuberous sclerosis complex–associated refractory seizures

ObjectiveThe present analysis examined the exposure-response relationship by means of the predose everolimus concentration (C-min) and the seizure response in patients with tuberous sclerosis complex-associated seizures in the EXIST-3 study. Recommendations have been made for the target C-min range of everolimus for therapeutic drug monitoring (TDM) and the doses necessary to achieve this target C-min

Typical performance of low-density parity-check codes over general symmetric channels

Typical performance of low-density parity-check (LDPC) codes over a general binary-input output-symmetric memoryless channel is investigated using methods of statistical mechanics. Theoretical framework for dealing with general symmetric channels is provided, based on which Gallager and MacKay-Neal codes are studied as examples of LDPC codes. It has been shown that the basic properties of these codes known for particular channels, including the property to potentially saturate Shannon's limit, hold for general symmetric channels. The binary-input additive-white-Gaussian-noise channel and the binary-input Laplace channel are considered as specific channel noise models.Comment: 10 pages, 4 figures, RevTeX4; an error in reference correcte

Synthesis of the elements in stars: forty years of progress

Forty years ago Burbidge, Burbidge, Fowler, and Hoyle combined what we would now call fragmentary evidence from nuclear physics, stellar evolution and the abundances of elements and isotopes in the solar system as well as a few stars into a synthesis of remarkable ingenuity. Their review provided a foundation for forty years of research in all of the aspects of low energy nuclear experiments and theory, stellar modeling over a wide range of mass and composition, and abundance studies of many hundreds of stars, many of which have shown distinct evidence of the processes suggested by B2FH. In this review we summarize progress in each of these fields with emphasis on the most recent developments

The historical development of sewers worldwide

Open Access articleAlthough there is evidence of surface-based storm drainage systems in early Babylonian and Mesopotamian Empires in Iraq (ca. 4000-2500 BC), it is not until after ca. 3000 BC that we find evidence of the well organized and operated sewer and drainage systems of the Minoans and Harappans in Crete and the Indus valley, respectively. The Minoans and Indus valley civilizations originally, and the Hellenes and Romans thereafter, are considered pioneers in developing basic sewerage and drainage technologies, with emphasis on sanitation in the urban environment. The Hellenes and Romans further developed these techniques and greatly increased the scale of these systems. Although other ancient civilizations also contributed, notably some of the Chinese dynasties, very little progress was made during the Dark ages from ca. 300 AD through to the middle of the 18th century. It was only from 1850 onwards that that modern sewerage was "reborn", but many of the principles grasped by the ancients are still in use today. This paper traces the development of the sewer from those earliest of civilizations through to the present day and beyond. A 6000 year technological history is a powerful validation of the vital contribution of sewers to human history. © 2014 by the authors

Evolutionary trajectories in rugged fitness landscapes

We consider the evolutionary trajectories traced out by an infinite population undergoing mutation-selection dynamics in static, uncorrelated random fitness landscapes. Starting from the population that consists of a single genotype, the most populated genotype \textit{jumps} from a local fitness maximum to another and eventually reaches the global maximum. We use a strong selection limit, which reduces the dynamics beyond the first time step to the competition between independent mutant subpopulations, to study the dynamics of this model and of a simpler one-dimensional model which ignores the geometry of the sequence space. We find that the fit genotypes that appear along a trajectory are a subset of suitably defined fitness \textit{records}, and exploit several results from the record theory for non-identically distributed random variables. The genotypes that contribute to the trajectory are those records that are not \textit{bypassed} by superior records arising further away from the initial population. Several conjectures concerning the statistics of bypassing are extracted from numerical simulations. In particular, for the one-dimensional model, we propose a simple relation between the bypassing probability and the dynamic exponent which describes the scaling of the typical evolution time with genome size. The latter can be determined exactly in terms of the extremal properties of the fitness distribution.Comment: Figures in color; minor revisions in tex

3D Spin Glass and 2D Ferromagnetic XY Model: a Comparison

We compare the probability distributions and Binder cumulants of the overlap in the 3D Ising spin glass with those of the magnetization in the ferromagnetic 2D XY model. We analyze similarities and differences. Evidence for the existence of a phase transition in the spin glass model is obtained thanks to the crossing of the Binder cumulant. We show that the behavior of the XY model is fully compatible with the Kosterlitz-Thouless scenario. Finite size effects have to be dealt with by using great care in order to discern among two very different physical pictures that can look very similar if analyzed without large attention.Comment: 14 pages and 6 figures. Also available at http://chimera.roma1.infn.it/index_papers_complex.htm

Competition between glassiness and order in a multi-spin glass

A mean-field multi-spin interaction spin glass model is analyzed in the presence of a ferromagnetic coupling. The static and dynamical phase diagrams contain four phases (paramagnet, spin glass, ordinary ferromagnet and glassy ferromagnet) and exhibit reentrant behavior. The glassy ferromagnet phase has anomalous dynamical properties. The results are consistent with a nonequilibrium thermodynamics that has been proposed for glasses.Comment: revised version, 4 pages Revtex, 2 eps-figures. Phys. Rev. E, Rapid Communication, to appea

Centerscope

Centerscope, formerly Scope, was published by the Boston University Medical Center "to communicate the concern of the Medical Center for the development and maintenance of improved health care in contemporary society.

The role of local and remote amino acid substitutions for optimizing fluorescence in bacteriophytochromes: A case study on iRFP

Bacteriophytochromes are promising tools for tissue microscopy and imaging due to their fluorescence in the near-infrared region. These applications require optimization of the originally low fluorescence quantum yields via genetic engineering. Factors that favour fluorescence over other non-radiative excited state decay channels are yet poorly understood. In this work we employed resonance Raman and fluorescence spectroscopy to analyse the consequences of multiple amino acid substitutions on fluorescence of the iRFP713 benchmark protein. Two groups of mutations distinguishing iRFP from its precursor, the PAS-GAF domain of the bacteriophytochrome P2 from Rhodopseudomonas palustris, have qualitatively different effects on the biliverdin cofactor, which exists in a fluorescent (state II) and a non-fluorescent conformer (state I). Substitution of three critical amino acids in the chromophore binding pocket increases the intrinsic fluorescence quantum yield of state II from 1.7 to 5.0% due to slight structural changes of the tetrapyrrole chromophore. Whereas these changes are accompanied by an enrichment of state II from ~40 to ~50%, a major shift to ~88% is achieved by remote amino acid substitutions. Additionally, an increase of the intrinsic fluorescence quantum yield of this conformer by ~34% is achieved. The present results have important implications for future design strategies of biofluorophores.DFG, 221545957, SFB 1078: Proteinfunktion durch ProtonierungsdynamikDFG, 53182490, EXC 314: Unifying Concepts in Catalysi

NuSTAR Spectroscopy of Multi-Component X-ray Reflection from NGC 1068

We report on observations of NGC1068 with NuSTAR, which provide the best constraints to date on its $>10$~keV spectral shape. We find no strong variability over the past two decades, consistent with its Compton-thick AGN classification. The combined NuSTAR, Chandra, XMM-Newton, and Swift-BAT spectral dataset offers new insights into the complex reflected emission. The critical combination of the high signal-to-noise NuSTAR data and a spatial decomposition with Chandra allow us to break several model degeneracies and greatly aid physical interpretation. When modeled as a monolithic (i.e., a single N_H) reflector, none of the common Compton-reflection models are able to match the neutral fluorescence lines and broad spectral shape of the Compton reflection. A multi-component reflector with three distinct column densities (e.g., N_H~1.5e23, 5e24, and 1e25 cm^{-2}) provides a more reasonable fit to the spectral lines and Compton hump, with near-solar Fe abundances. In this model, the higher N_H components provide the bulk of the Compton hump flux while the lower N_H component produces much of the line emission, effectively decoupling two key features of Compton reflection. We note that ~30% of the neutral Fe Kalpha line flux arises from >2" (~140 pc), implying that a significant fraction of the <10 keV reflected component arises from regions well outside of a parsec-scale torus. These results likely have ramifications for the interpretation of poorer signal-to-noise observations and/or more distant objects [Abridged].Comment: Submitted to ApJ; 23 pages (ApJ format); 11 figures and 3 tables; Comments welcomed