353 research outputs found
Near-equilibrium measurements of nonequilibrium free energy
A central endeavor of thermodynamics is the measurement of free energy
changes. Regrettably, although we can measure the free energy of a system in
thermodynamic equilibrium, typically all we can say about the free energy of a
non-equilibrium ensemble is that it is larger than that of the same system at
equilibrium. Herein, we derive a formally exact expression for the probability
distribution of a driven system, which involves path ensemble averages of the
work over trajectories of the time-reversed system. From this we find a simple
near-equilibrium approximation for the free energy in terms of an excess mean
time-reversed work, which can be experimentally measured on real systems. With
analysis and computer simulation, we demonstrate the accuracy of our
approximations for several simple models.Comment: 5 pages, 3 figure
Use of the Naturally-Occuring Quinones Thymoquinone and Dithymoquinone as Antineoplastic and Cytotoxic Agents
Nigella sativa derivatives, thymoquinone (TM) and dithymoquinone (DIM) are used in treatment of parental and multi-drug resistant human cancers
Agmatine and Agmatine Analogs in the Treatment of Epilepsy, Seizure, and Electroconvulsive Disorders
Pharmaceutical preparations containing of agmatine, congeners, analogs or derivatives thereof for use in preventing or treating epilepsy, seizures and other electroconvulsive disorders are provided. Embodiments include administering an effective amount of agmatine, an agmatine analog or a pharmaceutically acceptable salt thereof to a human subject in need of treatment or prevention of epilepsy, seizure or other electroconvulsive disorder to treat, reduce, or prevent the disorder in the subject
Thermodynamic metrics and optimal paths
A fundamental problem in modern thermodynamics is how a molecular-scale
machine performs useful work, while operating away from thermal equilibrium
without excessive dissipation. To this end, we derive a friction tensor that
induces a Riemannian manifold on the space of thermodynamic states. Within the
linear-response regime, this metric structure controls the dissipation of
finite-time transformations, and bestows optimal protocols with many useful
properties. We discuss the connection to the existing thermodynamic length
formalism, and demonstrate the utility of this metric by solving for optimal
control parameter protocols in a simple nonequilibrium model.Comment: 5 page
The geometry of thermodynamic control
A deeper understanding of nonequilibrium phenomena is needed to reveal the
principles governing natural and synthetic molecular machines. Recent work has
shown that when a thermodynamic system is driven from equilibrium then, in the
linear response regime, the space of controllable parameters has a Riemannian
geometry induced by a generalized friction tensor. We exploit this geometric
insight to construct closed-form expressions for minimal-dissipation protocols
for a particle diffusing in a one dimensional harmonic potential, where the
spring constant, inverse temperature, and trap location are adjusted
simultaneously. These optimal protocols are geodesics on the Riemannian
manifold, and reveal that this simple model has a surprisingly rich geometry.
We test these optimal protocols via a numerical implementation of the
Fokker-Planck equation and demonstrate that the friction tensor arises
naturally from a first order expansion in temporal derivatives of the control
parameters, without appealing directly to linear response theory
The thermodynamics of prediction
A system responding to a stochastic driving signal can be interpreted as
computing, by means of its dynamics, an implicit model of the environmental
variables. The system's state retains information about past environmental
fluctuations, and a fraction of this information is predictive of future ones.
The remaining nonpredictive information reflects model complexity that does not
improve predictive power, and thus represents the ineffectiveness of the model.
We expose the fundamental equivalence between this model inefficiency and
thermodynamic inefficiency, measured by dissipation. Our results hold
arbitrarily far from thermodynamic equilibrium and are applicable to a wide
range of systems, including biomolecular machines. They highlight a profound
connection between the effective use of information and efficient thermodynamic
operation: any system constructed to keep memory about its environment and to
operate with maximal energetic efficiency has to be predictive.Comment: 5 pages, 1 figur
Quantification of habitat fragmentation reveals extinction risk in terrestrial mammals
Although habitat fragmentation is often assumed to be a primary driver of extinction, global patterns of fragmentation and its relationship to extinction risk have not been consistently quantified for any major animal taxon. We developed high-resolution habitat fragmentation models and used phylogenetic comparative methods to quantify the effects of habitat fragmentation on the world's terrestrial mammals, including 4,018 species across 26 taxonomic Orders. Results demonstrate that species with more fragmentation are at greater risk of extinction, even after accounting for the effects of key macroecological predictors, such as body size and geographic range size. Species with higher fragmentation had smaller ranges and a lower proportion of high-suitability habitat within their range, andmost high-suitability habitat occurred outside of protected areas, further elevating extinction risk. Our models provide a quantitative evaluation of extinction risk assessments for species, allow for identification of emerging threats in species not classified as threatened, and provide maps of global hotspots of fragmentation for the world's terrestrial mammals. Quantification of habitat fragmentation will help guide threat assessment and strategic priorities for global mammal conservation
Human Developmental Chondrogenesis as a Basis for Engineering Chondrocytes from Pluripotent Stem Cells
Joint injury and osteoarthritis affect millions of people worldwide, but attempts to generate articular cartilage using adult stem/progenitor cells have been unsuccessful. We hypothesized that recapitulation of the human developmental chondrogenic program using pluripotent stem cells (PSCs) may represent a superior approach for cartilage restoration. Using laser-capture microdissection followed by microarray analysis, we first defined a surface phenotype (CD166(low/neg)CD146(low/neg)CD73(+)CD44(low)BMPR1B(+)) distinguishing the earliest cartilage committed cells (prechondrocytes) at 5-6 weeks of development. Functional studies confirmed these cells are chondrocyte progenitors. From 12 weeks, only the superficial layers of articular cartilage were enriched in cells with this progenitor phenotype. Isolation of cells with a similar immunophenotype from differentiating human PSCs revealed a population of CD166(low/neg)BMPR1B(+) putative cartilage-committed progenitors. Taken as a whole, these data define a developmental approach for the generation of highly purified functional human chondrocytes from PSCs that could enable substantial progress in cartilage tissue engineering.Fil: Wu, Ling. University of California at Los Angeles; Estados UnidosFil: Bluguermann, Carolina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Laboratorio de Biología del Desarrollo Celular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of California at Los Angeles; Estados UnidosFil: Kyupelyan, Levon. University of California at Los Angeles; Estados UnidosFil: Latour, Brooke. University of California at Los Angeles; Estados UnidosFil: Gonzalez, Stephanie. University of California at Los Angeles; Estados UnidosFil: Shah, Saumya. University of California at Los Angeles; Estados UnidosFil: Galic, Zoran. University of California at Los Angeles; Estados UnidosFil: Ge, Sundi. University of California at Los Angeles; Estados UnidosFil: Zhu, Yuhua. University of California at Los Angeles; Estados UnidosFil: Petrigliano, Frank A.. University of California at Los Angeles; Estados UnidosFil: Nsair, Ali. University of California at Los Angeles; Estados UnidosFil: Miriuka, Santiago Gabriel. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Laboratorio de Biología del Desarrollo Celular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Li, Xinmin. University of California at Los Angeles; Estados UnidosFil: Lyons, Karen M.. University of California at Los Angeles; Estados UnidosFil: Crooks, Gay M.. University of California at Los Angeles; Estados UnidosFil: McAllister, David R.. University of California at Los Angeles; Estados UnidosFil: Van Handel, Ben. Novogenix Laboratories; Estados UnidosFil: Adams, John S.. University of California at Los Angeles; Estados UnidosFil: Evseenko, Denis. University of California at Los Angeles; Estados Unido
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Development of a Novel Cell-Permeable Protein-Protein Interaction Inhibitor for the Polo-box Domain of Polo-like Kinase 1.
Polo-like kinase 1 (PLK1) is a key regulator of mitosis and a recognized drug target for cancer therapy. Inhibiting the polo-box domain of PLK1 offers potential advantages of increased selectivity and subsequently reduced toxicity compared with targeting the kinase domain. However, many if not all existing polo-box domain inhibitors have been shown to be unsuitable for further development. In this paper, we describe a novel compound series, which inhibits the protein-protein interactions of PLK1 via the polo-box domain. We combine high throughput screening with molecular modeling and computer-aided design, synthetic chemistry, and cell biology to address some of the common problems with protein-protein interaction inhibitors, such as solubility and potency. We use molecular modeling to improve the solubility of a hit series with initially poor physicochemical properties, enabling biophysical and biochemical characterization. We isolate and characterize enantiomers to improve potency and demonstrate on-target activity in both cell-free and cell-based assays, entirely consistent with the proposed binding model. The resulting compound series represents a promising starting point for further progression along the drug discovery pipeline and a new tool compound to study kinase-independent PLK functions
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