Regulation of Apoptosis by XIAP Ubiquitin- Ligase Activity

Virtually all animal cells have the known ability to self-destruct by undergoing apoptosis, a morphologically distinct form of programmed cell death. The proper regulation of apoptosis is critical for both development and tissue homeostasis, and inhibition of apoptosis contributes to the development and progression of cancer. Inhibitor of Apoptosis Proteins (IAPs) can bind to and inhibit caspases, the key executioners of apoptosis. Because IAPs are frequently over-expressed in human tumors, they have become major pharmacological targets for developing new cancer therapeutics. Many IAPs contain RING domains that function as E3 ubiquitin-ligases to regulate the abundance of IAPs themselves and their binding partners by engaging the ubiquitin system. The precise physiological function of individual mammalian IAPs and their role as E3- ubiquitin ligases in situ remain largely obscure. Here, we investigated the function of XIAP ubiquitin-ligase activity by deleting the RING motif via gene targeting in the mouse. Mice expressing XIAP ΔRING were fertile, born in expected proportions, and were not obviously prone to disease in a pathogen-free environment. Removing the RING finger motif stabilized XIAP protein in apoptotic thymocytes, demonstrating that XIAP ubiquitin-ligase activity is a major determinant of XIAP protein stability. However, consistent with earlier reports on XIAP-null mice, we found no detectable abnormalities in apoptosis of mutant thymocytes. On the other hand, ΔRING embryonic stem cells and fibroblasts had elevated caspase-3 enzyme activity and impaired ubiquitination of active caspase-3 during apoptosis. Furthermore, XIAP ΔRING embryonic fibroblasts were strongly sensitized to TNF-α-induced apoptosis. Similar results were obtained with XIAP-null mice. Finally, deletion of the RING also improved the survival of mice in the Eμ-Myc lymphoma model. The improved prognosis corresponded to increased apoptosis and decreased abundance of proliferating B-cells in the bone marrow, and a curtailed incidence of leukemia. This demonstrates a physiological requirement of XIAP E3 ubiquitin-ligase activity for the inhibition of apoptosis and for tumor suppression in vivo

Tests for, origins of, and corrections to non-Gaussian statistics. The dipole-flip model

The following article appeared in Schile, A. J., & Thompson, W. H. (2017). Tests for, origins of, and corrections to non-Gaussian statistics. The dipole-flip model. The Journal of Chemical Physics, 146(15), 154109. and may be found at https://aip.scitation.org/doi/abs/10.1063/1.4981009.Linear response approximations are central to our understanding and simulations of nonequilibrium statistical mechanics. Despite the success of these approaches in predicting nonequilibrium dynamics, open questions remain. Laird and Thompson [J. Chem. Phys. 126, 211104 (2007)] previously formalized, in the context of solvation dynamics, the connection between the static linear-response approximation and the assumption of Gaussian statistics. The Gaussian statistics perspective is useful in understanding why linear response approximations are still accurate for perturbations much larger than thermal energies. In this paper, we use this approach to address three outstanding issues in the context of the “dipole-flip” model, which is known to exhibit nonlinear response. First, we demonstrate how non-Gaussian statistics can be predicted from purely equilibrium molecular dynamics (MD) simulations (i.e., without resort to a full nonequilibrium MD as is the current practice). Second, we show that the Gaussian statistics approximation may also be used to identify the physical origins of nonlinear response residing in a small number of coordinates. Third, we explore an approach for correcting the Gaussian statistics approximation for nonlinear response effects using the same equilibrium simulation. The results are discussed in the context of several other examples of nonlinear responses throughout the literature

Nonadiabatic transition paths from quantum jump trajectories

We present a means of studying rare reactive pathways in open quantum systems using Transition Path Theory and ensembles of quantum jump trajectories. This approach allows for elucidation of reactive paths for dissipative, nonadiabatic dynamics when the system is embedded in a Markovian environment. We detail the dominant pathways and rates of thermally activated processes, as well as the relaxation pathways and photoyields following vertical excitation in a minimal model of a conical intersection. We find that the geometry of the conical intersection affects the electronic character of the transition state, as defined through a generalization of a committor function for a thermal barrier crossing event. Similarly, the geometry changes the mechanism of relaxation following a vertical excitation. Relaxation in models resulting from small diabatic coupling proceed through pathways dominated by pure dephasing, while those with large diabatic coupling proceed through pathways limited by dissipation. The perspective introduced here for the nonadiabatic dynamics of open quantum systems generalizes classical notions of reactive paths to fundamentally quantum mechanical processes.Comment: 15 pages, 15 figures, small revisions throughou

Análisis energético y exergético de un motor diesel de automoción operando en diferentes altitudes

RESUMEN: La densidad del aire disminuye con el aumento de la altitud sobre el nivel del mar, este aspecto afecta el proceso de combustión, la formación de emisiones contaminantes y por tanto el desempeño del motor. En este trabajo se presenta el diagnóstico del proceso de combustión de un motor diesel de automoción turbo-alimentado, mediante la medición de presión en cámara operando en tres alturas diferentes sobre el nivel del mar, bajo condiciones estacionarias, utilizando diesel convencional (acpm) como combustible. A medida que aumenta la altura sobre el nivel del mar se incrementa la relación combustible/aire (mezcla más rica) y con ello el consumo específico de combustible, la duración de la combustión, la combustión en fase premezclada, la temperatura máxima, el calor transferido a los gases y la exergía destruida, mientras que el rendimiento térmico efectivo del motor, la presión máxima y la exergía en el cilindro disminuyen. Sin embargo, la eficiencia mecánica y el tiempo de inyección se mantienen aproximadamente constantes. Las diferencias encontradas en la exergía destruida se deben a las variaciones del proceso de combustión, ya que no se encontraron efectos significativos en las carreras de compresión y expansión. La mayor irreversibilidad debida al aumento de la altura se debe a la baja calidad de la energía de los gases de escape.ABSTRACT: Altitude above sea level produces a reduction in air density affecting the combustion process, pollutant emissions, and engine performance. In this work the combustion diagnosis of an automotive turbocharged diesel engine was carried out from in-cylinder pressure signal. Tests were performed at three altitudes above sea level, under steady state operating conditions, using conventional diesel fuel. As altitude above sea level increased, the fuel/air mixture became richer. The brake specific fuel consumption, combustion duration, premixed combustion phase, maximum temperature, heat rejected to the gases and exergy destruction were also increased; at the same time, brake thermal efficiency, maximum in-cylinder pressure and in-cylinder exergy decreased. Mechanical efficiency and injection timing remained approximately invariable. Exergy destruction differences were caused by the combustion process, without significant effects during compression and expansion. The greater irreversibility resulting from altitude increase was linked with the lower energy quality of the exhaust gases

Climate Change and San Francisco Bay-Delta Tidal Wetlands

Climate change will affect tidal wetlands with higher rates of sea-level rise and higher concentrations of salt in brackish and freshwater tidal systems, in addition to causing increases in atmospheric CO2 concentration, warmer temperatures, and shifts in precipitation. In the San Francisco Bay–Delta, the areas most likely to be affected—brackish and freshwater tidal wetlands—are also the sites with the majority of endemic plant species and the greater biodiversity and productivity. Effects on the San Francisco Bay– Delta estuary are complex and difficult to predict, but a few things are clear. Biodiversity of the tidal wetland system in the San Francisco Bay–Delta region will decline, with subsequent effects on ecosystem functioning and services. Altered plant production, physiological tolerances, and shifts in rates of mortality will modify wetland plant communities in ways not yet predictable. Lower ecosystem productivity from salinity increases will affect both primary and detrital-based food webs. Such changes will cascade via the food webs into invertebrate, bird, and pelagic systems. Tidal wetlands are especially sensitive to processes that climate change will alter. Several of these altered processes are exacerbated by water diversions from the Delta

Protein coding variation in the J:ARC and J:DO outbred laboratory mouse stocks provides a molecular basis for distinct research applications.

Outbred laboratory mice (Mus musculus) are readily available and have high fecundity, making them a popular choice in biomedical research, especially toxicological and pharmacological applications. Direct high throughput genome sequencing (HTS) of these widely used research animals is an important genetic quality control measure that enhances research reproducibility. HTS data have been used to confirm the common origin of outbred stocks and to molecularly define distinct outbred populations. But these data have also revealed unexpected population structure and homozygosity in some populations; genetic features that emerge when outbred stocks are not properly maintained. We used exome sequencing to discover and interrogate protein-coding variation in a newly established population of Swiss-derived outbred stock (J:ARC) that is closely related to other, commonly used CD-1 outbred populations. We used these data to describe the genetic architecture of the J:ARC population including heterozygosity, minor allele frequency, LD decay, and we defined novel, protein-coding sequence variation. These data reveal the expected genetic architecture for a properly maintained outbred stock and provide a basis for the on-going genetic quality control. We also compared these data to protein-coding variation found in a multiparent outbred stock, the Diversity Outbred (J:DO). We found that the more recently derived, multiparent outbred stock has significantly higher interindividual variability, greater overall genetic variation, higher heterozygosity, and fewer novel variants than the Swiss-derived J:ARC stock. However, among the novel variants found in the J:DO stock, significantly more are predicted to be protein-damaging. The fact that individuals from this population can tolerate a higher load of potentially damaging variants highlights the buffering effects of allelic diversity and the differing selective pressures in these stocks. While both outbred stocks offer significant individual heterozygosity, our data provide a molecular basis for their intended applications, where the J:DO are best suited for studies requiring maximum, population-level genetic diversity and power for mapping, while the J:ARC are best suited as a general-purpose outbred stock with robust fecundity, relatively low allelic diversity, and less potential for extreme phenotypic variability