Treatment with rapamycin or rapamycin in combination with metformin contributes to mechanisms of mitochondrial proteostasis in vivo and in vitro

2018 Spring.Includes bibliographical references.This dissertation describes three sets of experiments with an overall objective of understanding how lifespan-extending treatments influence mechanisms of mitochondrial protein homeostasis (proteostasis). The specific aims of the three experiments were to 1) determine how the mTORC1 inhibitor rapamycin (Rap), or the anti-diabetes medication metformin in combination with rapamycin (Met+Rap) influence mitochondrial protein synthesis in young mice, and to determine if there are sex-specific differences in protein synthesis following treatment with Rap or Met+Rap; 2) examine the influence of Met+Rap treatment on protein synthesis in the heart, liver, and skeletal muscle of older mice and to determine if there are sex-specific differences in protein synthesis following Met+Rap treatment in old mice; 3) and, finally, to investigate the regulation of how protein turnover contributes to maintaining proteostasis during Rap and Met+Rap treatment, and the contribution of autophagic and mitophagic flux to protein turnover in cultured skeletal myotubes. In the first experiment, both Rap and Met+Rap treatments lowered mitochondrial protein synthesis in male mice compared to control in skeletal muscle. However, in female mice, only Met+Rap treatment significantly lowered skeletal muscle mitochondrial protein synthesis compared to control. Additionally, both Rap and Met+Rap treatments significantly elevated skeletal muscle mitochondrial protein synthesis in female animals compared to males. However, in the heart and liver tissue, there were no differences in mitochondrial protein synthesis between treatments or sexes. In the second experiment, Met+Rap treatment lowered protein synthesis in all three tissues, but in a fraction-specific manner. independent of sex-differences in old mice. For the third experiment, we measured protein synthesis and protein breakdown in cultured skeletal myotubes treated with Rap and Met+Rap. Rap treatment significantly increased mitochondrial protein:DNA compared to control, while Met+Rap did not. We demonstrate that autophagic flux is a large (29%) contributing process to degradation of mitochondrial proteins. Additionally, mitochondrial fission is not essential for mitochondrial protein degradation. The data from these experiments demonstrate that despite sexually dimorphic effects on lifespan, Rap and Met+Rap treatments both enhance the contribution of protein synthesis to maintaining proteostasis in vivo. Further, we demonstrate that both Rap and Met+Rap treatment increased protein:DNA in cultured skeletal myotubes. In summary, these data demonstrate that Rap and Met+Rap treatments increase proteostatic mechanisms, and further research is required to improve the understanding of how Met+Rap treatment influences lifespan

"A Comparison of Inequality and Living Standards in Canada and the United States Using an Expanded Measure of Economic Well-Being"

We use the Levy Institute Measure of Economic Well-being (LIMEW), the most comprehensive income measure available to date, to compare economic well-being in Canada and the United States in the first decade of the 21st century. This study represents the first international comparison based on LIMEW, which differs from the standard measure of gross money income (MI) in that it includes noncash government transfers, public consumption, income from wealth, and household production, and nets out all personal taxes. We find that, relative to the United States, median equivalent LIMEW was 11 percent lower in Canada in 2000. By 2005, this gap had narrowed to 7 percent, while the difference in median equivalent MI was only 3 percent. Inequality was notably lower in Canada, with a Gini coefficient of 0.285 for equivalent LIMEW in 2005, compared to a US coefficient of 0.376-a gap that primarily reflects the greater importance of income from wealth in the States. However, the difference in Gini coefficients declined between 2000 and 2005. We also find that the elderly were better off relative to the nonelderly in the United States, but that high school graduates did better relative to college graduates in Canada.Well-Being; Living Standards; Inequality; Income; International Comparisons

Using Common Academic Indicators to Predict Graduation Rates at CSUN, 2005-2014

The median time to graduation at California State University, Northridge (CSUN) is five years and fewer than fifty percent of first time freshmen graduate in less than eight years. We used data mining and predictive analytics to determine some of the key academic indicators of success at CSUN. The most important indicators that we found were (a) which math course the student was placed in (or took first); (b) student grade point average (GPA) at the end of each of the first two terms in residence; and (c) successful completion of a freshman experience seminar course (UNIV 100). When all three are considered simultaneously, we can correctly identify over two thirds of the students who will drop out without graduating, while misidentifying approximately one-fifth of students who ultimately graduate as at-risk of not graduating

Polymer brush collapse under shear flow

Shear responsive surfaces offer potential advances in a number of applications. Surface functionalisation using polymer brushes is one route to such properties, particularly in the case of entangled polymers. We report on neutron reflectometry measurements of polymer brushes in entangled polymer solutions performed under controlled shear, as well as coarse-grained computer simulations corresponding to these interfaces. Here we show a reversible and reproducible collapse of the brushes, increasing with the shear rate. Using two brushes of greatly different chain lengths and grafting densities, we demonstrate that the dynamics responsible for the structural change of the brush are governed by the free chains in solution rather than the brush itself, within the range of parameters examined. The phenomenon of the brush collapse could find applications in the tailoring of nanosensors, and as a way to dynamically control surface friction and adhesion

Feedbacks on climate in the Earth system: introduction.

This is the author accepted manuscript. The final version is available from Royal Society Publishing via http://dx.doi.org/10.1098/rsta.2014.042

Optical SETI at Harvard-Smithsonian

A high-intensity pulsed laser, teamed with a moderate sized transmitting telescope, forms an efficient interstellar beacon. To a distant observer in the direction of its slender beam, such a laser transmitter, built with "Earth 2000" technology only, would appear (during its brief pulse) a thousand times brighter than our sun in broadband visible light; even at ranges of 1000 light years a single nanosecond laser pulse would deliver roughly a thousand photons to a 10-meter receiving telescope. We have built a photometer to search for such unresolved pulses, and are using it in a piggyback targeted search of some 2500 nearby solar-type stars. The photometer receives about 1/3 of the light focused by the 1.5-meter optical reflector, otherwise unused by the primary experiment (a stellar radial-velocity survey). A beamsplitter followed by a pair of fast hybrid avalanche detectors is triggered in coincidence to record the time and intensity profile of large pulses. In the first year of operation the system has made ~8500 observations of ~2500 separate stellar candidates, amounting to 50 days of cumulative observation time. We review those observations, and suggest follow-on experiments

Targeted and all-sky search for nanosecond optical pulses at Harvard-Smithsonian

We have built a system to detect nanosecond pulsed optical signals from a target list of some 10,000 sun-like stars, and have made some 20,000 observations during its two years of operation. A beamsplitter feeds a pair of hybrid avalanche photodetectors at the focal plane of the 1.5m Cassegrain at the Harvard/Smithsonian Oak Ridge Observatory (Agassiz Station), with a coincidence triggering measurement of pulse width and intensity at sub-nanosecond resolution. A flexible web-enabled database, combined with mercifully low background coincidence rates (approximately 1 event per night), makes it easy to sort through far-flung data in search of repeated events from any candidate star. An identical system will soon begin observations, synchronized with ours, at the 0.9m Cassegrain at Princeton University. These will permit unambiguous identification of even a solitary pulse. We are planning an all-sky search for optical pulses, using a dedicated 1.8m f/2.4 spherical glass light bucket and an array of pixelated photomultipliers deployed in a pair of matched focal planes. The sky pixels, 1.5 arcmin square, tessellate a 1.6 by 0.2 degree patch of sky in transit mode, covering the Northern sky in approximately 150 clear nights. Fast custom IC electronics will monitor corresponding pixels for coincident optical pulses of nanosecond timescale, triggering storage of a digitized waveform of the light flash