Rapamycin-induced autophagy aggravates pathology and weakness in a mouse model of VCP-associated myopathy

Pathological phenotypes in inclusion body myopathy (IBM) associated with Paget disease of the bone (PDB), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (IBMPFD/ALS) include defective autophagosome and endosome maturation that result in vacuolation, weakness and muscle atrophy. The link between autophagy and IBMPFD/ALS pathobiology has been poorly understood. We examined the AKT-FOXO3 and MTOR pathways to characterize the regulation of autophagy in IBMPFD/ALS mouse muscle. We identified a defect in MTOR signaling that results in enhanced autophagosome biogenesis. Modulating MTOR signaling may therefore be a viable therapeutic target in IBMPFD/ALS

On the Scaling of Small, Heat Simulated Jet Noise Measurements to Moderate Size Exhaust Jets

Modern military aircraft jet engines are designed with variable geometry nozzles to provide optimum thrust in different operating conditions, depending on the flight envelope. However, the acoustic measurements for such nozzles are scarce, due to the cost involved in making full scale measurements and the lack of details about the exact geometry of these nozzles. Thus the present effort at The Pennsylvania State University and the NASA Glenn Research Center- in partnership with GE Aviation is aiming to study and characterize the acoustic field produced by supersonic jets issuing from converging-diverging military style nozzles. An equally important objective is to validate methodology for using data obtained from small and moderate scale experiments to reliably predict the most important components of full scale engine noise. The experimental results presented show reasonable agreement between small scale and moderate scale jet acoustic data, as well as between heated jets and heat-simulated ones. Unresolved issues however are identified that are currently receiving our attention, in particular the effect of the small bypass ratio airflow. Future activities will identify and test promising noise reduction techniques in an effort to predict how well such concepts will work with full scale engines in flight conditions

Real-time Loss Estimation for Instrumented Buildings

Motivation. A growing number of buildings have been instrumented to measure and record earthquake motions and to transmit these records to seismic-network data centers to be archived and disseminated for research purposes. At the same time, sensors are growing smaller, less expensive to install, and capable of sensing and transmitting other environmental parameters in addition to acceleration. Finally, recently developed performance-based earthquake engineering methodologies employ structural-response information to estimate probabilistic repair costs, repair durations, and other metrics of seismic performance. The opportunity presents itself therefore to combine these developments into the capability to estimate automatically in near-real-time the probabilistic seismic performance of an instrumented building, shortly after the cessation of strong motion. We refer to this opportunity as (near-) real-time loss estimation (RTLE). Methodology. This report presents a methodology for RTLE for instrumented buildings. Seismic performance is to be measured in terms of probabilistic repair cost, precise location of likely physical damage, operability, and life-safety. The methodology uses the instrument recordings and a Bayesian state-estimation algorithm called a particle filter to estimate the probabilistic structural response of the system, in terms of member forces and deformations. The structural response estimate is then used as input to component fragility functions to estimate the probabilistic damage state of structural and nonstructural components. The probabilistic damage state can be used to direct structural engineers to likely locations of physical damage, even if they are concealed behind architectural finishes. The damage state is used with construction cost-estimation principles to estimate probabilistic repair cost. It is also used as input to a quantified, fuzzy-set version of the FEMA-356 performance-level descriptions to estimate probabilistic safety and operability levels. CUREE demonstration building. The procedure for estimating damage locations, repair costs, and post-earthquake safety and operability is illustrated in parallel demonstrations by CUREE and Kajima research teams. The CUREE demonstration is performed using a real 1960s-era, 7-story, nonductile reinforced-concrete moment-frame building located in Van Nuys, California. The building is instrumented with 16 channels at five levels: ground level, floors 2, 3, 6, and the roof. We used the records obtained after the 1994 Northridge earthquake to hindcast performance in that earthquake. The building is analyzed in its condition prior to the 1994 Northridge Earthquake. It is found that, while hindcasting of the overall system performance level was excellent, prediction of detailed damage locations was poor, implying that either actual conditions differed substantially from those shown on the structural drawings, or inappropriate fragility functions were employed, or both. We also found that Bayesian updating of the structural model using observed structural response above the base of the building adds little information to the performance prediction. The reason is probably that Real-Time Loss Estimation for Instrumented Buildings ii structural uncertainties have only secondary effect on performance uncertainty, compared with the uncertainty in assembly damageability as quantified by their fragility functions. The implication is that real-time loss estimation is not sensitive to structural uncertainties (saving costly multiple simulations of structural response), and that real-time loss estimation does not benefit significantly from installing measuring instruments other than those at the base of the building. Kajima demonstration building. The Kajima demonstration is performed using a real 1960s-era office building in Kobe, Japan. The building, a 7-story reinforced-concrete shearwall building, was not instrumented in the 1995 Kobe earthquake, so instrument recordings are simulated. The building is analyzed in its condition prior to the earthquake. It is found that, while hindcasting of the overall repair cost was excellent, prediction of detailed damage locations was poor, again implying either that as-built conditions differ substantially from those shown on structural drawings, or that inappropriate fragility functions were used, or both. We find that the parameters of the detailed particle filter needed significant tuning, which would be impractical in actual application. Work is needed to prescribe values of these parameters in general. Opportunities for implementation and further research. Because much of the cost of applying this RTLE algorithm results from the cost of instrumentation and the effort of setting up a structural model, the readiest application would be to instrumented buildings whose structural models are already available, and to apply the methodology to important facilities. It would be useful to study under what conditions RTLE would be economically justified. Two other interesting possibilities for further study are (1) to update performance using readily observable damage; and (2) to quantify the value of information for expensive inspections, e.g., if one inspects a connection with a modeled 50% failure probability and finds that the connect is undamaged, is it necessary to examine one with 10% failure probability

Increased autophagy accelerates colchicine-induced muscle toxicity

Colchicine treatment is associated with an autophagic vacuolar myopathy in human patients. The presumed mechanism of colchicine-induced myotoxicity is the destabilization of the microtubule system that leads to impaired autophagosome-lysosome fusion and the accumulation of autophagic vacuoles. Using the MTOR inhibitor rapamycin we augmented colchicine's myotoxic effect by increasing the autophagic flux; this resulted in an acute myopathy with muscle necrosis. In contrast to myonecrosis induced by cardiotoxin, myonecrosis induced by a combination of rapamycin and colchicine was associated with accumulation of autophagic substrates such as LC3-II and SQSTM1; as a result, autophagic vacuoles accumulated in the center of myofibers, where LC3-positive autophagosomes failed to colocalize with the lysosomal protein marker LAMP2. A similar pattern of central LC3 accumulation and myonecrosis is seen in human patients with colchicine myopathy, many of whom have been treated with statins (HMGCR/HMG-CoA reductase inhibitors) in addition to colchicine. In mice, cotreatment with colchicine and simvastatin also led to muscle necrosis and LC3 accumulation, suggesting that, like rapamycin, simvastatin activates autophagy. Consistent with this, treatment of mice with four different statin medications enhanced autophagic flux in skeletal muscle in vivo. Polypharmacy is a known risk factor for toxic myopathies; our data suggest that some medication combinations may simultaneously activate upstream autophagy signaling pathways while inhibiting the degradation of these newly synthesized autophagosomes, resulting in myotoxicity

Sex Disparities in Access to Acute Stroke Care: Can Telemedicine Mitigate this Effect?

Background: Women have more frequent and severe ischemic strokes than men, and are less likely to receive treatment for acute stroke. Primary stroke centers (PSCs) have been shown to utilize treatment more frequently. Further, as telemedicine (TM) has expanded access to acute stroke care we sought to investigate the association between PSC, TM and access to acute stroke care in the state of Texas. Methods: Texas hospitals and resources were identified from the 2009 American Hospital Association Annual Survey. Hospitals were categorized as: (1) stand-alone PSCs not using telemedicine for acute stroke care, (2) PSCs using telemedicine for acute stroke care (PSC-TM), (3) non-PSC hospitals using telemedicine for acute stroke care, or (4) non-PSC hospitals not using telemedicine for acute stroke care. The proportion of the population who could reach a PSC within 60 minutes was determined for stand-alone PSCs, PSC-TM, and non-PSCs using TM for stroke care. Results: Overall, women were as likely to have 60-minute access to a PSC or PSC-TM as their male counterparts (POR 1.02, 95% CI 1.02-1.03). Women were also just as likely to have access to acute stroke care via PSC or PSC-TM or TM as men (POR 1.03, 95% CI 1.02-1.04). Discussion: Our study found no sex disparities in access to stand alone PSCs or to hospitals using TM in the state of Texas. The results of this study suggest that telemedicine can be used as part of an inclusive strategy to improve access to care equally for men and women

Effect of Ventricular Shock Strength on Cardiac Hemodynamics

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75115/1/j.1540-8167.1998.tb00118.x.pd

Internal solitons in the northeastern south China Sea. Part I: sources and deep water propagation

Author Posting. © IEEE, 2004. This article is posted here by permission of IEEE for personal use, not for redistribution. The definitive version was published in IEEE Journal of Oceanic Engineering 29 (2004): 1157-1181, doi:10.1109/JOE.2004.840839.A moored array of current, temperature, conductivity, and pressure sensors was deployed across the Chinese continental shelf and slope in support of the Asian Seas International Acoustics Experiment. The goal of the observations was to quantify the water column variability in order to understand the along- and across-shore low-frequency acoustic propagation in shallow water. The moorings were deployed from April 21–May 19, 2001 and sampled at 1–5 min intervals to capture the full range of temporal variability without aliasing the internal wave field. The dominant oceanographic signal by far was in fact the highly nonlinear internal waves (or solitons) which were generated near the Batan Islands in the Luzon Strait and propagated 485 km across deep water to the observation region. Dubbed trans-basin waves, to distinguish them from other, smaller nonlinear waves generated locally near the shelf break, these waves had amplitudes ranging from 29 to greater than 140 m and were among the largest such waves ever observed in the world’s oceans. The waves arrived at the most offshore mooring in two clusters lasting 7–8 days each separated by five days when no waves were observed.Within each cluster, two types of waves arrived which have been named type-a and type-b. The type-a waves had greater amplitude than the type-b waves and arrived with remarkable regularity at the same time each day, 24 h apart. The type-b waves were weaker than the type-a waves, arrived an hour later each day, and generally consisted of a single soliton growing out of the center of the wave packet. Comparison with modeled barotropic tides from the generation region revealed that: 1) The two clusters were generated around the time of the spring tides in the Luzon strait; and 2) The type-a waves were generated on the strong side of the diurnal inequality while the type-b waves were generated on the weaker beat. The position of the Kuroshio intrusion into the Luzon Strait may modulate the strength of the waves being produced. As the waves shoaled, the huge lead solitons first split into two solitons then merged together into a broad region of thermocline depression at depths less than 120 m. Elevation waves sprang up behind them as they continued to propagate onshore. The elevation waves also grew out of regions where the locally-generated internal tide forced the main thermocline down near the bottom. The “critical point” where the upper and lower layers were equal was a good indicator of when the depression or elevation waves would form, however this was not a static point, but rather varied in both space and time according to the presence or absence of the internal tides and the incoming trans-basin waves themselves.The planning, execution, and analysis of this work was supported by the U.S. Office of Naval Research Ocean Acoustics and Physical Oceanography Programs. Significant funding contributions were also made by the National Science Council of Taiwan

Pharmacology of DB844, an Orally Active aza Analogue of Pafuramidine, in a Monkey Model of Second Stage Human African Trypanosomiasis

Novel drugs to treat human African trypanosomiasis (HAT) are still urgently needed despite the recent addition of nifurtimox-eflornithine combination therapy (NECT) to WHO Model Lists of Essential Medicines against second stage HAT, where parasites have invaded the central nervous system (CNS). The pharmacology of a potential orally available lead compound, N-methoxy-6-{5-[4-(N-methoxyamidino) phenyl]-furan-2-yl}-nicotinamidine (DB844), was evaluated in a vervet monkey model of second stage HAT, following promising results in mice. DB844 was administered orally to vervet monkeys, beginning 28 days post infection (DPI) with Trypanosoma brucei rhodesiense KETRI 2537. DB844 was absorbed and converted to the active metabolite 6-[5-(4-phenylamidinophenyl)-furanyl-2-y​l]-nicotinamide(DB820), exhibiting plasma Cmax values of 430 and 190 nM for DB844 and DB820, respectively, after the 14th dose at 6 mg/kg qd. A 100-fold reduction in blood trypanosome counts was observed within 24 h of the third dose and, at the end of treatment evaluation performed four days post the last drug dose, trypanosomes were not detected in the blood or cerebrospinal fluid of any monkey. However, some animals relapsed during the 300 days of post treatment monitoring, resulting in a cure rate of 3/8 (37.5%) and 3/7 (42.9%) for the 5 mg/kg×10 days and the 6 mg/kg×14 days dose regimens respectively. These DB844 efficacy data were an improvement compared with pentamidine and pafuramidine both of which were previously shown to be non-curative in this model of CNS stage HAT. These data show that synthesis of novel diamidines with improved activity against CNS-stage HAT was possible.This investigation received financial support from the Bill and Melinda Gates Foundation through the Consortium for Parasitic Drug Development

First Results from COPSS: The CO Power Spectrum Survey

We present constraints on the abundance of carbon monoxide in the early universe from the CO Power Spectrum Survey. We utilize a data set collected between 2005 and 2008 using the Sunyaev–Zel'dovich Array (SZA), which was previously used to measure arcminute-scale fluctuations of the cosmic microwave background. This data set features observations of 44 fields, covering an effective area of 1.7 square degrees, over a frequency range of 27–35 GHz. Using the technique of intensity mapping, we are able to probe the CO(1–0) transition, with sensitivity to spatial modes between k = 0.5–2 h Mpc^(−1) over a range in redshift of z = 2.3–3.3, spanning a comoving volume of 3.6 × 10^6 h^(−3) Mpc^3. We demonstrate our ability to mitigate foregrounds, and present estimates of the impact of continuum sources on our measurement. We constrain the CO power spectrum to P_(CO) < 2.6 × 10^4 μK^2 (h^(−1) Mpc)^3, or Δ^2_(CO)(k = 1 h Mpc^(−1)) < 1.3 × 10^3 μK^2, at 95% confidence. This limit resides near optimistic predictions for the CO power spectrum. Under the assumption that CO emission is proportional to halo mass during bursts of active star formation, this corresponds to a limit on the ratio of CO(1–0) luminosity to host halo mass of A_(CO) < 1.2 × 10^(−5) L⊙_ M_⊙^(−1). Further assuming a Milky Way-like conversion factor between CO luminosity and molecular gas mass (α_(CO) = 4.3 M_⊙ (K km s^(−1) pc^(−2))^(−1)), we constrain the global density of molecular gas to ρ_(z~3) (M_H_2) ⩽ 2.8 x 10^8 M_☉ Mpc^(-3)

Mapping Cosmic Dawn and Reionization: Challenges and Synergies

Cosmic dawn and the Epoch of Reionization (EoR) are among the least explored observational eras in cosmology: a time at which the first galaxies and supermassive black holes formed and reionized the cold, neutral Universe of the post-recombination era. With current instruments, only a handful of the brightest galaxies and quasars from that time are detectable as individual objects, due to their extreme distances. Fortunately, a multitude of multi-wavelength intensity mapping measurements, ranging from the redshifted 21 cm background in the radio to the unresolved X-ray background, contain a plethora of synergistic information about this elusive era. The coming decade will likely see direct detections of inhomogenous reionization with CMB and 21 cm observations, and a slew of other probes covering overlapping areas and complementary physical processes will provide crucial additional information and cross-validation. To maximize scientific discovery and return on investment, coordinated survey planning and joint data analysis should be a high priority, closely coupled to computational models and theoretical predictions.Comment: 5 pages, 1 figure, submitted to the Astro2020 Decadal Survey Science White Paper cal