1,065 research outputs found
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 21âMay
19, 2001 and sampled at 1â5 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 worldâs oceans. The waves arrived
at the most offshore mooring in two clusters lasting 7â8 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 âcritical pointâ 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-yâl]-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/kgĂ10 days and the 6 mg/kgĂ14 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 SunyaevâZel'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 27â35 GHz. Using the technique of intensity mapping, we are able to probe the CO(1â0) transition, with sensitivity to spatial modes between k = 0.5â2 h Mpc^(â1) over a range in redshift of z = 2.3â3.3, spanning a comoving volume of 3.6 Ă 10^6 h^(â3) 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 Ă 10^4 ÎŒK^2 (h^(â1) Mpc)^3, or Î^2_(CO)(k = 1 h Mpc^(â1)) < 1.3 Ă 10^3 ÎŒK^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(1â0) luminosity to host halo mass of A_(CO) < 1.2 Ă 10^(â5) Lâ_ M_â^(â1). Further assuming a Milky Way-like conversion factor between CO luminosity and molecular gas mass (α_(CO) = 4.3 M_â (K km s^(â1) pc^(â2))^(â1)), we constrain the global density of molecular gas to Ï_(z~3) (M_H_2) â©œ 2.8 x 10^8 M_â 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
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