P4‐154: The Protein Quality Control Protein, Ubiquilin‐2, Regulates Tau Accumulation

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152960/1/alzjjalz2019063816.pd

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

Global, regional, and national under-5 mortality, adult mortality, age-specific mortality, and life expectancy, 1970–2016: a systematic analysis for the Global Burden of Disease Study 2016

BACKGROUND: Detailed assessments of mortality patterns, particularly age-specific mortality, represent a crucial input that enables health systems to target interventions to specific populations. Understanding how all-cause mortality has changed with respect to development status can identify exemplars for best practice. To accomplish this, the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) estimated age-specific and sex-specific all-cause mortality between 1970 and 2016 for 195 countries and territories and at the subnational level for the five countries with a population greater than 200 million in 2016. METHODS: We have evaluated how well civil registration systems captured deaths using a set of demographic methods called death distribution methods for adults and from consideration of survey and census data for children younger than 5 years. We generated an overall assessment of completeness of registration of deaths by dividing registered deaths in each location-year by our estimate of all-age deaths generated from our overall estimation process. For 163 locations, including subnational units in countries with a population greater than 200 million with complete vital registration (VR) systems, our estimates were largely driven by the observed data, with corrections for small fluctuations in numbers and estimation for recent years where there were lags in data reporting (lags were variable by location, generally between 1 year and 6 years). For other locations, we took advantage of different data sources available to measure under-5 mortality rates (U5MR) using complete birth histories, summary birth histories, and incomplete VR with adjustments; we measured adult mortality rate (the probability of death in individuals aged 15-60 years) using adjusted incomplete VR, sibling histories, and household death recall. We used the U5MR and adult mortality rate, together with crude death rate due to HIV in the GBD model life table system, to estimate age-specific and sex-specific death rates for each location-year. Using various international databases, we identified fatal discontinuities, which we defined as increases in the death rate of more than one death per million, resulting from conflict and terrorism, natural disasters, major transport or technological accidents, and a subset of epidemic infectious diseases; these were added to estimates in the relevant years. In 47 countries with an identified peak adult prevalence for HIV/AIDS of more than 0·5% and where VR systems were less than 65% complete, we informed our estimates of age-sex-specific mortality using the Estimation and Projection Package (EPP)-Spectrum model fitted to national HIV/AIDS prevalence surveys and antenatal clinic serosurveillance systems. We estimated stillbirths, early neonatal, late neonatal, and childhood mortality using both survey and VR data in spatiotemporal Gaussian process regression models. We estimated abridged life tables for all location-years using age-specific death rates. We grouped locations into development quintiles based on the Socio-demographic Index (SDI) and analysed mortality trends by quintile. Using spline regression, we estimated the expected mortality rate for each age-sex group as a function of SDI. We identified countries with higher life expectancy than expected by comparing observed life expectancy to anticipated life expectancy on the basis of development status alone. FINDINGS: Completeness in the registration of deaths increased from 28% in 1970 to a peak of 45% in 2013; completeness was lower after 2013 because of lags in reporting. Total deaths in children younger than 5 years decreased from 1970 to 2016, and slower decreases occurred at ages 5-24 years. By contrast, numbers of adult deaths increased in each 5-year age bracket above the age of 25 years. The distribution of annualised rates of change in age-specific mortality rate differed over the period 2000 to 2016 compared with earlier decades: increasing annualised rates of change were less frequent, although rising annualised rates of change still occurred in some locations, particularly for adolescent and younger adult age groups. Rates of stillbirths and under-5 mortality both decreased globally from 1970. Evidence for global convergence of death rates was mixed; although the absolute difference between age-standardised death rates narrowed between countries at the lowest and highest levels of SDI, the ratio of these death rates-a measure of relative inequality-increased slightly. There was a strong shift between 1970 and 2016 toward higher life expectancy, most noticeably at higher levels of SDI. Among countries with populations greater than 1 million in 2016, life expectancy at birth was highest for women in Japan, at 86·9 years (95% UI 86·7-87·2), and for men in Singapore, at 81·3 years (78·8-83·7) in 2016. Male life expectancy was generally lower than female life expectancy between 1970 and 2016, an

P3‐188: Ubiquilin‐2 Regulation Of Tau And Α‐Synuclein In Neurodegenerative Disease

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152733/1/alzjjalz2018061546.pd

Geothermal Investigations of California Submerged Lands and Spherical Flow in Naturally Fractured Reservoirs

A large portion of California State-owned land is the tidal and submerged land along the coastline and around the islands that extends seaward for three geographical miles. Other large areas of State-owned lands form the beds of lakes and navigable rivers. Some evidence, such as the proximity of hot springs, indicates there may be important geothermal potential on these lands. The purpose of this project is to develop methods, tools, and interpretive techniques to explore for and evaluate geothermal resources on submerged lands. Presently, the state of the art is primitive because there has been little interest or effort in assessing the resource potential of submerged lands, and the limited work carried out thus far has been for scientific purposes. There has been a moderate amount of water temperature measuring for oceanographic or limnologic studies and fairly reliable techniques exist. There have been limited measurements of the temperature, thermal gradient, and heat flow in bottom sediment of the ocean area off California and from the lakes. Probably less than a dozen data points exist for State-owned land. This work was done using large equipment, such as piston corers with outrigger-mounted thermistors arrayed along the core barrels. To achieve penetration, such equipment requires heavy weights, strong cable, heavy duty winches, large crews and oceanographic research-type vessels or large barges, and this entails considerable expenses and logistical problems. Clearly, many hundreds, or thousands of data points are required for a remotely reliable evaluation of the resources. The first problem is to assess existing methods and develop others that will enable economical and efficient exploration for geothermal resources on submerged lands

Ubiquilin‐2 exacerbates tau toxicity in vivo

BackgroundUbiquilin‐2 (UBQLN2) is a protein quality control protein involved primarily in shuttling ubiquitinated substrates to the proteasome for degradation and by modulating autophagy. UBQLN2 has been implicated in neurodegenerative disease due to its accumulation in neuropathological deposits and its potential role in regulating protein dyshomeostasis common across different neurodegenerative disorders. The relationship of UBQLN2 to one of the most common aggregating proteins in disease, tau, is unknown.MethodTo evaluate whether UBQLN2 regulates tau clearance, we assessed levels of tau in human embryonic kidney‐293 cells with and without UBQLN2. To determine whether UBQLN2 acts on tau in vivo, P301S tau transgenic mice were crossed with UBQLN2 transgenic and knockout mice and brain levels of tau were assessed at 3, 6 and 9 months of age. To define changes in UBQLN2 in human disease, we measured levels of soluble and insoluble UBQLN2 in human tauopathy brain tissue.ResultCo‐expressed UBQLN2 markedly lowered levels of tau in a cellular model. Conversely, siRNA knockdown of UBQLN2 significantly elevated levels of tau. Surprisingly, a UBQLN2 mutant incapable of binding ubiquitin was more effective at lowering tau than wildtype UBQLN2, suggesting that ubiquitin‐independent pathways may allow UBQLN2 to “handle” tau. In contrast, wildtype UBQLN2 overexpression in vivo did not alter total levels of tau at 3, 6 or 9 months of age. However, UBQLN2 overexpression specifically increased phosphorylated tau while UBQLN2 knockout decreased phosphorylated tau at 9 months. Furthermore, UBQLN2 overexpression increased premature hindlimb paralysis and fatality. The possibility that UBQLN2 also undergoes alterations in disease was evidenced by the fact that UBQLN2 solubility is decreased in human brains with tau pathology.ConclusionOur findings highlight a new role for UBQLN2 in altering tau in the brain. Collectively, our results suggest that while on a rapid time scale UBQLN2 can decrease tau levels, long‐term expression of UBQLN2 in vivo exacerbates tau toxicity. Ongoing research will determine how changing UBQLN2 levels alters components of proteostasis pathways to affect tau toxicity and whether ubiquitin‐independent processes may compete with UBQLN2’s function as a ubiquitin‐proteasome shuttle factor to yield differential effects on tau toxicity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163894/1/alz046096.pd