Examining the mechanistic regulation of starvation-induced autophagy via the identification and characterisation of novel ULK kinase substrates

Autophagy involves the formation of an endoplasmic reticulum-derived membrane termed a phagophore which expands to engulf cytoplasmic cargo before sealing to form an autophagosome. Amino acid starvation is amongst the most potent autophagic stimuli, however whilst the key signalling complexes involved in starvation-induced autophagy are known, the precise regulatory mechanisms remain poorly understood. The serine/threonine kinase ULK1 and close homolog ULK2 assume the most upstream position in the autophagic signalling cascade and play a crucial yet enigmatic role in coordinating the autophagic machinery. To further understand the mechanisms of starvation-induced autophagy, I performed a number of unbiased phosphoproteomic screens to identify ULK substrates before classifying their roles in starvation-induced autophagy. Analysis of these datasets has revealed that loss of ULK results in significant changes to the phosphoproteome and has yielded a high confidence list of potential substrates whilst also offering interesting insights into the veracity of the published ULK consensus signature. Amongst the novel phosphorylation targets are components of the retromer and AMPK complexes along with multiple components of the class III PI3K VPS34 complex. The pseudokinase p150, scaffolding component of the VPS34 complex, is phosphorylated by ULK1 in vitro and in vivo at serine 861. CRISPR-based knockout of p150 results in inhibition of autophagy and endosomal trafficking, whilst mutating the phosphorylated residue in p150 alters both omegasome establishment and autophagic flux. Furthermore, incorporation of phosphomutant p150 into the VPS34 complex modulates its lipid kinase activity in vitro. These data identify a novel ULK-dependent signalling axis and help illuminate the complexities of signal transduction in autophagy

ECONOMICALLY OPTIMAL WILDFIRE INTERVENTION REGIMES

Wildfires in the United States result in total damages and costs that are likely to exceed billions of dollars annually. Land managers and policy makers propose higher rates of prescribed burning and other kinds of vegetation management to reduce amounts of wildfire and the risks of catastrophic losses. A wildfire public welfare maximization function, using a wildfire production function estimated using a time series model of a panel of Florida counties, is employed to simulate the publicly optimal level of prescribed burning in an example county in Florida (Volusia). Evaluation of the production function reveals that prescribed fire is not associated with reduced catastrophic wildfire risks in Volusia County Florida, indicating a short-run elasticity of -0.16 and a long-run elasticity of wildfire with respect to prescribed fire of -0.07. Stochastic dominance is used to evaluate the optimal amount of prescribed fire most likely to maximize a measure of public welfare. Results of that analysis reveal that the optimal amount of annual prescribed fire is about 3 percent (9,000 acres/year) of the total forest area, which is very close to the actual average amount of prescribed burning (12,700 acres/year) between 1994-99.Resource /Energy Economics and Policy,

Improvements to the Tendon-Actuated Lightweight In-Space MANipulator (TALISMAN)

Devices for manipulating and precisely placing payloads are critical for efficient space operations including berthing of spacecraft, in-space assembly, construction and repair. Key to the success of many NASA space activities has been the availability of long-reach crane-like devices such as the Shuttle Remote Manipulation System (SRMS) and the Space Station Remote Manipulation System (SSRMS). These devices have been used for many operations including berthing visiting spacecraft to the International Space Station, deployment of spacecraft, space station assembly, astronaut positioning, payload transfer, and spacecraft inspection prior to atmospheric re-entry. Retiring the Space Transportation System has led to the removal of the SRMS from consideration for in-space missions, thus creating a capability gap. Recognizing this gap, work was initiated at NASA on a new architecture for long-reach space manipulators. Most current devices are constructed by joining revolute joints with carbon composite tubes, with the joints accounting for the majority of the device mass. For example in the case of the SRMS, the entire device mass is 410 kg (904 lbm); the joint structure, motors, gear train, cabling, etc., accounts for the majority of the system mass because the carbon composite tubes mass is 46 kg (101 lbm). An alternate space manipulator concept, the Tendon-Actuated Lightweight In-Space MANipulator (TALISMAN) was created to address deficiencies in the current state-of-the-art in long-reach manipulators. The antagonistic tendon actuated joint architecture allows the motors actuating the joint to be removed from the joint axis, which simplifies the joint design while simultaneously providing mechanical advantage for the motors. The improved mechanical advantage, in turn, reduces the size and power requirements for the motor and gear train. This paper will describe recent architectural improvements to the TALISMAN design that: 1) improve the operational robustness of the system by enabling maneuvers not originally possible by varying the TALISMAN geometry; 2) enable efficient active antagonistic control of a joint while sharing cable between antagonistic tension networks; and 3) uses a unique arrangement of differential capstans to reduce motor torque requirements by an order of magnitude. The paper will also summarize recent efforts to enable autonomous deployment of a TALISMAN including the deployment concept of operations and associated hardware system design. The deployment forces are provided by the same motor systems that are used for articulation, thus reducing the mass associated with the deployment system. The deployment approach is being tested on a TALISMAN prototype which is designed to provide the same operational performance as a shuttle-class manipulator. The prototype has been fabricated and is operational in a new facility at NASA Langley Research Center that has a large area (15.2 m by 21.3 m [50 ft by 70 ft]) air-bearing floor

Hinge for Use in a Tension Stiffened and Tendon Actuated Manipulator

A tension stiffened and tendon actuated manipulator is provided performing robotic-like movements when acquiring a payload. The manipulator design can be adapted for use in-space, lunar or other planetary installations as it is readily configurable for acquiring and precisely manipulating a payload in both a zero-g environment and in an environment with a gravity field. The manipulator includes a plurality of link arms, a hinge connecting adjacent link arms together to allow the adjacent link arms to rotate relative to each other and a cable actuation and tensioning system provided between adjacent link arms. The cable actuation and tensioning system includes a spreader arm and a plurality of driven and non-driven elements attached to the link arms and the spreader arm. At least one cable is routed around the driven and non-driven elements for actuating the hinge

Physical multimorbidity, health service use and catastrophic health expenditure by socio-economic groups in China::a population-based panel data analysis

Background Multimorbidity, the presence of two or more mental or physical chronic non-communicable diseases (NCDs), is a major challenge for the health system in China, which faces unprecedented ageing of its population. This study examined: (1) the distribution of physical multimorbidity in relation to socio-economic status, (2) the relationships between physical multimorbidity, healthcare service use, and catastrophic health expenditures, and (3) whether these relationships varied by socio-economic groups and social health insurance schemes. Methods Panel data study design utilized three waves of the nationally-representative China Health and Retirement Longitudinal Study (CHARLS 2011, 2013, 2015), which included 11 718 participants aged ≥50 years, and 11 physical NCDs. Findings Overall, 62% of participants had physical multimorbidity in China in 2015. Multimorbidity increased with age, female gender, higher per capita household expenditure, and higher educational level. However, multimorbidity was more common in poorer regions compared with the most affluent regions. An additional chronic NCD was associated with an increase in the number of outpatient visits of 28.8% (IRR=1.29, 95% CI: 1.27 to 1.31), and days of hospitalisation (IRR=1.38, 95% CI: 1.35 to 1.41). There were similar effects in different socio-economic groups and among those covered by different social health insurance programmes. Overall, multimorbidity was associated with a substantially greater odds of experiencing CHE (AOR=1·29 for the overall population, 95% CI=1·26, 1·32). The effect of multimorbidity on catastrophic health expenditures persisted even among the higher socio-economic groups and those with more generous health insurance coverage. Interpretation Multimorbidity was associated with higher levels of health service use and greater financial burden. Concerted efforts are needed to reduce health inequalities that arise due to multimorbidity, and its adverse economic impact in population groups in China. Social health insurance reforms must place emphasis on reducing out-of-pocket spending for patients with multimorbidity to provide greater financial risk protection

Systematic review and network meta-analysis with individual participant data on cord management at preterm birth (iCOMP): study protocol

Introduction Timing of cord clamping and other cord management strategies may improve outcomes at preterm birth. However, it is unclear whether benefits apply to all preterm subgroups. Previous and current trials compare various policies, including time-based or physiology-based deferred cord clamping, and cord milking. Individual participant data (IPD) enable exploration of different strategies within subgroups. Network meta-analysis (NMA) enables comparison and ranking of all available interventions using a combination of direct and indirect comparisons. Objectives (1) To evaluate the effectiveness of cord management strategies for preterm infants on neonatal mortality and morbidity overall and for different participant characteristics using IPD meta-analysis. (2) To evaluate and rank the effect of different cord management strategies for preterm births on mortality and other key outcomes using NMA. Methods and analysis Systematic searches of Medline, Embase, clinical trial registries, and other sources for all ongoing and completed randomised controlled trials comparing cord management strategies at preterm birth (before 37 weeks’ gestation) have been completed up to 13 February 2019, but will be updated regularly to include additional trials. IPD will be sought for all trials; aggregate summary data will be included where IPD are unavailable. First, deferred clamping and cord milking will be compared with immediate clamping in pairwise IPD meta-analyses. The primary outcome will be death prior to hospital discharge. Effect differences will be explored for prespecified participant subgroups. Second, all identified cord management strategies will be compared and ranked in an IPD NMA for the primary outcome and the key secondary outcomes. Treatment effect differences by participant characteristics will be identified. Inconsistency and heterogeneity will be explored. Ethics and dissemination Ethics approval for this project has been granted by the University of Sydney Human Research Ethics Committee (2018/886). Results will be relevant to clinicians, guideline developers and policy-makers, and will be disseminated via publications, presentations and media releases

Recent Developments in the Design, Capabilities and Autonomous Operations of a Lightweight Surface Manipulation System and Test-bed

The first generation of a versatile high performance device for performing payload handling and assembly operations on planetary surfaces, the Lightweight Surface Manipulation System (LSMS), has been designed and built. Over the course of its development, conventional crane type payload handling configurations and operations have been successfully demonstrated and the range of motion, types of operations and the versatility greatly expanded. This enhanced set of 1st generation LSMS hardware is now serving as a laboratory test-bed allowing the continuing development of end effectors, operational techniques and remotely controlled and automated operations. This paper describes the most recent LSMS and test-bed development activities, that have focused on two major efforts. The first effort was to complete a preliminary design of the 2nd generation LSMS that has the capability for limited mobility and can reposition itself between lander decks, mobility chassis, and fixed base locations. A major portion of this effort involved conducting a study to establish the feasibility of, and define, the specifications for a lightweight cable-drive waist joint. The second effort was to continue expanding the versatility and autonomy of large planetary surface manipulators using the 1st generation LSMS as a test-bed. This has been accomplished by increasing manipulator capabilities and efficiencies through both design changes and tool and end effector development. A software development effort has expanded the operational capabilities of the LSMS test-bed to include; autonomous operations based on stored paths, use of a vision system for target acquisition and tracking, and remote command and control over a communications bridge

Evaluating the impact of programmatic mass drug administration for malaria in Zambia using routine incidence data.

BACKGROUND NlmCategory: BACKGROUND content: In 2016, the Zambian National Malaria Elimination Centre started programmatic mass drug administration (pMDA) campaigns with dihydroartemisinin-piperaquine as a malaria elimination tool in Southern Province. Two rounds were administered, two months apart (coverage 70% and 57% respectively). We evaluated the impact of one year of pMDA on malaria incidence using routine data. - Label: METHODS NlmCategory: METHODS content: We conducted an interrupted time series with comparison group analysis on monthly incidence data collected at the health facility catchment area (HFCA) level, with a negative binomial model using generalized estimating equations. pMDA was conducted in HFCAs with greater than 50 cases/1,000 people/year. Ten HFCAs with incidence rates marginally above this threshold (pMDA group) were compared to 20 HFCAs marginally below (comparison group). - Label: RESULTS NlmCategory: RESULTS content: "The pMDA HFCAs saw a 46% greater decrease in incidence at the time of intervention than the comparison areas (incidence rate ratio: 0.536 [0.337-0.852]); however, incidence increased toward the end of the season. No HFCAs saw a transmission interruption." - Label: CONCLUSION NlmCategory: CONCLUSIONS content: pMDA, implemented during one year with imperfect coverage in low transmission areas with sub-optimal vector control coverage, significantly reduced incidence. However, elimination will require additional tools. Routine data are important resources for programmatic impact evaluations and should be considered for future analyses

Benefits of Power and Propulsion Technology for a Piloted Electric Vehicle to an Asteroid

NASA's goal for human spaceflight is to expand permanent human presence beyond low Earth orbit (LEO). NASA is identifying potential missions and technologies needed to achieve this goal. Mission options include crewed destinations to LEO and the International Space Station; high Earth orbit and geosynchronous orbit; cis-lunar space, lunar orbit, and the surface of the Moon; near-Earth objects; and the moons of Mars, Mars orbit, and the surface of Mars. NASA generated a series of design reference missions to drive out required functions and capabilities for these destinations, focusing first on a piloted mission to a near-Earth asteroid. One conclusion from this exercise was that a solar electric propulsion stage could reduce mission cost by reducing the required number of heavy lift launches and could increase mission reliability by providing a robust architecture for the long-duration crewed mission. Similarly, solar electric vehicles were identified as critical for missions to Mars, including orbiting Mars, landing on its surface, and visiting its moons. This paper describes the parameterized assessment of power and propulsion technologies for a piloted solar electric vehicle to a near-Earth asteroid. The objective of the assessment was to determine technology drivers to advance the state of the art of electric propulsion systems for human exploration. Sensitivity analyses on the performance characteristics of the propulsion and power systems were done to determine potential system-level impacts of improved technology. Starting with a "reasonable vehicle configuration" bounded by an assumed launch date, we introduced technology improvements to determine the system-level benefits (if any) that those technologies might provide. The results of this assessment are discussed and recommendations for future work are described