HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium

Background: While acute lung injury (ALI) contributes significantly to critical illness, it resolves spontaneously in many instances. The majority of patients experiencing ALI require mechanical ventilation. Therefore, we hypothesized that mechanical ventilation and concomitant stretch-exposure of pulmonary epithelia could activate endogenous pathways important in lung protection. Methods and Findings: To examine transcriptional responses during ALI, we exposed pulmonary epithelia to cyclic mechanical stretch conditions—an in vitro model resembling mechanical ventilation. A genome-wide screen revealed a transcriptional response similar to hypoxia signaling. Surprisingly, we found that stabilization of hypoxia-inducible factor 1A (HIF1A) during stretch conditions in vitro or during ventilator-induced ALI in vivo occurs under normoxic conditions. Extension of these findings identified a functional role for stretch-induced inhibition of succinate dehydrogenase (SDH) in mediating normoxic HIF1A stabilization, concomitant increases in glycolytic capacity, and improved tricarboxylic acid (TCA) cycle function. Pharmacologic studies with HIF activator or inhibitor treatment implicated HIF1A-stabilization in attenuating pulmonary edema and lung inflammation during ALI in vivo. Systematic deletion of HIF1A in the lungs, endothelia, myeloid cells, or pulmonary epithelia linked these findings to alveolar-epithelial HIF1A. In vivo analysis of 13C-glucose metabolites utilizing liquid-chromatography tandem mass-spectrometry demonstrated that increases in glycolytic capacity, improvement of mitochondrial respiration, and concomitant attenuation of lung inflammation during ALI were specific for alveolar-epithelial expressed HIF1A. Conclusions: These studies reveal a surprising role for HIF1A in lung protection during ALI, where normoxic HIF1A stabilization and HIF-dependent control of alveolar-epithelial glucose metabolism function as an endogenous feedback loop to dampen lung inflammation

Habitable Climate Scenarios for Proxima Centauri b With a Dynamic Ocean

The nearby exoplanet Proxima Centauri b will be a prime future target for characterization, despite questions about its retention of water. Climate models with static oceans suggest that an Earth-like Proxima b could harbor a small dayside region of surface liquid water at fairly warm temperatures despite its weak instellation. We present the first 3-dimensional climate simulations of Proxima b with a dynamic ocean. We find that an ocean-covered Proxima b could have a much broader area of surface liquid water but at much colder temperatures than previously suggested, due to ocean heat transport and depression of the freezing point by salinity. Elevated greenhouse gas concentrations do not necessarily produce more open ocean area because of possible dynamic regime transitions. For an evolutionary path leading to a highly saline present ocean, Proxima b could conceivably be an inhabited, mostly open ocean planet dominated by halophilic life. For an ocean planet in 3:2 spin-orbit resonance, a permanent tropical waterbelt exists for moderate eccentricity. Simulations of Proxima Centauri b may also be a model for the habitability of planets receiving similar instellation from slightly cooler or warmer stars, e.g., in the TRAPPIST-1, LHS 1140, GJ 273, and GJ 3293 systems.Comment: Submitted to Astrobiology; 38 pages, 12 figures, 5 table

Global Entrepreneurship Monitor Special Report : A Global Perspective on Entrepreneurship Education and Training

In 2008 the Global Entrepreneurship Monitor set out to investigate the prevalence and sources of entrepreneurship education and training, and the effect of this training on starting a business. Thirty-eight national teams participated in this study, adding specialized questions to the standard GEM Adult Populations Surveys (APS). In addition, 30 countries added questions to the National Expert Surveys (NES). This report expands on the eight-page education and training section found on pages 41-48 of the Global Entrepreneurship Monitor 2008 Executive Report. After a brief literature review, we present expert opinions on the current state of entrepreneurship education and training in 30 countries. The report then details the level and sources of training received by the adult population (18-64) in the 38 countries surveyed by GEM. By examining data from the APS, GEM is able to develop profiles of individuals most and least likely to have received training. Additionally, we present new information on the effects of training on an individual’s entrepreneurial awareness, attitudes, intentions and activity in each of the participating countries. Then, five GEM countries provide insights about the types of advisors used by entrepreneurs. The report concludes with possible implications of these new findings and suggests areas for further research

Evaluation of automated decisionmaking methodologies and development of an integrated robotic system simulation. Appendix A: ROBSIM user's guide

The purpose of the Robotics Simulation Program is to provide a broad range of computer capabilities to assist in the design, verification, simulation, and study of robotics systems. ROBSIM is program in FORTRAN 77 for use on a VAX 11/750 computer under the VMS operating system. This user's guide describes the capabilities of the ROBSIM programs, including the system definition function, the analysis tools function and the postprocessor function. The options a user may encounter with each of these executables are explained in detail and the different program prompts appearing to the user are included. Some useful suggestions concerning the appropriate answers to be given by the user are provided. An example user interactive run in enclosed for each of the main program services, and some of the capabilities are illustrated

Evaluation of automated decision making methodologies and development of an integrated robotic system simulation: Study results

The implementation of a generic computer simulation for manipulator systems (ROBSIM) is described. The program is written in FORTRAN, and allows the user to: (1) Interactively define a manipulator system consisting of multiple arms, load objects, targets, and an environment; (2) Request graphic display or replay of manipulator motion; (3) Investigate and simulate various control methods including manual force/torque and active compliance control; and (4) Perform kinematic analysis, requirements analysis, and response simulation of manipulamotion. Previous reports have described the algorithms and procedures for using ROBSIM. These reports are superseded and additional features which were added are described. They are: (1) The ability to define motion profiles and compute loads on a common base to which manipulator arms are attached; (2) Capability to accept data describing manipulator geometry from a Computer Aided Design data base using the Initial Graphics exchange Specification format; (3) A manipulator control algorithm derived from processing the TV image of known reference points on a target; and (4) A vocabulary of simple high level task commands which can be used to define task scenarios

Resolving Orbital and Climate Keys of Earth and Extraterrestrial Environments with Dynamics 1.0: A General Circulation Model for Simulating the Climates of Rocky Planets

Resolving Orbital and Climate Keys of Earth and Extraterrestrial Environments with Dynamics (ROCKE-3D) is a 3-Dimensional General Circulation Model (GCM) developed at the NASA Goddard Institute for Space Studies for the modeling of atmospheres of Solar System and exoplanetary terrestrial planets. Its parent model, known as ModelE2 (Schmidt et al. 2014), is used to simulate modern and 21st Century Earth and near-term paleo-Earth climates. ROCKE-3D is an ongoing effort to expand the capabilities of ModelE2 to handle a broader range of atmospheric conditions including higher and lower atmospheric pressures, more diverse chemistries and compositions, larger and smaller planet radii and gravity, different rotation rates (slowly rotating to more rapidly rotating than modern Earth, including synchronous rotation), diverse ocean and land distributions and topographies, and potential basic biosphere functions. The first aim of ROCKE-3D is to model planetary atmospheres on terrestrial worlds within the Solar System such as paleo-Earth, modern and paleo-Mars, paleo-Venus, and Saturn's moon Titan. By validating the model for a broad range of temperatures, pressures, and atmospheric constituents we can then expand its capabilities further to those exoplanetary rocky worlds that have been discovered in the past and those to be discovered in the future. We discuss the current and near-future capabilities of ROCKE-3D as a community model for studying planetary and exoplanetary atmospheres.Comment: Revisions since previous draft. Now submitted to Astrophysical Journal Supplement Serie

Validation of the English Language Pain Sensitivity Questionnaire

Background and Objectives: The Pain Sensitivity Questionnaire (PSQ) is predictive of pain-related responses to experimental stimuli in German-speaking individuals. Here, we explored the validation of the English translation of the PSQ (PSQ-E). Methods: One hundred thirty-six patients scheduled to undergo a low back interventional procedure completed the PSQ-E and other questionnaires including the Brief Pain Inventory. Pain ratings on a visual analog scale (VAS) were obtained following 2 standardized injections of subcutaneous lidocaine (VAS 1, infiltration in hand; VAS 2, infiltration of procedural site). The VAS measures were compared with the PSQ-E data and other inventories using linear regression analysis with stepwise selection of variables. Results: The PSQ-E properties were in all respects similar to those of the original German PSQ. VAS 1 magnitude was predicted by PSQ-E-minor (r = 0.26, P < 0.01). VAS 2 magnitude was predicted by PSQ-E-minor (r = 0.34, P < 0.001), and the prediction was significantly enhanced by further inclusion of the Brief Pain Inventory interference score (total r = 0.40, P < 0.001). Conclusions: The study demonstrated that a significant correlation exists between the PSQ-E and clinically relevant pain ratings. This study validates the PSQ-E both in terms of measuring pain sensitivity and as possible means of recognizing patients with high pain sensitivity. Defining this subset of patients may have clinical utility in the future