Unraveling Adaptation in Eukaryotic Pathways: Lessons from Protocells

Eukaryotic adaptation pathways operate within wide-ranging environmental conditions without stimulus saturation. Despite numerous differences in the adaptation mechanisms employed by bacteria and eukaryotes, all require energy consumption. Here, we present two minimal models showing that expenditure of energy by the cell is not essential for adaptation. Both models share important features with large eukaryotic cells: they employ small diffusible molecules and involve receptor subunits resembling highly conserved G-protein cascades. Analyzing the drawbacks of these models helps us understand the benefits of energy consumption, in terms of adjustability of response and adaptation times as well as separation of cell-external sensing and cell-internal signaling. Our work thus sheds new light on the evolution of adaptation mechanisms in complex systems.Comment: accepted for publication in PLoS Computational Biology; 19 pages, 8 figure

A Compact Five-Channel VLF Wave Receiver for CubeSat Missions

Very low frequency (VLF) waves play an important role in controlling the evolution of energetic electron distributions in near-Earth space. This paper describes the design of a VLF receiver for the Climatology of Anthropogenic and Natural VLF Wave Activity in Space (CANVAS) CubeSat mission, designed to make continuous observations of VLF waves in low-Earth orbit originating from lightning and ground-based transmitters. The CANVAS VLF receiver will observe five components of VLF waves in the 0.3–40 kHz frequency range, using three orthogonal magnetic search coils deployed on the end of a 1-meter carbon fiber boom and four deployable electric field antennas operated as two orthogonal dipoles. Together, these five wave components will be used to calculate real and imaginary spectral matrix components using real-time fast Fourier transforms calculated in an onboard FPGA. Spectral matrix components will be averaged to obtain 1 second time resolution and frequency resolution better than 10%. The averaged spectral matrix will be used to determine the complete set of wave parameters, including Poynting flux, polarization, planarity, and k-vector direction. CANVAS is currently in the manufacturing and assembly phase and is planned to launch at the end of 2022

The CANVAS Mission: Quantifying the Very-Low-Frequency Radio Energy Input from the Ground into the Earth\u27s Magnetosphere

Very-low-frequency (VLF) electromagnetic waves, emitted by ground-based sources including lightning and VLF transmitters, can impact the lower ionosphere and magnetosphere through their interaction with the local plasma and energetic particle environments. Quantifying the impacts of these waves requires an accurate assessment of the propagation and attenuation of these waves. The Climatology of Anthropogenic and Natural VLF wave Activity in Space (CANVAS) mission is designed to measure VLF waves in low Earth orbit originating from these ground-based sources. The mission aims to characterize the VLF environment in low Earth orbit to address two main goals: i) constrain the VLF wave injection from the ground into the magnetosphere, and ii) improve models of VLF wave attenuation during propagation through the ionosphere. CANVAS will measure VLF waves using three search coil magnetometers and two electric field dipole antennas that comprise its payload. The search coils are integrated into a 3D-printed Carbon PEEK holder, along with the magnetic field preamplifier board. The search coil system is deployed 1 meter from the spacecraft using a carbon fiber deployable boom, in order to isolate the sensitive search coils from spacecraft noise. The electric field system is composed of four 40 cm monopole antennas, making two orthogonal dipole antennas, integrated into the spacecraft “crown”, along with a custom preamplifier circuit for each monopole. The payload is completed by a custom analog receiver board, providing amplification, anti-alias filtering, and centering for the analog-to-digital converters (ADCs); and a custom digital board, which includes an FPGA for onboard signal processing. Spectral data spanning 0.3–40 kHz are saved at 1-second cadence, providing a continuous “fast survey” data mode for the duration of the mission. The CANVAS spacecraft is a 4U CubeSat, 10 × 10 × 45 cm and under 6 kg. In addition to the 1-meter deployable carbon fiber boom and electric field antennas, the spacecraft incorporates deployable solar panels and a monopole antenna for UHF communications. Data is downlinked in S-band. The spacecraft structure and avionics are custom-designed and built at CU Boulder, while the radios and attitude determination and control system (ADCS) are vendor-supplied components. The CANVAS mission is designed to operate at ∼500 km altitude in a moderate-inclination orbit (∼50 degrees), to ensure global coverage of lightning-generating regions; most lightning globally is confined to within ±50 degrees latitude. Spectra at 1-second cadence account for ∼424 MB of data per day, after housekeeping and encoding overhead. A one-year mission will ensure seasonal coverage to observe the Marshall 1 36th Annual Small Satellite Conference variability in global lightning activity. This paper presents a detailed overview of the CANVAS science goals, payload, spacecraft, and mission. The instrument is now completed and undergoing functional testing and performance characterization, and the spacecraft is beginning integration, expected to be completed in Fall 2022. The CANVAS mission will be ready to launch in early 2023

A Methodology for Successful University Graduate CubeSat Programs

The University of Colorado Smead Department of Aerospace Engineering has over a decade of success in designing, building, and operating student led CubeSat missions. The experience and lessons learned from building and operating the CSSWE, MinXSS-1, MinXSS-2, and QB50-Challenger missions have helped grow a knowledge base on the most effective and efficient ways to manage some of the “tall poles” when it comes to student run CubeSat missions. Among these “tall poles” we have seen student turnover, software, and documentation become some of the hardest to knock-down and we present our strategies for doing so. We use the MAXWELL mission (expected to launch in 2021) as a road-map to detail the methodology we have built over the last decade to ensure the greatest chance of mission success

Cysteamine decreases low density lipoprotein oxidation, causes regression of atherosclerosis and improves liver and muscle function in LDL receptor deficient mice

Background: We have shown previously that low density lipoprotein (LDL) can be oxidized in the lysosomes of macrophages, that this oxidation can be inhibited by cysteamine, an antioxidant which accumulates in lysosomes, and that this drug decreases atherosclerosis in LDL receptor-deficient mice fed a high-fat diet. We have now carried out a regression study with cysteamine, which is of more relevance to the treatment of human disease. Methods and Results: LDL receptor-deficient mice were fed a high fat diet to induce atherosclerotic lesions. They were then reared on chow diet and drinking water containing cysteamine or plain drinking water. Aortic atherosclerosis was assessed, and samples of liver and skeletal muscle analysed. There was no regression of atherosclerosis in the control mice, but cysteamine caused regression of between 32 and 56% compared to the control group, depending on the site of the lesions. Cysteamine substantially increased markers of lesions stability, decreased ceroid, and greatly decreased oxidised phospholipids in the lesions. The liver lipid levels and expression of CD68, ACAT2, CYP27 and pro-inflammatory cytokines and chemokines were decreased by cysteamine. Skeletal muscle function and oxidative fibers were increased by cysteamine. There were no changes in the plasma total cholesterol, LDL cholesterol, HDL cholesterol or triacylglycerol concentrations due to cysteamine. Conclusions: Inhibiting the lysosomal oxidation of LDL in atherosclerotic lesions by antioxidants targeted at lysosomes causes the regression of atherosclerosis and improves liver and muscle characteristics in mice and might be a promising novel therapy for atherosclerosis in patients

Nutrition therapy for critically ill patients across the Asia-Pacific and Middle East Regions: a consensus statement

Background & Aims: Guidance on managing the nutritional requirements of critically ill patients in the intensive care unit (ICU) has been issued by several international bodies. While these guidelines are consulted in ICUs across the Asia Pacific and Middle East, there is little guidance available that is tailored to the unique healthcare environments and demographics across these regions. Furthermore, the lack of consistent data from randomized controlled clinical trials, reliance on expert consensus, and differing recommendations in international guidelines necessitate further expert guidance on regional best practice when providing nutrition therapy for critically ill patients in ICUs in Asia Pacific and the Middle East. Methods: The Asia-Pacific and Middle East Working Group on Nutrition in the ICU has identified major areas of uncertainty in clinical practice for healthcare professionals providing nutrition therapy in Asia Pacific and Middle East and developed a series of consensus statements to guide nutrition therapy in the ICU in these regions. Results: Accordingly, consensus statements have been provided on nutrition risk assessment and parenteral and enteral feeding strategies in the ICU, monitoring adequacy of, and tolerance to, nutrition in the ICU and institutional processes for nutrition therapy in the ICU. Furthermore, the Working Group has noted areas requiring additional research, including the most appropriate use of hypocaloric feeding in the ICU. Conclusions: The objective of the Working Group in formulating these statements is to guide healthcare professionals in practicing appropriate clinical nutrition in the ICU, with a focus on improving quality of care, which will translate into improved patient outcomes

Single-Step Syngas-to-Distillates (S2D) Synthesis via Methanol and Dimethyl Ether Intermediates: Final Report

The objective of the work was to enhance price-competitive, synthesis gas (syngas)-based production of transportation fuels that are directly compatible with the existing vehicle fleet (i.e., vehicles fueled by gasoline, diesel, jet fuel, etc.). To accomplish this, modifications to the traditional methanol-to-gasoline (MTG) process were investigated. In this study, we investigated direct conversion of syngas to distillates using methanol and dimethyl ether intermediates. For this application, a Pd/ZnO/Al2O3 (PdZnAl) catalyst previously developed for methanol steam reforming was evaluated. The PdZnAl catalyst was shown to be far superior to a conventional copper-based methanol catalyst when operated at relatively high temperatures (i.e., >300°C), which is necessary for MTG-type applications. Catalytic performance was evaluated through parametric studies. Process conditions such as temperature, pressure, gas-hour-space velocity, and syngas feed ratio (i.e., hydrogen:carbon monoxide) were investigated. PdZnAl catalyst formulation also was optimized to maximize conversion and selectivity to methanol and dimethyl ether while suppressing methane formation. Thus, a PdZn/Al2O3 catalyst optimized for methanol and dimethyl ether formation was developed through combined catalytic material and process parameter exploration. However, even after compositional optimization, a significant amount of undesirable carbon dioxide was produced (formed via the water-gas-shift reaction), and some degree of methane formation could not be completely avoided. Pd/ZnO/Al2O3 used in combination with ZSM-5 was investigated for direct syngas-to-distillates conversion. High conversion was achieved as thermodynamic constraints are alleviated when methanol and dimethyl are intermediates for hydrocarbon formation. When methanol and/or dimethyl ether are products formed separately, equilibrium restrictions occur. Thermodynamic relaxation also enables the use of lower operating pressures than what would be allowed for methanol synthesis alone. Aromatic-rich hydrocarbon liquid (C5+), containing a significant amount of methylated benzenes, was produced under these conditions. However, selectivity control to liquid hydrocarbons was difficult to achieve. Carbon dioxide and methane formation was problematic. Furthermore, saturation of the olefinic intermediates formed in the zeolite, and necessary for gasoline production, occurred over PdZnAl. Thus, yield to desirable hydrocarbon liquid product was limited. Evaluation of other oxygenate-producing catalysts could possibly lead to future advances. Potential exists with discovery of other types of catalysts that suppress carbon dioxide and light hydrocarbon formation. Comparative techno-economics for a single-step syngas-to-distillates process and a more conventional MTG-type process were investigated. Results suggest operating and capital cost savings could only modestly be achieved, given future improvements to catalyst performance. Sensitivity analysis indicated that increased single-pass yield to hydrocarbon liquid is a primary need for this process to achieve cost competiveness

Accurate Encoding and Decoding by Single Cells: Amplitude Versus Frequency Modulation

Cells sense external concentrations and, via biochemical signaling, respond by regulating the expression of target proteins. Both in signaling networks and gene regulation there are two main mechanisms by which the concentration can be encoded internally: amplitude modulation (AM), where the absolute concentration of an internal signaling molecule encodes the stimulus, and frequency modulation (FM), where the period between successive bursts represents the stimulus. Although both mechanisms have been observed in biological systems, the question of when it is beneficial for cells to use either AM or FM is largely unanswered. Here, we first consider a simple model for a single receptor (or ion channel), which can either signal continuously whenever a ligand is bound, or produce a burst in signaling molecule upon receptor binding. We find that bursty signaling is more accurate than continuous signaling only for sufficiently fast dynamics. This suggests that modulation based on bursts may be more common in signaling networks than in gene regulation. We then extend our model to multiple receptors, where continuous and bursty signaling are equivalent to AM and FM respectively, finding that AM is always more accurate. This implies that the reason some cells use FM is related to factors other than accuracy, such as the ability to coordinate expression of multiple genes or to implement threshold crossing mechanisms

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe