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The purpose of this test was to determine the heavy ion-induced single-event effect (SEE) susceptibility of the Samsung solid state drive (SSD) containing the Vertical-NAND (VNAND) flash technology. This test was supported by the NASA Electronics Parts and Packaging (NEPP) Program.
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Pediatric patient-reported outcome (PRO) data can help inform the US Food and Drug Administration’s (FDA’s) benefit-risk assessment of cancer therapeutics by quantifying symptom and functional outcomes from the patient’s perspective. This study assessed use of PROs in commercial pediatric oncology trials submitted to the FDA for regulatory review. FDA databases were searched to identify pediatric oncology product applications approved between 1997 and 2020. Sponsor-submitted documents were reviewed to determine whether PRO data were collected, which instruments were used, and the quality of collected data (ie, sample size, completion rates, and use of fit-for-purpose instruments). The role of PROs in each trial (endpoint hierarchy) was also recorded in addition to whether any PRO endpoints were included in product labeling. We reviewed 17 pediatric oncology applications, 4 of which included PRO data: denosumab, tisagenlecleucel, larotrectinib, and selumetinib. In these 4 instances, PROs served as exploratory endpoints and were not incorporated in product labeling. Trials that collected PRO data were phase II or phase I/II single-arm studies with sample sizes of 28 to 88 patients. Symptomatic adverse events (AEs) were characterized using clinician-reported Common Terminology Criteria for Adverse Events (CTCAE) without additional patient self-report. PROs were infrequently used in pediatric cancer registration trials. When PROs were used, PRO data were limited by lack of a clear research objective and corresponding prospective statistical analysis plan. Contemporary PRO symptom libraries, such as the National Cancer Institute’s Pediatric PRO-CTCAE, may provide an opportunity to better evaluate the occurrence and impact of symptomatic AEs, from the patient’s perspective, in pediatric oncology trials.
As an essential enzyme of SARS-CoV-2, the COVID-19 pathogen, main protease (M Pro ) is a viable target to develop antivirals for the treatment of COVID-19. By varying chemical compositions at both P2 and P3 positions and the N-terminal protection group, we synthesized 18 tripeptidyl M Pro inhibitors that contained also an aldehyde warhead and β-(S-2-oxopyrrolidin-3-yl)-alaninal at the P1 position. Systematic characterizations of these inhibitors were conducted, including their in vitro enzymatic inhibition potency, X-ray crystal structures of their complexes with M Pro , their inhibition of M Pro transiently expressed in 293T cells, and cellular toxicity and SARS-CoV-2 antiviral potency of selected inhibitors. These inhibitors have a large variation of determined in vitro enzymatic inhibition IC 50 values that range from 4.8 to 650 nM. Here, the determined in vitro enzymatic inhibition IC 50 values reveal that relatively small side chains at both P2 and P3 positions are favorable for achieving high in vitro M Pro inhibition potency, the P3 position is tolerable toward unnatural amino acids with two alkyl substituents on the α-carbon, and the inhibition potency is sensitive toward the N-terminal protection group. X-ray crystal structures of M Pro bound with 16 inhibitors were determined. In all structures, the M Pro active site cysteine interacts covalently with the aldehyde warhead of the bound inhibitor to form a hemithioacetal that takes an S configuration. For all inhibitors, election density around the N-terminal protection group is weak indicating possible flexible binding of this group to M Pro . In M Pro , large structural variations were observed on residues N142 and Q189. Unlike their high in vitro enzymatic inhibition potency, most inhibitors showed low potency to inhibit M Pro that was transiently expressed in 293T cells. Inhibitors that showed high potency to inhibit M Pro transiently expressed in 293T cells all contain O-tert-butyl-threonine at the P3 position. These inhibitors also exhibited relatively low cytotoxicity and high antiviral potency. Overall, our current and previous studies indicate that O-tert-butyl-threonine at the P3 site is a key component to achieve high cellular and antiviral potency for tripeptidyl aldehyde inhibitors of M Pro .
This data package contains data from terrestrial laser scanning (TLS) at the Pasoh Forest Reserve, Malaysia. The Pasoh Forest Reserve is a facility of the Forest Research Institute Malaysia, and contains evergreen lowland dipterocarp forest. The Next-Generation Ecosystem Experiments Tropics (NGEE-Tropics) study areas at Pasoh were established to study how different species respond to climatic variation and soil water availability. Two study areas were chosen representing different topography and species. The TLS data archived here were collected to provide detailed, three-dimensional information about forest structure. Specifically, data were collected to allow tree-level characterization of woody structure and leaf area for 12 focal trees with FloraPulse and sap flux sensors, facilitating estimation of woody biomass and leaf area to allow upscaling of water content and transpiration data to the tree-level. Scan positions were not selected to provide consistent data for non-focal trees with the study areas. This data package contains the following data: - High-level files document further details of the campaign and data package: 1_CampaignSummary.csv provides details about the campaign and study site, 2_ScanAreasDetail.csv provides details about each separate scan area (groups of scans post-processed into a single point cloud), 3_TerrestrialLidarSensor.csv provides further technical details about the Riegl VZ-400i TLS sensor, TLS_CSV_dd.csv is a CSV Data Dictionary providing information about the fields in CSV files following the ESS-DIVE CSV File Formatting Guidelines Reporting Format, TLS_flmd.csv is a File Level Metadata file providing information about each file in the data package following the ESS-DIVE File Level Metadata Reporting Format, and README.txt is a text file describing the overall project and file structure. - Level 0 data are the raw data (.PROJ folders) as recorded by the Riegl VZ-400i TLS instrument before scan co-registration and post-processing with the Riegl's proprietary RiSCAN PRO software, which requires a license. - Level 1 data contain post-processed, co-registered data from each scan area. The "PointClouds" folder for each scan area contains a .las file with 1 cm resolution point cloud data exported from RiSCAN PRO. These are the main files likely to be of interest to most users and can be further processed with any software capable of manipulating .las files (e.g. Python, R CloudCompare). The "Project Information" folder contains log files from post-processing in RiSCAN PRO that may be of interest to users who want to see detailed records of post-processing, including all PDF reports generated by RiSCAN PRO. The "ScanPositions" folder contains information about the final position of all TLS scans, after post-processing, in multiple formats. The file ScanPositions_*.csv provides final geo-referenced scan positions, and the file SOP_backup_*.csv can be used in RiSCAN PRO to restore the co-registered scan positions if users wish to re-process raw data (Level 0 .PROJ folders) with RiSCAN PRO software (e.g., subsample to a different resolution, exclude a certain scan position, or apply different filters on reflectance or deviation values) without redoing time-consuming co-registration steps.
This data package contains data from terrestrial laser scanning (TLS) at five urban park sites in Knoxville, Tennessee, USA. All parks include open-grown and/or closed-canopy trees and mixed nearby land use. These study sites were established as part of the Urban Biogeochemistry Pilot Project, which has an overall goal of better understanding how hydrobiogeochemical cycling is altered within the human environment. These five sites represent a gradient of urbanization, and were instrumented to understand hydrological and biogeochemical cycling (e.g., soil moisture, soil physical properties and biogeochemistry, tree transpiration, species type). The TLS data archived here were collected to provide detailed, three-dimensional information about forest structure. Specifically, data were collected to allow tree- and stand-level characterization of woody structure and leaf area. TLS scans were placed to capture the area around trees with sap flow sensors, and as much of a 50 m radius area around the meteorological station as possible given site property limits. Derived products will allow upscaling of water content and transpiration data. This data package contains the following data: - High-level files document further details of the campaign and data package: 1_CampaignSummary.csv provides details about the campaign and study site, 2_ScanAreasDetail.csv provides details about each separate scan area (groups of scans post-processed into a single point cloud), 3_TerrestrialLidarSensor.csv provides further technical details about the Riegl VZ-400i TLS sensor, TLS_CSV_dd.csv is a CSV Data Dictionary providing information about the fields in CSV files following the ESS-DIVE CSV File Formatting Guidelines Reporting Format, TLS_flmd.csv is a File Level Metadata file providing information about each file in the data package following the ESS-DIVE File Level Metadata Reporting Format, and README.txt is a text file describing the overall project and file structure. - Level 0 data are the raw data (.PROJ folders) as recorded by the Riegl VZ-400i TLS instrument before scan co-registration and post-processing with the Riegl's proprietary RiSCAN PRO software, which requires a license. - Level 1 data contain post-processed, co-registered data from each scan area. The "PointClouds" folder for each scan area contains a .las file with 1 cm resolution point cloud data exported from RiSCAN PRO. These are the main files likely to be of interest to most users and can be further processed with any software capable of manipulating .las files (e.g. Python, R CloudCompare). The "Project Information" folder contains log files from post-processing in RiSCAN PRO that may be of interest to users who want to see detailed records of post-processing, including all PDF reports generated by RiSCAN PRO. The "ScanPositions" folder contains information about the final position of all TLS scans, after post-processing, in multiple formats. The file ScanPositions_*.csv provides final geo-referenced scan positions, and the file SOP_backup_*.csv can be used in RiSCAN PRO to restore the co-registered scan positions if users wish to re-process raw data (Level 0 .PROJ folders) with RiSCAN PRO software (e.g., subsample to a different resolution, exclude a certain scan position, or apply different filters on reflectance or deviation values) without redoing time-consuming co-registration steps.
The ongoing SARS-CoV-2 pandemic continues to be a significant threat to global health. First reported in November 2021, the Omicron variant (B.1.1.529) is more transmissible and can evade immunity better than previous SARS-CoV-2 variants, fueling an unprecedented surge in cases. To produce functional proteins from its polyprotein, SARS-CoV-2 relies on the cysteine proteases Nsp3/papain-like protease (PL pro ) and Nsp5/main protease (M pro )/3C-like protease to cleave at three and more than 11 sites, respectively. Therefore, M pro and PL pro inhibitors are considered to be one of the most promising SARS-CoV-2 antivirals. On December 22, 2021, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for PAXLOVID, a ritonavir-boosted formulation of nirmatrelvir. Nirmatrelvir is a first-in-class orally bioavailable SARS-CoV-2 M pro inhibitor. Thus, the scientific community must vigilantly monitor potential mechanisms of drug resistance, especially because SARS-CoV-2 is naïve to M pro inhibitors. Mutations have been well identified in variants to this point. Notably, Omicron M pro (OM pro ) harbors a single mutation—P132H. Here, we characterized the enzymatic activity, drug inhibition, and structure of OM pro while evaluating the past and future implications of M pro mutations.
Boceprevir is an HCV NSP3 inhibitor that was explored as a repurposed drug for COVID-19. It inhibits the SARS-CoV-2 main protease (M Pro ) and contains an α-ketoamide warhead, a P1 β-cyclobutylalanyl moiety, a P2 dimethylcyclopropylproline, a P3 tert-butylglycine, and a P4 N-terminal tert-butylcarbamide. By introducing modifications at all four positions, we synthesized 20 boceprevir-based M Pro inhibitors including PF-07321332 and characterized their M Pro inhibition potency in test tubes (in vitro) and 293T cells (in cellulo). Crystal structures of M Pro bound with 10 inhibitors and cytotoxicity and antiviral potency of 4 inhibitors were characterized as well. Replacing the P1 site with a β-(S-2-oxopyrrolidin-3-yl)-alanyl (Opal) residue and the warhead with an aldehyde leads to high in vitro potency. The original moieties at P2, P3 and the P4 N-terminal cap positions in boceprevir are better than other tested chemical moieties for high in vitro potency. In crystal structures, all inhibitors form a covalent adduct with the M Pro active site cysteine. Here, the P1 Opal residue, P2 dimethylcyclopropylproline and P4 N-terminal tert-butylcarbamide make strong hydrophobic interactions with M Pro , explaining high in vitro potency of inhibitors that contain these moieties. A unique observation was made with an inhibitor that contains a P4 N-terminal isovaleramide. In its M Pro complex structure, the P4 N-terminal isovaleramide is tucked deep in a small pocket of M Pro that originally recognizes a P4 alanine side chain in a substrate. Although all inhibitors show high in vitro potency, they have drastically different in cellulo potency to inhibit ectopically expressed M Pro in human 293T cells. In general, inhibitors with a P4 N-terminal carbamide or amide have low in cellulo potency. This trend is reversed when the P4 N-terminal cap is changed to a carbamate. The installation of a P3 O-tert-butyl-threonine improves in cellulo potency. Three molecules that contain a P4 N-terminal carbamate were advanced to cytotoxicity tests on 293T cells and antiviral potency tests on three SARS-CoV-2 variants. They all have relatively low cytotoxicity and high antiviral potency with EC 50 values around 1 μM. A control compound with a nitrile warhead and a P4 N-terminal amide has undetectable antiviral potency. Based on all observations, we conclude that a P4 N-terminal carbamate in a boceprevir derivative is key for high antiviral potency against SARS-CoV-2.
The papain-like protease (PL pro ) of SARS-CoV-2 is a validated antiviral drug target. Through a fluorescence resonance energy transfer-based high-throughput screening and subsequent lead optimization, we identified several PL pro inhibitors including Jun9-72-2 and Jun9-75-4 with improved enzymatic inhibition and antiviral activity compared to GRL0617, which was reported as a SARS-CoV PL pro inhibitor. Significantly, we developed a cell-based FlipGFP assay that can be applied to predict the cellular antiviral activity of PL pro inhibitors in the BSL-2 setting. X-ray crystal structure of PL pro in complex with GRL0617 showed that binding of GRL0617 to SARS-CoV-2 induced a conformational change in the BL2 loop to a more closed conformation. Molecular dynamics simulations showed that Jun9-72-2 and Jun9-75-4 engaged in more extensive interactions than GRL0617. Overall, the PL pro inhibitors identified in this study represent promising candidates for further development as SARS-CoV-2 antivirals, and the FlipGFP-PL pro assay is a suitable surrogate for screening PL pro inhibitors in the BSL-2 setting.
Pressure-Retarded Osmosis (PRO) is an osmotic process that has been used to harvest energy from salinity gradients using a semi permeable membrane. A comparison between open-loop PRO (OLPRO) and closed-loop PRO (CLPRO) was made regarding their performance and costs. In CLPRO, where the diluted draw solution is re-concentrated in the regeneration system to be reutilized in the process, has recently received an intensive focus as the most viable configuration for a standalone power plant. The choice of the PRO draw solution in CLPRO is crucial to garner a high osmotic pressure as the key for the feasibility of the process. Here, in this review, the draw solutions are critically evaluated in the literature in terms of energy output as well as the method of regeneration used to recirculate them. A set of practical criteria has been suggested to appraise the adequacy of the solution for CLPRO application. It was concluded that NH 3 – CO 2 theoretically can produce 170 W/m 2 of power density. Inorganic draw solutes such as NaCl can generate high power density up to 87 W/m 2 . Organic draw solutes with their remarkably low reverse salt flux (RSF) have promising potential for future application in PRO. Similarly, the regeneration systems of the diluted draw solutions have also been reviewed and discussed. How the energy consumption of the regeneration process affects the feasibility of CLPRO is explained. For the specific case of osmotic heat engines (OHEs), when the energy of the regeneration process is supplied by heat waste, the range of applicability of the heat waste in CLPRO in terms of efficiency is defined and compared to Organic Rankine Cycle (ORC). The results showed that CLPRO has better efficiency than ORC for temperatures T < 80 °C, which makes it a promising process or low-grade heat energy recovery. In addition, a PRO-RO hybrid system coupled with solar power can reduce the net specific energy consumption (SEC) to 0.39 kWh/m 3 . The conditions that regeneration processes should operate under to make PRO viable are discussed in the last section. Overall, the study indicates the key factors for optimizing the performance of CLPRO process.
To assess DC fast charging station network required for electrified road trips by 2030 in California, a new charging infrastructure simulation tool/model, EVI-Pro (Electric Vehicle Infrastructure Projection) RoadTrip, has been developed. In contrast to the existing EVI-Pro model that is primarily for short-distance travels, EVI-Pro RoadTrip is exclusively focused on road trips (long-distance travels, 100 or miles per day per vehicle). Also, the charging paradigm or strategy is different. EVI-Pro RoadTrip is built upon waypoint charging, in which vehicles are forced to stop to charge or replenish the on-board batteries, along the routes between origins and destinations. On the other hand, EVI-Pro is based on destination charging, in which charging is conducted when vehicles are parked in destinations (e.g., work, home). EVI-Pro RoadTrip takes coordinate-level origin and destination data for road trips (intra-state as well as domestic or international out-of-state) and estimates energy consumption and charging needs along the routes between origins and destinations on a minute-by-minute resolution. Based on charging demands for electrified road trips across the state, the optimal locations of charging stations are determined accounting for preferred land use types (e.g., commercial areas) and station service area (e.g., 5 or less miles). Based on station-by-station charging load profiles, the required number of plugs/connectors is estimated for each station and entire state. By comparing hosting capacity of the electric grid (circuit-level) and the charging load output from EVI-Pro RoadTrip, capacity deficit is also evaluated.
Excessive accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes ER stress, which is an underlying cause of major crop losses and devastating human conditions. Here, ER proteostasis surveillance is mediated by the conserved master regulator of the unfolded protein response (UPR), Inositol Requiring Enzyme 1 (IRE1), which determines cell fate by controlling pro-life and pro-death outcomes through as yet largely unknown mechanisms. Here we report that Arabidopsis IRE1 determines cell fate in ER stress by balancing the ubiquitin–proteasome system (UPS) and UPR through the plant-unique E3 ligase, PHOSPHATASE TYPE 2CA (PP2CA)-INTERACTING RING FINGER PROTEIN 1 (PIR1). Indeed, PIR1 loss leads to suppression of pro-death UPS and the lethal phenotype of an IRE1 loss-of-function mutant in unresolved ER stress in addition to activating pro-survival UPR. Specifically, in ER stress, PIR1 loss stabilizes ABI5, a basic leucine zipper (bZIP) transcription factor, that directly activates expression of the critical UPR regulator gene, bZIP60, triggering transcriptional cascades enhancing pro-survival UPR. Collectively, our results identify new cell fate effectors in plant ER stress by showing that IRE1’s coordination of cell death and survival hinges on PIR1, a key pro-death component of the UPS, which controls ABI5, a pro-survival transcriptional activator of bZIP60.
Eukaryotic N-degron pathways are proteolytic systems whose unifying feature is their ability to recognize proteins containing N-terminal (Nt) degradation signals called N-degrons, and to target these proteins for degradation by the 26S proteasome or autophagy. GID4, a subunit of the GID ubiquitin ligase, is the main recognition component of the proline (Pro)/N-degron pathway. GID4 targets proteins through their Nt-Pro residue or a Pro at position 2, in the presence of specific downstream sequence motifs. Here we show that human GID4 can also recognize hydrophobic Nt-residues other than Pro. One example is the sequence Nt-IGLW, bearing Nt-Ile. Nt-IGLW binds to wild-type human GID4 with a $K_d$ of 16 μM, whereas the otherwise identical Nt-Pro–bearing sequence PGLW binds to GID4 more tightly, with a $K_d$ of 1.9 μM. Despite this difference in affinities of GID4 for Nt-IGLW vs. Nt-PGLW, we found that the GID4-mediated Pro/N-degron pathway of the yeast Saccharomyces cerevisiae can target an Nt-IGLW–bearing protein for rapid degradation. We solved crystal structures of human GID4 bound to a peptide bearing Nt-Ile or Nt-Val. We also altered specific residues of human GID4 and measured the affinities of resulting mutant GID4s for Nt-IGLW and Nt-PGLW, thereby determining relative contributions of specific GID4 residues to the GID4-mediated recognition of Nt-Pro vs. Nt-residues other than Pro. These and related results advance the understanding of targeting by the Pro/N-degron pathway and greatly expand the substrate recognition range of the GID ubiquitin ligase in both human and yeast cells.