Marshall Space Flight Center Research and Technology Report 2017

This report features over 60 technology development and scientific research efforts that collectively aim to enable new capabilities in spaceflight, expand the reach of human exploration, and reveal new knowledge about the universe in which we live. These efforts include a wide array of strategic developments: launch propulsion technologies that facilitate more reliable, routine, and cost effective access to space; in-space propulsion developments that provide new solutions to space transportation requirements; autonomous systems designed to increase our utilization of robotics to accomplish critical missions; life support technologies that target our ability to implement closed-loop environmental resource utilization; science instruments that enable terrestrial, solar, planetary and deep space observations and discovery; and manufacturing technologies that will change the way we fabricate everything from rocket engines to in situ generated fuel and consumables

Structure–activity relationship and liver microsome stability studies of pyrrole necroptosis inhibitors

Necroptosis is a regulated caspase-independent cell death pathway resulting in morphology reminiscent of passive non-regulated necrosis. Several diverse structure classes of necroptosis inhibitors have been reported to date, including a series of [1,2,3]thiadiazole benzylamide derivatives. However, initial evaluation of mouse liver microsome stability indicated that this series of compounds was rapidly degraded. A structure–activity relationship (SAR) study of the [1,2,3]thiadiazole benzylamide series revealed that increased mouse liver microsome stability and increased necroptosis inhibitory activity could be accomplished by replacement of the 4-cyclopropyl-[1,2,3]thiadiazole with a 5-cyano-1-methylpyrrole. In addition, the SAR and the cellular activity profiles, utilizing different cell types and necroptosis-inducing stimuli, of representative [1,2,3]thiadiazole and pyrrole derivatives were very similar suggesting that the two compound series inhibit necroptosis in the same manner

Optimization of tricyclic Nec-3 necroptosis inhibitors for in vitro liver microsomal stability

Necroptosis is a regulated caspase-independent cell death pathway with morphological features resembling passive non-regulated necrosis. Several diverse structure classes of necroptosis inhibitors have been reported to date, including a series of 3,3a,4,5-tetrahydro-2H-benz[g]indazoles (referred to as the Nec-3 series) displaying potent activity in cellular assays. However, evaluation of the tricyclic necroptosis inhibitor’s stability in mouse liver microsomes indicated that they were rapidly degraded. A structure–activity relationship (SAR) study of this compound series revealed that increased liver microsomal stability could be accomplished by modification of the pendent phenyl ring and by introduction of a hydrophilic substituent (i.e., ?-hydroxyl) to the acetamide at the 2-position of the tricyclic ring without significantly compromising necroptosis inhibitory activity. Further increases in microsomal stability could be achieved by utilizing the 5,5-dioxo-3-phenyl-2,3,3a,4-tetrahydro-[1]benzothiopyrano[4,3-c]pyrazoles. However, in this case necroptosis inhibitory activity was not maintained. Overall, these results provide a strategy for generating potent and metabolically stable tricyclic necrostatin analogs (e.g., 33, LDN-193191) potentially suitable for in vivo studies

Structure activity relationship study of [1,2,3]thiadiazole necroptosis inhibitors

Necroptosis is a regulated caspase-independent cell death mechanism that results in morphological features resembling non-regulated necrosis. This form of cell death can be induced in an array of cell types in apoptotic deficient conditions with death receptor family ligands. A series of [1,2,3]thiadiazole benzylamides was found to be potent necroptosis inhibitors (called necrostatins). A structure activity relationship study revealed that small cyclic alkyl groups (i.e. cyclopropyl) and 2,6-dihalobenzylamides at the 4- and 5-positions of the [1,2,3]thiadiazole, respectively, were optimal. In addition, when a small alkyl group (i.e. methyl) was present on the benzylic position all the necroptosis inhibitory activity resided with the (S)-enantiomer. Finally, replacement of the [1,2,3]thiadiazole with a variety of thiophene derivatives was tolerated, although some erosion of potency was observed

Outcomes of Convalescent Plasma with Defined High versus Lower Neutralizing Antibody Titers against SARS-CoV-2 among Hospitalized Patients: CoronaVirus Inactivating Plasma (CoVIP) Study

COVID-19 convalescent plasma (CCP) was an early and widely adopted putative therapy for severe COVID-19. Results from randomized control trials and observational studies have failed to demonstrate a clear therapeutic role for CCP for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Underlying these inconclusive findings is a broad heterogeneity in the concentrations of neutralizing antibodies (nAbs) between different CCP donors. We conducted this study to evaluate the effectiveness and safety of nAb titer-defined CCP in adults admitted to an academic referral hospital. Patients positive by a SARS-CoV-2 nucleic acid amplification test and with symptoms for 1:640 (high-titer group) or ≥1:160 to 1:640 (standard-titer group) in addition to standard of care treatments. The primary clinical outcome was time to hospital discharge, with mortality and respiratory support evaluated as secondary outcomes. Adverse events were contrasted by CCP titer. Between 28 August and 4 December 2020, 316 participants were screened, and 55 received CCP, with 14 and 41 receiving high- versus standard-titer CCP, respectively. Time to hospital discharge was shorter among participants receiving high- versus standard-titer CCP, accounting for death as a competing event (hazard ratio, 1.94; 95% confidence interval [CI], 1.05 to 3.58; Gray’s P = 0.02). Severe adverse events (SAEs) (≥grade 3) occurred in 4 (29%) and 23 (56%) of participants receiving the high versus standard titer, respectively, by day 28 (risk ratio, 0.51; 95% CI, 0.21 to 1.22; Fisher’s P = 0.12). There were no observed treatment-related AEs. (This study has been registered at ClinicalTrials.gov under registration no. NCT04524507)

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

A multi-level approach to understanding the regulation of translation initiation

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2016.Cataloged from PDF version of thesis. "September 2016."Includes bibliographical references.mRNA translation is an extremely complex process required for life. Translation consumes vast amounts of cellular resources, and organisms have evolved tight regulatory mechanisms to control this process, which are often deregulated in cancer and other disease states. Initiation, as the rate-limiting step in translation, is particularly well regulated. Two kinase pathways that respond to cellular stresses, the GCN2 and mTORC1 pathways, sense amino acid insufficiency to inhibit translation initiation at distinct points. GCN2 is activated in response to amino acid deprivation and inhibits formation of the ternary complex, comprising elF2, GTP, and the initiator methionyl-tRNA, which is required for recognition of the start codon. Although translation of most mRNAs is greatly suppressed when GCN2 is activated, mRNAs with certain cis elements escape inhibition. In contrast, the mTORC1 pathway is inhibited by the lack of amino acids, which ultimately results in the disruption of eIF4F, a multiprotein initiation factor complex that coordinates the recruitment of the small ribosomal subunit to the 5' end of mRNA. Like a decrease in the amount of ternary complex, disruption of eIF4F also suppresses translation of most mRNAs; however, the translation of a subset of mRNAs harboring a 5'TOP motif is even more dramatically reduced when mTORC1 is inhibited. Here we describe the translational program downstream of amino acid insufficiency, and present evidence of a novel uORF in murine ATF4 whose ribosome occupancy is regulated by the presence of amino acids. We identify the 4EBPs as the mTORC1 substrates that mediate the major effects of mTORC1 inhibition on translation of mRNAs both globally and on 5'TOP mRNAs specifically. Although we cannot mechanistically explain the dependence of 5'TOP mRNA translation on mTORC1 activity, we uncover a surprising role of the cap-proximal sequence in eIF4E recruitment. We systematically assess how the juxtacap sequence modulates eIF4E binding and translation, and present a model whereby the juxtacap sequence dictates the cap-proximal RNA secondary structure in an mRNA-context-dependent manner.by Heather R. Keys.Ph. D

Nervous nation: fear, conflict and narratives of fortified domestic architecture on the Queensland frontier

The frontier of nineteenth- and twentieth-century Australia was a place in which colonists routinely lived in fear of retaliation by the Aboriginal peoples whose traditional lands they had forcibly dispossessed. It has been suggested this concern manifested itself in domestic architecture, in both active and passive defensive strategies designed to afford protection against various forms of potential attack. Yet there remains a lack of substantive research to support such assertions. In this article, we present an analysis of accounts drawn from a range of sources of 97 domestic structures across Queensland with claims for defensive features. Although suggesting that fortified domestic structures were more common than previously envisaged, our review indicates that defensive features were usually minimal – holes in walls and barrable doors, windows or other ports of entry – reflecting the often expedient nature of the structures themselves. First-hand accounts of these buildings are rare, although not entirely absent, with most written accounts being reminiscences told in hindsight by later descendants, resulting in both distortions and myth-building. Accounts of fortified domestic structures peak in the decades following Federation and through both World Wars as the newly minted Australian nation explicitly engaged in nation-building and constructing the ‘glorious pioneer’ narrativ