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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 1,567 records · Page 87
All sourcesNASA NTRSDOE OSTI
DOE OSTI2014

The Cucumber leaf spot virus p25 auxiliary replicase protein binds and modifies the endoplasmic reticulum via N-terminal transmembrane domains

Cucumber leaf spot virus (CLSV) is a member of the Aureusvirus genus, family Tombusviridae. The auxiliary replicase of Tombusvirids has been found to localize to endoplasmic reticulum (ER), peroxisomes or mitochondria; however, localization of the auxiliary replicase of aureusviruses has not been determined. We have found that the auxiliary replicase of CLSV (p25) fused to GFP colocalizes with ER and that three predicted transmembrane domains (TMDs) at the N-terminus of p25 are sufficient for targeting, although the second and third TMDs play the most prominent roles. Confocal analysis of CLSV infected 16C plants shows that the ER becomes modified including the formation of punctae at connections between ER tubules and in association with the nucleus. Ultrastructural analysis shows that the cytoplasm contains numerous vesicles which are also found between the perinuclear ER and nuclear membrane. It is proposed that these vesicles correspond to modified ER used as sites for CLSV replication. - Highlights: • The CLSV p25 auxiliary replicase targets the endoplasmic reticulum (ER). • Targeting of CLSV p25 is associated with ER restructuring. • Restructuring of the ER occurs during CLSV infection. • CLSV p25 contains 3 predicted transmembrane domains 2 of which are required for ER targeting. • Vesicles derived from the ER may be sites of CLSV replication.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Cellular alignment and fusion: Quantifying the effect of macrophages and fibroblasts on myoblast terminal differentiation

Highlights: • We present a method for cellular alignment calculation during routine cell culture. • Application revealed that macrophages promote myoblast alignment, but delay fusion. • Furthermore, fibroblasts regulate myoblast fusion, but not alignment. • Effect of macrophages on alignment is not altered by co-culture with fibroblasts. Successful skeletal muscle wound repair requires the alignment and fusion of myoblasts to generate multinucleated myofibers. In vitro, the accurate quantification of cellular alignment remains a challenge. Here we present the application of ImageJ and ct-FIRE to quantify muscle cell orientation by means of an alignment index (AI). Our optimised method, which does not require programming skills, allows the alignment of myoblasts in vitro to be determined independently of a predefined reference point. Using this method, we demonstrate that co-culture of myoblasts with macrophages, but not fibroblasts, promotes myoblast alignment in a cell density-dependent manner. Interestingly, myoblast fusion was significantly decreased in response to co-culture with macrophages, while the effect of fibroblasts on fusion was density-dependent. At lower numbers, fibroblasts significantly increased myoblast fusion, whereas at higher numbers a significant decrease was observed. Finally, triple co-culture revealed that the effect of macrophages on myoblast alignment and fusion is unaltered by the additional presence of fibroblasts. Application of our optimised method has therefore revealed quantitative differences in the roles of macrophages versus fibroblasts during alignment and fusion: while successful myoblast alignment is promoted by increasing macrophage numbers, regenerative fusion coincides with a decreasing macrophage population and initial rise in fibroblast numbers.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Influence of Terminal Carboxyl Groups on the Structure and Reactivity of Functionalized m-Carboranethiolate Self-Assembled Monolayers

The structure and function of self-assembled monolayers (SAMs) at the nanoscale are determined by the steric and electronic effects of their building blocks. Carboranethiol molecules form pristine monolayers that provide tunable two-dimensional systems to probe lateral and interfacial interactions. Additional ω-functionality, such as carboxyl groups, can be introduced to change the properties of the exposed surfaces. Here, two geometrically similar isomeric m-carborane analogues of m-mercaptobenzoic acid, 1-COOH-7-SH-1,7-C 2 B 10 H 10 and racem-1-COOH-9-SH-1,7-C 2 B 10 H 10 , are characterized and their SAMs on Au{111} are examined. The latter isomer belongs to the rare group of chiral cage molecules and becomes, to our knowledge, the first example assembled on Au{111}. Although different in symmetry, molecules of both isomers assemble into similar hexagonal surface patterns. The nearest-neighbor spacing of 8.4 ± 0.4 Å is larger than that of non-carboxylated isomers, consistent with the increased steric demands of the carboxyl groups. Computational modeling reproduced this spacing and suggests a tilt relative to the surface normal. However, tilt domains are not observed experimentally, suggesting the presence of strong lateral interactions. Analyses of the influence of the functional groups through the pseudo-aromatic m-carborane skeleton showed that the thiol group attached to either carbon or boron atoms increases the carboxyl group acidity in solution. In contrast, the acidity of the exposed carboxyl group in the SAMs decreases upon surface attachment; computational analyses suggest that the driving force of this shift is the dielectric of the environment in the monolayer as a result of confined intermolecular interactions, proximity to the Au surface, and partial desolvation.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2017

Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors

Members of the BET family of bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a phenylpyridazinone fragment with a weak binding affinity (1, Ki = 160 μM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of potent pyridone and macrocyclic pyridone inhibitors exhibiting single digit nanomolar potency in both biochemical and cell based assays. Advanced analogs in these series exhibited high oral exposures in rodent PK studies and demonstrated significant tumor growth inhibition efficacy in mouse flank xenograft models.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗