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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 757 records · Page 42
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Structures of drug-specific monoclonal antibodies bound to opioids and nicotine reveal a common mode of binding

Opioid-related fatal overdoses have reached epidemic proportions. Because existing treatments for opioid use disorders offer limited long-term protection, accelerating the development of newer approaches is critical. Monoclonal antibodies (mAbs) are an emerging treatment strategy that targets and sequesters selected opioids in the bloodstream, reducing drug distribution across the blood-brain barrier, thus preventing or reversing opioid toxicity. We previously identified a series of murine mAbs with high affinity and selectivity for oxycodone, morphine, fentanyl, and nicotine. To determine their binding mechanism, we used X-ray crystallography to solve the structures of mAbs bound to their respective targets, to 2.2 Å resolution or higher. Structural analysis showed a critical convergent hydrogen bonding mode that is dependent on a glutamic acid residue in the mAbs’ heavy chain and a tertiary amine of the ligand. Further, characterizing drug-mAb complexes represents a significant step toward rational antibody engineering and future manufacturing activities to support clinical evaluation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Depth-specific distribution of bacterial MAGs in permafrost active layer in Ny Ålesund, Svalbard (79°N)

Arctic soil microbial communities may shift with increasing temperatures and water availability from climate change. We examined temperature and volumetric liquid water content (VWC) in the upper 80 cm of permafrost-affected soil over 2 years (2018–2019) at the Bayelva monitoring station, Ny Ålesund, Svalbard. We show VWC increases with depth, whereas in situ temperature is more stable vertically, ranging from -5°C to 5°C seasonally. Prokaryotic metagenome-assembled genomes (MAGs) were obtained at 2–4 cm vertical resolution collected while frozen in April 2018 and at 10 cm vertical resolution collected while thawed in September 2019. The most abundant MAGs were Acidobacteriota, Actinomycetota, and Chloroflexota. Actinomycetota and Chloroflexota increase with depth, while Acidobacteriota classes Thermoanaerobaculia Gp7-AA8, Blastocatellia UBA7656, and Vicinamibacteria Vicinamibacterales are found above 6 cm, below 6 cm, and below 20cm, respectively. All MAGs have diverse carbon-degrading genes, and Actinomycetota and Chloroflexota have autotrophic genes. Further, genes encoding β -glucosidase, N-acetyl-β-D-glucosaminidase, and xylosidase increase with depth, indicating a greater potential for organic matter degradation with higher VWC. Acidobacteriota dominate the top 6 cm with their classes segregating by depth, whereas Actinomycetota and Chloroflexota dominate below ~6 cm. This suggests that Acidobacteriota classes adapt to lower VWC at the surface, while Actinomycetota and Chloroflexota persist below 6cm with higher VWC. This indicates that VWC may be as important as temperature in microbial climate change responses in Arctic mineral soils. Here we describe MAG-based Seqcode type species in the Acidobacteriota, Onstottus arcticum, Onstottus frigus, and Gilichinskyi gelida and in the Actinobacteriota, Mayfieldus profundus.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2021

Noonan syndrome patient-specific induced cardiomyocyte model carrying SOS1 gene variant c.1654A>G

Noonan syndrome (NS) is a dominant autosomal genetic disorder, associated with mutations in several genes that exhibit multisystem abnormal development including cardiac defects. NS associated with the Son of Sevenless homolog 1 (SOS1) gene mutation attributes to the development of cardiomyopathy and congenital heart defects. Since the treatment option for NS is very limited, an in vitro disease model with SOS1 gene mutation would be beneficial for exploring therapeutic possibilities for NS. We reprogrammed cardiac fibroblasts obtained from a NS patient and normal control skin fibroblasts (C-SF) into induced pluripotent stem cells (iPSCs). We identified NS-iPSCs carry a heterozygous single nucleotide variation in the SOS1 gene at the c.1654A > G. Furthermore, the control and NS-iPSCs were differentiated into induced cardiomyocytes (iCMCs), and the electron microscopic analysis showed that the sarcomeres of the NS-iCMCs were highly disorganized. FACS analysis showed that 47.5% of the NS-iCMCs co-expressed GATA4 and cardiac troponin T proteins, and the mRNA expression levels of many cardiac related genes, studied by qRT-PCR array, were significantly reduced when compared to the control C-iCMCs. We report for the first time that NS-iPSCs carry a single nucleotide variation in the SOS1 gene at the c.1654A>G were showing significantly reduced cardiac genes and proteins expression as well as structurally and functionally compromised when compared to C-iCMCs. These iPSCs and iCMCs can be used as a modeling platform to unravel the pathologic mechanisms and also the development of novel drug for the cardiomyopathy in patients with NS.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Adipose-specific knockout of Protein Kinase D1 suppresses de novo lipogenesis in mice via SREBP1c-dependent signaling

Highlights: • Protein Kinase D1 is a functional regulator in adipocyte and white adipose tissue. • PKD1 drives de novo lipogenesis in adipocyte. • SREBP1c signaling regulates lipogenesis in adipocyte. • PKD1-mediated de novo lipogenesis relies on SREBP1c. Having healthy adipose tissue is essential for metabolic health, as excessive adipose tissue in the body can cause its dysregulation and driving chronic metabolic diseases. Protein kinase D1 (PKD1) is considered to be a key kinase in signal transduction, which regulates multiple cellular functions, but its physiological functions in adipose are still not fully understood. This study aimed at elucidating the function of adipocyte PKD1 on lipogenesis. From RNA-Sequencing data, we found that the fatty acid biosynthesis pathway in white adipose tissue lacking PKD1 was significantly affected. Critical rate-limiting enzymes for de novo lipogenesis in adipocytes, such as FASN, ACCα, and SCD1, were significantly repressed after deleting PKD1 in vivo and in vitro. Further studies revealed that blockade of PKD1 significantly increased phosphorylation of SREBP1c at serine 372 site. Co-immunoprecipitation analysis showed that PKD1 interacts with SREBP1c in vitro and in vivo. Importantly, overexpression of SREBP1c reversed the inhibition of FASN and ACCα expression caused by PKD1 silencing. Together, adipocyte PKD1 promotes de novo lipogenesis via SREBP1c-dependent manner in visceral white adipose tissue and might provide a new target for the development of anti-obesity therapies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Molecular Specificity and Proton Transfer Mechanisms in Aerosol Prenucleation Clusters Relevant to New Particle Formation

Atmospheric aerosol particles influence Earth’s radiative energy balance and cloud properties either directly through interacting with the solar radiation or indirectly through acting as cloud condensation nuclei (CCN), thus impacting Earth’s climate change, air quality, and human health. Regarding both the important scientific and overarching practical implications of aerosols, the past two decades have seen an extensive research effort, with emphasis on the chemical compositions and underlying mechanisms of aerosol formation. New particle formation (NPF) has been recognized as an important pathway, contributing up to 50% of atmospheric aerosols. Nowadays, the general consensus in NPF is that it proceeds via two distinct stages—the nucleation from gaseous precursors to form critical nuclei of sub-1–2 nanometer size, and the subsequent growth into large particles. However, a fundamental understanding of both the NPF process and the molecular-level characterization of the critical size aerosol clusters is still largely missing, hampering the development of reliable and predictive aerosol nucleation and climate models.

Hou, Gao-Lei↗