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Xu, Ke

Publications and source records attributed to Xu, Ke.

9 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Multiomic Network Analysis Identifies Dysregulated Neurobiological Pathways in Opioid Addiction

BACKGROUND: Opioid addiction is a worldwide public health crisis. In the United States, for example, opioids cause more drug overdose deaths than any other substance. However, opioid addiction treatments have limited efficacy, meaning that additional treatments are needed. METHODS: To help address this problem, we used network-based machine learning techniques to integrate results from genome-wide association studies of opioid use disorder and problematic prescription opioid misuse with transcriptomic, proteomic, and epigenetic data from the dorsolateral prefrontal cortex of people who died of opioid overdose and control individuals. RESULTS: Here we identified 211 highly interrelated genes identified by genome-wide association studies or dysregulation in the dorsolateral prefrontal cortex of people who died of opioid overdose that implicated the Akt, BDNF (brain-derived neurotrophic factor), and ERK (extracellular signal-regulated kinase) pathways, identifying 414 drugs targeting 48 of these opioid addiction–associated genes. Some of the identified drugs are approved to treat other substance use disorders or depression. CONCLUSIONS: Our synthesis of multiomics using a systems biology approach revealed key gene targets that could contribute to drug repurposing, genetics-informed addiction treatment, and future discovery.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Effect of TiN coating on suppressing Ce-Fe interaction under irradiation

Advanced cladding is critical for fast reactors with the adequate thermal conductivity, mechanical stability and radiation tolerance of the cladding base material, corrosion resistance and high temperature coolant compatibility of the cladding surface, and chemical stability of the cladding inner wall against fuel cladding chemical interaction (FCCI). The preliminary results of recent ion irradiation studies of two diffusion-couple samples of cerium (Ce)/oxide-dispersion strengthened steel (ODS) and Ce/TiN/ODS, irradiated with 80 MeV xenon (Xe) ions to 100 displacements per atom (dpa) at 500°C, are summarized. Significant Ce-Fe interaction occurred in the Ce/ODS sample, and no noticeable Ce-Fe interaction was found in the Ce/TiN/ODS sample. It shows the effectiveness of 1-µm TiN diffusion barrier coated by the pulsed laser deposition on suppressing Ce-Fe interaction, a major contributor to FCCI in cladding. Here, density function theory (DFT) calculations of the impurity diffusivities of Ce and Fe within the Ti sublattice of TiN were performed to assist a mechanistic understanding of the experimental results.

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗
DOE OSTI2024

Large Area Transfer of Bismuth‐Based Layered Oxide Thin Films Using a Flexible Polymer Transfer Method

Magnetic and ferroelectric oxide thin films have long been studied for their applications in electronics, optics, and sensors. The properties of these oxide thin films are highly dependent on the film growth quality and conditions. To maximize the film quality, epitaxial oxide thin films are frequently grown on single-crystal oxide substrates such as strontium titanate (SrTiO 3 ) and lanthanum aluminate (LaAlO 3 ) to satisfy lattice matching and minimize defect formation. However, these single-crystal oxide substrates cannot readily be used in practical applications due to their high cost, limited availability, and small wafer sizes. One leading solution to this challenge is film transfer. In this demonstration, a material from a new class of multiferroic oxides is selected, namely bismuth-based layered oxides, for the transfer. A water-soluble sacrificial layer of Sr 3 Al 2 O 6 is inserted between the oxide substrate and the film, enabling the release of the film from the original substrate onto a polymer support layer. The films are transferred onto new substrates of silicon and lithium niobate (LiNbO 3 ) and the polymer layer is removed. These substrates allow for the future design of electronic and optical devices as well as sensors using this new group of multiferroic layered oxide films.

36 MATERIALS SCIENCE↗
DOE OSTI2024

STORM Super-Resolution Visualization of Self-Assembled γPFD Chaperone Ultrastructures in Methanocaldococcus jannaschii

Gamma-prefoldin (γPFD), a unique chaperone found in the extremely thermophilic methanogen Methanocaldococcus jannaschii, self-assembles into filaments in vitro, which so far have been observed using transmission electron microscopy and cryo-electron microscopy. Utilizing three-dimensional stochastic optical reconstruction microscopy (3D-STORM), here we achieve ~20 nm resolution by precisely locating individual fluorescent molecules, hence resolving γPFD ultrastructure both in vitro and in vivo. Through CF647 NHS ester labeling, we first demonstrate the accurate visualization of filaments and bundles with purified γPFD. Next, by implementing immunofluorescence labeling after creating a 3xFLAG-tagged γPFD strain, we successfully visualize γPFD in M. jannaschii cells. Through 3D-STORM and two-color STORM imaging with DNA, we show the widespread distribution of filamentous γPFD structures within the cell. These findings provide valuable insights into the structure and localization of γPFD, opening up possibilities for studying intriguing nanoscale components not only in archaea but also in other microorganisms.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2024

A multi-ancestry genetic study of pain intensity in 598,339 veterans

Chronic pain is a common problem, with more than one-fifth of adult Americans reporting pain daily or on most days. It adversely affects the quality of life and imposes substantial personal and economic costs. Efforts to treat chronic pain using opioids had a central role in precipitating the opioid crisis. Despite an estimated heritability of 25–50%, the genetic architecture of chronic pain is not well-characterized, in part because studies have largely been limited to samples of European ancestry. To help address this knowledge gap, we conducted a cross-ancestry meta-analysis of pain intensity in 598,339 participants in the Million Veteran Program, which identified 126 independent genetic loci, 69 of which are new. Pain intensity was genetically correlated with other pain phenotypes, level of substance use and substance use disorders, other psychiatric traits, education level and cognitive traits. Integration of the genome-wide association studies findings with functional genomics data shows enrichment for putatively causal genes (n = 142) and proteins (n = 14) expressed in brain tissues, specifically in GABAergic neurons. Drug repurposing analysis identified anticonvulsants, β-blockers and calcium-channel blockers, among other drug groups, as having potential analgesic effects. Our results provide insights into key molecular contributors to the experience of pain and highlight attractive drug targets.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Asymmetric oligomerization state and sequence patterning can tune multiphase condensate miscibility

Endogenous biomolecular condensates, composed of a multitude of proteins and RNAs, can organize into multiphasic structures with compositionally distinct phases. This multiphasic organization is generally understood to be critical for facilitating their proper biological function. However, the biophysical principles driving multiphase formation are not completely understood. Here we use in vivo condensate reconstitution experiments and coarse-grained molecular simulations to investigate how oligomerization and sequence interactions modulate multiphase organization in biomolecular condensates. We demonstrate that increasing the oligomerization state of an intrinsically disordered protein results in enhanced immiscibility and multiphase formation. Interestingly, we find that oligomerization tunes the miscibility of intrinsically disordered proteins in an asymmetric manner, with the effect being more pronounced when the intrinsically disordered protein, exhibiting stronger homotypic interactions, is oligomerized. Our findings suggest that oligomerization is a flexible biophysical mechanism that cells can exploit to tune the internal organization of biomolecular condensates and their associated biological functions.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗